In this editorial,we discussed the apparent discrepancy between the findings described by Colapietro et al,in their case report and data found in the literature.Colapietro et al reported a case of hepatitis B virus(HB...In this editorial,we discussed the apparent discrepancy between the findings described by Colapietro et al,in their case report and data found in the literature.Colapietro et al reported a case of hepatitis B virus(HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton’s tyrosine kinase(BTK)inhibitor therapy.First of all,we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response,focusing our attention on the protective role of anti-HBs.We then carefully analyzed literature data on the risk of HBV reactivation(HBVr)in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies.Based on literature data,we suggested that several factors may contribute to the different risks of HBVr:The type of hematologic malignancy;the type of therapy(BTK inhibitors,especially second-generation,seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors);previous exposure to an anti-CD20 as first-line therapy;and ethnicity and HBV genotype.Therefore,the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation.展开更多
During recent decades, substantial progress has been made in clinical strategies for treating hematological malignancies. Not only did China benefit from the global progression in the management of acute promyelocytic...During recent decades, substantial progress has been made in clinical strategies for treating hematological malignancies. Not only did China benefit from the global progression in the management of acute promyelocytic leukemia, risk-stratification-directed strategies for acute or chronic leukemia and haploidentical hematopoietic stem cell transplantation, the unique system developed by Chinese doctors has also become inspiration for refining global clinical practice. The multicenter trials and collaborations adhering to international standards might further strengthen the global impact and lead the way in specific fields of research worldwide.展开更多
The integrity of lysosomes is of vital importance to survival of tumor cells.We demonstrated that LW-218,a synthetic flavonoid,induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization i...The integrity of lysosomes is of vital importance to survival of tumor cells.We demonstrated that LW-218,a synthetic flavonoid,induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy.LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D,as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents,which can alter the activity of cathepsins.Lysophagy,was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB.LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator.Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy.LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1.Moreover,LW-218 inhibited the leukemia cell growth in vivo.Thus,the necessary impact of integral lysosomal function in cell rescue and death were illustrated.展开更多
Hematological malignancies are usually life-limiting conditions.Limitations of care need to be decided early,based on acceptability to the patient,family,physician,and community.Inappropriate intensive care unit(ICU)a...Hematological malignancies are usually life-limiting conditions.Limitations of care need to be decided early,based on acceptability to the patient,family,physician,and community.Inappropriate intensive care unit(ICU)admission is likely to result in significant physical,psychological,and economic burden.There is little published on the impact of non-acute preadmission disease factors on ICU outcomes in hematological malignancies.Aim:To identify baseline performance and disease-associated factors before admission to ICU in patients with hematological malignancy that contribute to subsequent ICU mortality.Methods:A retrospective analysis of electronic medical records,laboratory results,and Intensive Care data for all patients(n=184)with hematological malignancy admitted to the Calvary Mater Hospital ICU between January 1,2013 and June 30,2017 was undertaken.Baseline age,gender,condition,Eastern Cooperative Oncology,and Charlson Comorbidity scores were compared to ICU outcome and overall survival.Disease-specific prognostic risk scores were compared to ICU outcome.Results:Overall,73.9%survived the ICU admission,with 31.6%surviving at 12 months.Superior ejection fractions(>55%)and prognosis>12 months(based on disease-specific risk scores)were significantly associated with overall survival(P=0.024 and P=0.001).Induction and posttransplantation therapy were predictive of poor ICU survival outcome(P<0.0001 and P=0.041).APACHE scores were significant predictors of ICU mortality(P=0.002 for APACHE II and P<0.0001 for APACHE III).Conclusion:Survival outcomes for patients with hematological malignancy admitted to the ICU correlate with functional and comorbidity status.Disease-specific prognostic scores can assist in recognizing patients likely to benefit from ICU admission.展开更多
Degrader–antibody conjugates(DACs)represent a promising drug modality for targeting hematological malignancy,but still lack rational design frameworks.Here,we show the strategies of reasonable antibody-degrader compa...Degrader–antibody conjugates(DACs)represent a promising drug modality for targeting hematological malignancy,but still lack rational design frameworks.Here,we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration.Inspired by the success of IKZF1/3 degraders,we sought to explore the potential of cereblon E3 ligase modulators(CELMoDs)in constructing novel conjugates.By combining a modular library with neo-substrate screening and further conjugatable derivation,I034 was identified,a potent CELMoD payload with picomolar degradation activity and antiproliferative effects.Through linker chemistry,I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo,with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses.Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates,highlighting the need for compatibility between payloads and antigens.These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.展开更多
Gastrointestinal bleeding(GIB)presents a significant challenge for patients with hematologic malignancies,especially those with severe thrombocytopenia.Although endoscopic intervention is frequently used in managing G...Gastrointestinal bleeding(GIB)presents a significant challenge for patients with hematologic malignancies,especially those with severe thrombocytopenia.Although endoscopic intervention is frequently used in managing GIB,its safety and effectiveness in this high-risk group remain unclear.A recent study by Alhumayyd et al provided insight into this issue.However,it has notable limitations,including its retrospective nature,small sample size,and failure to adjust for important confounding factors such as disease severity,hemodynamic status,and platelet function.The study’s findings indicated that urgent endoscopy may help decrease the incidence of recurrent bleeding;however,it did not show a clear benefit in terms of mortality.Future research ought to prioritize prospective,multicenter studies that employ standardized protocols and incorporate risk stratification models to better understand the impact of endoscopic treatment for GIB in these patients.Additionally,integrating platelet function assays could improve clinical decision-making.Addressing these research gaps is essential for improving patient outcomes and developing effective guidelines for managing GIB in individuals with thrombocytopenia.展开更多
Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networ...Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networks(CNNs)excel in local feature extraction,their ability to capture global contextual relationships in complex cellular morphologies is limited.This study introduces a hybrid CNN-Transformer framework to enhance normal blood cell classification,laying the groundwork for future leukemia diagnostics.Methods:The proposed architecture integrates pre-trained CNNs(ResNet50,EfficientNetB3,InceptionV3,CustomCNN)with Vision Transformer(ViT)layers to combine local and global feature modeling.Four hybrid models were evaluated on the publicly available Blood Cell Images dataset from Kaggle,comprising 17,092 annotated normal blood cell images across eight classes.The models were trained using transfer learning,fine-tuning,and computational optimizations,including cross-model parameter sharing to reduce redundancy by reusing weights across CNN backbones and attention-guided layer pruning to eliminate low-contribution layers based on attention scores,improving efficiency without sacrificing accuracy.Results:The InceptionV3-ViT model achieved a weighted accuracy of 97.66%(accounting for class imbalance by weighting each class’s contribution),a macro F1-score of 0.98,and a ROC-AUC of 0.998.The framework excelled in distinguishing morphologically similar cell types demonstrating robustness and reliable calibration(ECE of 0.019).The framework addresses generalization challenges,including class imbalance and morphological similarities,ensuring robust performance across diverse cell types.Conclusion:The hybrid CNN-Transformer framework significantly improves normal blood cell classification by capturing multi-scale features and long-range dependencies.Its high accuracy,efficiency,and generalization position it as a strong baseline for automated hematological analysis,with potential for extension to leukemia subtype classification through future validation on pathological samples.展开更多
BACKGROUND Gastrointestinal bleeding(GIB)is a major cause of hospitalization worldwide.Patients with hematologic malignancies have a higher risk of GIB as a result of thrombocytopenia and platelet dysfunction.There is...BACKGROUND Gastrointestinal bleeding(GIB)is a major cause of hospitalization worldwide.Patients with hematologic malignancies have a higher risk of GIB as a result of thrombocytopenia and platelet dysfunction.There is no consensus on the optimal platelet level that would be safe for endoscopic intervention,although a platelet level of>50×10^(9)/L was suggested based on expert opinion.There is a paucity of data on whether endoscopic intervention and the timing of endoscopy impacted the outcome of patients with hematologic malignancy and severe thrombocytopenia who experienced acute overt GIB.AIM To assess the safety of endoscopic intervention of inpatients with hematological malignancies and severe thrombocytopenia presenting with acute overt GIB.METHODS This is a single center retrospective study.The data was collected from the electronic health record from 2018 to 2020.Inpatients with hematologic malignancy who presented with acute overt GIB and platelet count≤50×10^(9)/L were included in the study.Outcomes included mortality,transfusion requirements,length of stay,intensive care unit admission and recurrent bleeding.A subgroup analysis was performed to compare the outcomes of urgent endoscopy within 24 hours of GIB vs endoscopy>24 hours.RESULTS A total of 76 patients were identified.The mean platelet count is 24.3 in the endoscopy arm and 14.6 in the conservative management arm.There was no statistically significant difference between patients who had endoscopy vs conservative management in 30-day(P=0.13)or 1 year(P=0.78)mortality,recurrent bleeding(P=0.68),transfusion of red blood cells(P=0.47),platelets(P=0.31),or length of stay(P=0.94).A subgroup analysis comparing urgent endoscopy within 24 hours compared with delayed endoscopy showed urgent endoscopy was not associated with improved 30-day or 1 year mortality(P=0.11 and 0.46,respectively)compared to routine endoscopy,but was associated with decreased recurrent bleeding in 30 days(P=0.01).CONCLUSION Medical supportive treatment without endoscopy could be considered as an alternative to endoscopic therapy for patients with hematologic malignancy complicated by severe thrombocytopenia and acute non-variceal GIB.展开更多
Background:Patients with hemato-oncological malignancies may respond insufficiently to vaccination,especially in terms of antibody titer.The antibody response depends on the type of malignancy as well as the type and ...Background:Patients with hemato-oncological malignancies may respond insufficiently to vaccination,especially in terms of antibody titer.The antibody response depends on the type of malignancy as well as the type and timing of treatment.We intended to evaluate this using real-world data from patients of our regional hospital.This study also considers the role of immune status,including T-cell activation markers,in predicting vaccination success.Methods:Seventeen patients of our hospital having a hematological malignancy were included in this study,including myeloma,lymphoma,as well as acute myeloid leukemia(AML)and chronic lymphoid leukemia(CLL).All patients were vaccinated against Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)using Tozinameran following current recommendations.Circulating antibodies directed against the spike protein of SARS-CoV-2 were determined by a commercial immune assay.Immune status was determined from peripheral blood by flow cytometry.Both parameters were followed in fifteen patients who provided sufficient follow-up data for up to one year.Patients were categorized as responders or non-responders,and differences in diagnosis,treatment,and immune status were analyzed.Results:Antibody response depended on both diagnosis and treatment.Active treatment directed against B-cells,such as anti-Cluster of Differentiation 20(CD20)therapy,was associated with weak seroconversion.For CD38-as well as proteasome-directed therapies,the data suggest that responders as well as non-responders exist.Notably,low peripheral B-cell numbers and high CD3+HLADR+cell counts correlated withweak seroconversion upon vaccination.Conclusions:We suggest that peripheral immune status can be applied as a predictive biomarker for seroconversion upon vaccinations.展开更多
Flow cytometry(FCM),characterized by its simplicity,rapid processing,multiparameter analysis,and high sen-sitivity,is widely used in the diagnosis,treatment,and prognosis of hematological malignancies.FCM testing of t...Flow cytometry(FCM),characterized by its simplicity,rapid processing,multiparameter analysis,and high sen-sitivity,is widely used in the diagnosis,treatment,and prognosis of hematological malignancies.FCM testing of tissue samples not only aids in diagnosing and classifying hematological cancers,but also enables the detection of solid tumors.Its ability to detect numerous marker parameters from small samples is particularly useful when dealing with limited cell quantities,such as in fine-needle biopsy samples.This attribute not only addresses the challenge posed by small sample sizes,but also boosts the sensitivity of tumor cell detection.The significance of FCM in clinical and pathological applications continues to grow.To standardize the use of FCM in detecting hematological malignant cells in tissue samples and to improve quality control during the detection process,experts from the Cell Analysis Professional Committee of the Chinese Society of Biotechnology jointly drafted and agreed upon this consensus.This consensus was formulated based on current literature and clinical practices of all experts across clinical,laboratory,and pathological fields in China.It outlines a comprehensive workflow of FCM-based assay for the detection of hematological malignancies in tissue samples,including report content,interpretation,quality control,and key considerations.Additionally,it provides recommendations on antibody panel designs and analytical approaches to enhancing FCM tests,particularly in cases with limited sample sizes.展开更多
Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical out...Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical outcome.It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome.In this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).展开更多
In order to delineate the infectious status of HGV in pediatric hemato-logical patients and its clinical features, 38 children were studied for HGV by reverse transcription nested polymerase chain reaction (RT-nPCR). ...In order to delineate the infectious status of HGV in pediatric hemato-logical patients and its clinical features, 38 children were studied for HGV by reverse transcription nested polymerase chain reaction (RT-nPCR). The overall positive rate was 23. 68 %; the positive rate in 1-10 time transfusion recipients (mean 3. 26 times) was 3. 70 % while in over 10 time transfusion recipients (mean 20. 09 times) was 72. 73 %. A statistically significant difference was found between the two groups (P<0. 001). All HGV positive children showed diminished immunity and most were single HGV infection with no clinical and biochemical evidences of acute hepatitis. Our results suggest that HGV is one of the main causes of post-transfusion hepatic virus infection and the prevalence is related to transfusion times. Hematological malignancy maybe the most susceptible confluence of HGV.展开更多
BACKGROUND The mortality rate from septic shock in patients with hematological malignancies(HMs)remains significantly higher than that in patients without HMs.A longer resuscitation time would definitely be harmful be...BACKGROUND The mortality rate from septic shock in patients with hematological malignancies(HMs)remains significantly higher than that in patients without HMs.A longer resuscitation time would definitely be harmful because of the irreversibly immunocompromised status of the patients.Shortening the resuscitation time through continuous renal replacement therapy(CRRT)with oXiris^(■)would be an attractive strategy in managing such patients.AIM To explore the effects of CRRT and oXiris^(■)in shortening the resuscitation time and modifying the host response by reducing inflammation mediator levels.METHODS Forty-five patients with HM were diagnosed with septic shock and underwent CRRT between 2018 and 2022.Patients were divided into two groups based on the hemofilter used for CRRT(oXiris^(■)group,n=26;M150 group,n=19).We compared the number of days of negative and total fluid balance after 7 d of CRRT between the groups.The heart rate,norepinephrine dose,Sequential Organ Failure Assessment(SOFA)score,and blood lactic acid levels at different time points in the two groups were also compared.Blood levels of inflammatory mediators in the 26 patients in the oXiris^(■)group were measured to further infer the possible mechanism.RESULTS The average total fluid balance after 7 d of CRRT in the oXiris^(■)group was significantly lower than that of patients in the M150 hemofilter group.The SOFA scores of patients after CRRT with oXiris^(■)therapy were significantly lower than those before treatment on day 1(d1),d3 and d7 after CRRT;these parameters were also significantly lower than those of the control group on d7.The lac level after oXiris^(■)therapy was significantly lower than that before treatment on d3 and d7 after CRRT.There were no significant differences in the above parameters between the two groups at the other time points.In the oXiris^(■)group,procalcitonin levels decreased on d7,whereas interleukin-6 and tumor necrosis factor levels decreased significantly on d3 and d7 after treatment.CONCLUSION CRRT with oXiris^(■)hemofilter may improve hemodynamics by reducing inflammatory mediators and playing a role in shortening the resuscitation period and decreasing total fluid balance in the resuscitation phases.展开更多
Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabc...Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabcontaining therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBs Ag) and antibody to hepatitis B core antigen(antiHBc). Patients found to be positive for HBs Ag should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving highrisk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBs Ag-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.展开更多
TMTP1, a 5-amino acid peptide NVVRQ, obtained by using the flagella peptide library screening in our previous studies, can be used for the labeling of malignant in situ and metastatic lesions, and even micro-metastase...TMTP1, a 5-amino acid peptide NVVRQ, obtained by using the flagella peptide library screening in our previous studies, can be used for the labeling of malignant in situ and metastatic lesions, and even micro-metastases. In this study, TMTP1 was assessed for its ability to specifically target the malignant hematopoietic cells and metastatic lesions of hematological malignancies. FITC-TMTP1 was chemically synthesized. Immunofluorescence assay and competitive test were carried out to determine the specific binding capacity of TMTPl to hematological malignant cell lines, including HL60, k562, SHI-1, Jurkat, Raji, El-4 and umbilical cord blood mononuclear cells. Mononuclear cells were isolated from the bone marrow of healthy subjects and patients with chronic myeloid leukemia. Then the cells were co-clutured with TMTP1 or scrambled peptides and the binding and affinity of TMTP1 peptide to the primary cells of hematological malignancies were flow cytometrically analyzed. The binding speci-ficity of TMTP1 to target hematological malignancies was measured in vivo by intravenous injection of FITC-conjugated TMTP1 into El-4 lymphoma-bearing mice. The results showed that TMTP1 specifi-cally bound to the cells of a series of hematological malignancies, including HL60, k562, Jurkat, Raji , El-4 and chronic myeloid leukemia primary cells but not to bone marrow mononuclear cells from healthy subjects. By contrast, TMTP1 could bind to the metastatic foci of lymphoma originating from the EL-4 cell line while the scrambled peptide failed to do so. Moreover, the occult metastases could be identified, with high specificity, by detecting FITC-TMTP1. We are led to conclude that TMTP1, as a novel tumor-homing peptide, can serve as a marker for primary malignant and metastatic lesions for the early diagnosis of hematological malignances and a carrier of anticancer drugs for cancer treatment.展开更多
As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malig...As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.展开更多
AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus(HBV)infections in patients with hematological malignancies in South Egypt.METHODS Serum samples were collected from 165 pat...AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus(HBV)infections in patients with hematological malignancies in South Egypt.METHODS Serum samples were collected from 165 patients with hematological malignancies to monitor titers of HBV DNA,hepatitis B surface antigen(HBs Ag),and antibodies to HBV core(anti-HBc)and surface antigens.Serum samples negative for HBs Ag and positive for anti-HBc were subjected to nucleic acid extraction and HBV DNA detection by real-time polymerase chain reaction.DNA sequences spanning the S region were analyzed in cases with occult HBV infection.In vitro comparative study of constructed 1.24-fold wild type and S protein mutant HBV genotype D clones was further performed.RESULTS HBV DNA was detected in 23(42.6%)of 54 patients with hematological malignancies who were HBsA g negative,but anti-HBc positive,suggesting the presence of occult HBV infection.The complete HBV genome was retrieved from 6 occult HBV patients,and P120 T and S143 L were detected in 3 and 2 cases,respectively.Site directed mutagenesis was done to produce 1.24-fold genotype D clones with amino acid mutations T120 and L143.The in vitro analyses revealed that a lower level of extracellular HBsA g was detected by chemiluminescence enzyme immunoassay(CLEIA)with the clone containing T120 mutation,compared with the wild type or the clone with S143 L mutation despite the similar levels of extracellular and intracellular HBs Ag detected by Western blot.Southern blot experiments showed that the levels of intracellular HBV DNA were not different between these clones.CONCLUSION Occult HBV infection is common in patients with hematological malignancies and associated with P120 T and S143 L mutations.120 T mutation impairs the detection of HBsA g by CLEIA.展开更多
Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicitie...Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.展开更多
The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a g...The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents.In patients with COVID-19,underlying chronic diseases and comorbidities are associated with dismal treatment outcomes.Owing to their immunosuppressive status,patients with hematological malignancies(HMs)are at an increased risk of infection and have a worse prognosis than patients without HMs.Accordingly,intensive attention should be paid to this cohort.In this review,we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs.Furthermore,we briefly de-scribe customized management strategies and interventions for this susceptible cohort.This review is intended to guide clinical practice.展开更多
Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymer...Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymerase chain reaction （PCR） in 103 acute myeloid leukemia （AML） cases, 63 acute lymphocytic leukemia （ALL） cases, 53 chronic myelogenous leukemia （CML） cases in chronic phase （CML-CP）, 34 CML cases in blast crisis （CML-BC）, 11 chronic lymphatic leukemia （CLL） cases, 36 myelodysplastic syndrome （MDS） cases, 9 multiple myeloma （MM） cases and 13 non-hodgkin＇s lymphoma （NHL） cases with marrow infiltration. Results： The expressions of FLT3/ITD gene mutations were detected in 22.3% AML cases, in 6.5% CML-BC cases, in 5.6% MDS cases and in 2.6% ALL cases. The two ALL cases with FLT3/ITD mutation were diagnosed as ALL-L2 with morphology and both with myeloid antigen expression, but finally were diagnosed as acute mixed-lineage leukemia after immunology examination. FLT3/ITD gene mutations were not detected in CML-CP, MM, NHL and CLL cases. In the 23 AML patients with FLT3/ITD gene mutation, including 2 of 8 M1 （2.5%）, 8 of 33 M2 （24.2%）, 7 of 24 M3 （29.3%）, 2 of 11 M4 （18.2%）, 3 of 21 M5 （14.3%）, 1 of 5 M6 （20%）, and 0 of 1 M7 cases, and there were no significant differences in the positive rates of FLT3/ITD mutations between the FAB subtypes （P 〉 0.05）. Statistical analyses showed that in AML patients, FLT3/ITD was associated with a higher peripheral blood white cell （WBC） counts [（41.23 ± 32.56） x 109/L vs （11.36 ± 9.89） × 10^9/L （P 〈 0.01 ）], higher percentage of bone marrow blast cells [（72.78 ± 21.79）% vs （51.26 ± 20.78）% （P 〈 0.05）], and higher cumulative relapse rates （63.6% vs 27.7%, P 〈 0.025） than those negative. Conclusion： FLT3/ITD gene mutation mainly occurred in AML patients, and might be a strong prognostic factor which was associated with high peripheral WBC counts, bone marrow blast cell proportion and a increased relapse risk in AML. Detection of FLT3/ITD gene mutation might provide insights to explore a more accurate genotyping of leukemia, differential diagnosis between AML and ALL, subdivide risk level in AML and estimate prognosis of leukemia.展开更多
文摘In this editorial,we discussed the apparent discrepancy between the findings described by Colapietro et al,in their case report and data found in the literature.Colapietro et al reported a case of hepatitis B virus(HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton’s tyrosine kinase(BTK)inhibitor therapy.First of all,we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response,focusing our attention on the protective role of anti-HBs.We then carefully analyzed literature data on the risk of HBV reactivation(HBVr)in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies.Based on literature data,we suggested that several factors may contribute to the different risks of HBVr:The type of hematologic malignancy;the type of therapy(BTK inhibitors,especially second-generation,seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors);previous exposure to an anti-CD20 as first-line therapy;and ethnicity and HBV genotype.Therefore,the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation.
基金supported by the National Natural Science Foundation of China(8123001381400146+1 种基金81530046)the Beijing Municipal Science and Technology Program(Z141100000214011)
文摘During recent decades, substantial progress has been made in clinical strategies for treating hematological malignancies. Not only did China benefit from the global progression in the management of acute promyelocytic leukemia, risk-stratification-directed strategies for acute or chronic leukemia and haploidentical hematopoietic stem cell transplantation, the unique system developed by Chinese doctors has also become inspiration for refining global clinical practice. The multicenter trials and collaborations adhering to international standards might further strengthen the global impact and lead the way in specific fields of research worldwide.
基金supported by the Nation Natural Science Foundation of China(81873046,81830105,81903647,81503096,and 81673461)the Drug Innovation Major Project(2017ZX09301014,2018ZX09711001-003-007,and 2017ZX09101003-005-023,China)+4 种基金Natural Science Foundation of Jiangsu province(BK20190560 and BE2018711,China)Nanjing Medical Science and Technology Development Project(YKK17074 and YKK19064,China)Research and Innovation Project for College Graduates of Jiangsu Province(KYCX180803,China)China Postdoctoral Science Foundation(No.2018M642373)“Double First-Class”University project(CPU 2018GF11 and CPU2018GF05,China)。
文摘The integrity of lysosomes is of vital importance to survival of tumor cells.We demonstrated that LW-218,a synthetic flavonoid,induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy.LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D,as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents,which can alter the activity of cathepsins.Lysophagy,was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB.LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator.Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy.LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1.Moreover,LW-218 inhibited the leukemia cell growth in vivo.Thus,the necessary impact of integral lysosomal function in cell rescue and death were illustrated.
文摘Hematological malignancies are usually life-limiting conditions.Limitations of care need to be decided early,based on acceptability to the patient,family,physician,and community.Inappropriate intensive care unit(ICU)admission is likely to result in significant physical,psychological,and economic burden.There is little published on the impact of non-acute preadmission disease factors on ICU outcomes in hematological malignancies.Aim:To identify baseline performance and disease-associated factors before admission to ICU in patients with hematological malignancy that contribute to subsequent ICU mortality.Methods:A retrospective analysis of electronic medical records,laboratory results,and Intensive Care data for all patients(n=184)with hematological malignancy admitted to the Calvary Mater Hospital ICU between January 1,2013 and June 30,2017 was undertaken.Baseline age,gender,condition,Eastern Cooperative Oncology,and Charlson Comorbidity scores were compared to ICU outcome and overall survival.Disease-specific prognostic risk scores were compared to ICU outcome.Results:Overall,73.9%survived the ICU admission,with 31.6%surviving at 12 months.Superior ejection fractions(>55%)and prognosis>12 months(based on disease-specific risk scores)were significantly associated with overall survival(P=0.024 and P=0.001).Induction and posttransplantation therapy were predictive of poor ICU survival outcome(P<0.0001 and P=0.041).APACHE scores were significant predictors of ICU mortality(P=0.002 for APACHE II and P<0.0001 for APACHE III).Conclusion:Survival outcomes for patients with hematological malignancy admitted to the ICU correlate with functional and comorbidity status.Disease-specific prognostic scores can assist in recognizing patients likely to benefit from ICU admission.
基金supported by the National Natural Science Foundation of China[82173660(Xiaowu Dong),82273951(Yubo Zhou),82404655(Hanlin Wang),92253306(Jia Li)]China Postdoctoral Science Foundation 2024M750708(Jingyu Zhang)Shanghai Science and Technology Development Foundation 24YF275530(Hanlin Wang).
文摘Degrader–antibody conjugates(DACs)represent a promising drug modality for targeting hematological malignancy,but still lack rational design frameworks.Here,we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration.Inspired by the success of IKZF1/3 degraders,we sought to explore the potential of cereblon E3 ligase modulators(CELMoDs)in constructing novel conjugates.By combining a modular library with neo-substrate screening and further conjugatable derivation,I034 was identified,a potent CELMoD payload with picomolar degradation activity and antiproliferative effects.Through linker chemistry,I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo,with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses.Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates,highlighting the need for compatibility between payloads and antigens.These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.
文摘Gastrointestinal bleeding(GIB)presents a significant challenge for patients with hematologic malignancies,especially those with severe thrombocytopenia.Although endoscopic intervention is frequently used in managing GIB,its safety and effectiveness in this high-risk group remain unclear.A recent study by Alhumayyd et al provided insight into this issue.However,it has notable limitations,including its retrospective nature,small sample size,and failure to adjust for important confounding factors such as disease severity,hemodynamic status,and platelet function.The study’s findings indicated that urgent endoscopy may help decrease the incidence of recurrent bleeding;however,it did not show a clear benefit in terms of mortality.Future research ought to prioritize prospective,multicenter studies that employ standardized protocols and incorporate risk stratification models to better understand the impact of endoscopic treatment for GIB in these patients.Additionally,integrating platelet function assays could improve clinical decision-making.Addressing these research gaps is essential for improving patient outcomes and developing effective guidelines for managing GIB in individuals with thrombocytopenia.
基金the Deanship of Graduate Studies and Scientific Research at Najran University,Saudi Arabia,for their financial support through the Easy Track Research program,grant code(NU/EFP/MRC/13).
文摘Background:Accurate classification of normal blood cells is a critical foundation for automated hematological analysis,including the detection of pathological conditions like leukemia.While convolutional neural networks(CNNs)excel in local feature extraction,their ability to capture global contextual relationships in complex cellular morphologies is limited.This study introduces a hybrid CNN-Transformer framework to enhance normal blood cell classification,laying the groundwork for future leukemia diagnostics.Methods:The proposed architecture integrates pre-trained CNNs(ResNet50,EfficientNetB3,InceptionV3,CustomCNN)with Vision Transformer(ViT)layers to combine local and global feature modeling.Four hybrid models were evaluated on the publicly available Blood Cell Images dataset from Kaggle,comprising 17,092 annotated normal blood cell images across eight classes.The models were trained using transfer learning,fine-tuning,and computational optimizations,including cross-model parameter sharing to reduce redundancy by reusing weights across CNN backbones and attention-guided layer pruning to eliminate low-contribution layers based on attention scores,improving efficiency without sacrificing accuracy.Results:The InceptionV3-ViT model achieved a weighted accuracy of 97.66%(accounting for class imbalance by weighting each class’s contribution),a macro F1-score of 0.98,and a ROC-AUC of 0.998.The framework excelled in distinguishing morphologically similar cell types demonstrating robustness and reliable calibration(ECE of 0.019).The framework addresses generalization challenges,including class imbalance and morphological similarities,ensuring robust performance across diverse cell types.Conclusion:The hybrid CNN-Transformer framework significantly improves normal blood cell classification by capturing multi-scale features and long-range dependencies.Its high accuracy,efficiency,and generalization position it as a strong baseline for automated hematological analysis,with potential for extension to leukemia subtype classification through future validation on pathological samples.
文摘BACKGROUND Gastrointestinal bleeding(GIB)is a major cause of hospitalization worldwide.Patients with hematologic malignancies have a higher risk of GIB as a result of thrombocytopenia and platelet dysfunction.There is no consensus on the optimal platelet level that would be safe for endoscopic intervention,although a platelet level of>50×10^(9)/L was suggested based on expert opinion.There is a paucity of data on whether endoscopic intervention and the timing of endoscopy impacted the outcome of patients with hematologic malignancy and severe thrombocytopenia who experienced acute overt GIB.AIM To assess the safety of endoscopic intervention of inpatients with hematological malignancies and severe thrombocytopenia presenting with acute overt GIB.METHODS This is a single center retrospective study.The data was collected from the electronic health record from 2018 to 2020.Inpatients with hematologic malignancy who presented with acute overt GIB and platelet count≤50×10^(9)/L were included in the study.Outcomes included mortality,transfusion requirements,length of stay,intensive care unit admission and recurrent bleeding.A subgroup analysis was performed to compare the outcomes of urgent endoscopy within 24 hours of GIB vs endoscopy>24 hours.RESULTS A total of 76 patients were identified.The mean platelet count is 24.3 in the endoscopy arm and 14.6 in the conservative management arm.There was no statistically significant difference between patients who had endoscopy vs conservative management in 30-day(P=0.13)or 1 year(P=0.78)mortality,recurrent bleeding(P=0.68),transfusion of red blood cells(P=0.47),platelets(P=0.31),or length of stay(P=0.94).A subgroup analysis comparing urgent endoscopy within 24 hours compared with delayed endoscopy showed urgent endoscopy was not associated with improved 30-day or 1 year mortality(P=0.11 and 0.46,respectively)compared to routine endoscopy,but was associated with decreased recurrent bleeding in 30 days(P=0.01).CONCLUSION Medical supportive treatment without endoscopy could be considered as an alternative to endoscopic therapy for patients with hematologic malignancy complicated by severe thrombocytopenia and acute non-variceal GIB.
基金supported by a grant of the Deutsche Forschungsgemeinschaft(DFG)to G.B.(#405833349).
文摘Background:Patients with hemato-oncological malignancies may respond insufficiently to vaccination,especially in terms of antibody titer.The antibody response depends on the type of malignancy as well as the type and timing of treatment.We intended to evaluate this using real-world data from patients of our regional hospital.This study also considers the role of immune status,including T-cell activation markers,in predicting vaccination success.Methods:Seventeen patients of our hospital having a hematological malignancy were included in this study,including myeloma,lymphoma,as well as acute myeloid leukemia(AML)and chronic lymphoid leukemia(CLL).All patients were vaccinated against Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)using Tozinameran following current recommendations.Circulating antibodies directed against the spike protein of SARS-CoV-2 were determined by a commercial immune assay.Immune status was determined from peripheral blood by flow cytometry.Both parameters were followed in fifteen patients who provided sufficient follow-up data for up to one year.Patients were categorized as responders or non-responders,and differences in diagnosis,treatment,and immune status were analyzed.Results:Antibody response depended on both diagnosis and treatment.Active treatment directed against B-cells,such as anti-Cluster of Differentiation 20(CD20)therapy,was associated with weak seroconversion.For CD38-as well as proteasome-directed therapies,the data suggest that responders as well as non-responders exist.Notably,low peripheral B-cell numbers and high CD3+HLADR+cell counts correlated withweak seroconversion upon vaccination.Conclusions:We suggest that peripheral immune status can be applied as a predictive biomarker for seroconversion upon vaccinations.
基金supported by grants from the National Natural Science Foundation of China(grant numbers:82370195,82270203,81770211)the Fundamental Research Funds for the Central Univer-sities(grant number:2022CDJYGRH-001)Chongqing Technology Innovation and Application Development Special Key Project(grant number:CSTB2024TIAD-KPX0031).
文摘Flow cytometry(FCM),characterized by its simplicity,rapid processing,multiparameter analysis,and high sen-sitivity,is widely used in the diagnosis,treatment,and prognosis of hematological malignancies.FCM testing of tissue samples not only aids in diagnosing and classifying hematological cancers,but also enables the detection of solid tumors.Its ability to detect numerous marker parameters from small samples is particularly useful when dealing with limited cell quantities,such as in fine-needle biopsy samples.This attribute not only addresses the challenge posed by small sample sizes,but also boosts the sensitivity of tumor cell detection.The significance of FCM in clinical and pathological applications continues to grow.To standardize the use of FCM in detecting hematological malignant cells in tissue samples and to improve quality control during the detection process,experts from the Cell Analysis Professional Committee of the Chinese Society of Biotechnology jointly drafted and agreed upon this consensus.This consensus was formulated based on current literature and clinical practices of all experts across clinical,laboratory,and pathological fields in China.It outlines a comprehensive workflow of FCM-based assay for the detection of hematological malignancies in tissue samples,including report content,interpretation,quality control,and key considerations.Additionally,it provides recommendations on antibody panel designs and analytical approaches to enhancing FCM tests,particularly in cases with limited sample sizes.
基金supported by grants from the National Natural Science Foundation of China(No.82293630,No.82293632 and No.82070152)the Guangdong Natural Science Foundation(No.2023A1515012968)Medical Scientific Research Foundation of Guangdong Province(No.A2023330)。
文摘Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical outcome.It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome.In this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).
文摘In order to delineate the infectious status of HGV in pediatric hemato-logical patients and its clinical features, 38 children were studied for HGV by reverse transcription nested polymerase chain reaction (RT-nPCR). The overall positive rate was 23. 68 %; the positive rate in 1-10 time transfusion recipients (mean 3. 26 times) was 3. 70 % while in over 10 time transfusion recipients (mean 20. 09 times) was 72. 73 %. A statistically significant difference was found between the two groups (P<0. 001). All HGV positive children showed diminished immunity and most were single HGV infection with no clinical and biochemical evidences of acute hepatitis. Our results suggest that HGV is one of the main causes of post-transfusion hepatic virus infection and the prevalence is related to transfusion times. Hematological malignancy maybe the most susceptible confluence of HGV.
基金Hebei Health Science and Education Project,No.20200852.
文摘BACKGROUND The mortality rate from septic shock in patients with hematological malignancies(HMs)remains significantly higher than that in patients without HMs.A longer resuscitation time would definitely be harmful because of the irreversibly immunocompromised status of the patients.Shortening the resuscitation time through continuous renal replacement therapy(CRRT)with oXiris^(■)would be an attractive strategy in managing such patients.AIM To explore the effects of CRRT and oXiris^(■)in shortening the resuscitation time and modifying the host response by reducing inflammation mediator levels.METHODS Forty-five patients with HM were diagnosed with septic shock and underwent CRRT between 2018 and 2022.Patients were divided into two groups based on the hemofilter used for CRRT(oXiris^(■)group,n=26;M150 group,n=19).We compared the number of days of negative and total fluid balance after 7 d of CRRT between the groups.The heart rate,norepinephrine dose,Sequential Organ Failure Assessment(SOFA)score,and blood lactic acid levels at different time points in the two groups were also compared.Blood levels of inflammatory mediators in the 26 patients in the oXiris^(■)group were measured to further infer the possible mechanism.RESULTS The average total fluid balance after 7 d of CRRT in the oXiris^(■)group was significantly lower than that of patients in the M150 hemofilter group.The SOFA scores of patients after CRRT with oXiris^(■)therapy were significantly lower than those before treatment on day 1(d1),d3 and d7 after CRRT;these parameters were also significantly lower than those of the control group on d7.The lac level after oXiris^(■)therapy was significantly lower than that before treatment on d3 and d7 after CRRT.There were no significant differences in the above parameters between the two groups at the other time points.In the oXiris^(■)group,procalcitonin levels decreased on d7,whereas interleukin-6 and tumor necrosis factor levels decreased significantly on d3 and d7 after treatment.CONCLUSION CRRT with oXiris^(■)hemofilter may improve hemodynamics by reducing inflammatory mediators and playing a role in shortening the resuscitation period and decreasing total fluid balance in the resuscitation phases.
文摘Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabcontaining therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBs Ag) and antibody to hepatitis B core antigen(antiHBc). Patients found to be positive for HBs Ag should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving highrisk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBs Ag-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.
基金supported by the National Science Foundation of China (No. 30800402)
文摘TMTP1, a 5-amino acid peptide NVVRQ, obtained by using the flagella peptide library screening in our previous studies, can be used for the labeling of malignant in situ and metastatic lesions, and even micro-metastases. In this study, TMTP1 was assessed for its ability to specifically target the malignant hematopoietic cells and metastatic lesions of hematological malignancies. FITC-TMTP1 was chemically synthesized. Immunofluorescence assay and competitive test were carried out to determine the specific binding capacity of TMTPl to hematological malignant cell lines, including HL60, k562, SHI-1, Jurkat, Raji, El-4 and umbilical cord blood mononuclear cells. Mononuclear cells were isolated from the bone marrow of healthy subjects and patients with chronic myeloid leukemia. Then the cells were co-clutured with TMTP1 or scrambled peptides and the binding and affinity of TMTP1 peptide to the primary cells of hematological malignancies were flow cytometrically analyzed. The binding speci-ficity of TMTP1 to target hematological malignancies was measured in vivo by intravenous injection of FITC-conjugated TMTP1 into El-4 lymphoma-bearing mice. The results showed that TMTP1 specifi-cally bound to the cells of a series of hematological malignancies, including HL60, k562, Jurkat, Raji , El-4 and chronic myeloid leukemia primary cells but not to bone marrow mononuclear cells from healthy subjects. By contrast, TMTP1 could bind to the metastatic foci of lymphoma originating from the EL-4 cell line while the scrambled peptide failed to do so. Moreover, the occult metastases could be identified, with high specificity, by detecting FITC-TMTP1. We are led to conclude that TMTP1, as a novel tumor-homing peptide, can serve as a marker for primary malignant and metastatic lesions for the early diagnosis of hematological malignances and a carrier of anticancer drugs for cancer treatment.
基金the Key Program of the National Natural Science Foundation(NNSF)of China(No.81230052 and No.81630006).
文摘As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.
基金Supported by Japan Society for the Promotion of Science,No.15H05289
文摘AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus(HBV)infections in patients with hematological malignancies in South Egypt.METHODS Serum samples were collected from 165 patients with hematological malignancies to monitor titers of HBV DNA,hepatitis B surface antigen(HBs Ag),and antibodies to HBV core(anti-HBc)and surface antigens.Serum samples negative for HBs Ag and positive for anti-HBc were subjected to nucleic acid extraction and HBV DNA detection by real-time polymerase chain reaction.DNA sequences spanning the S region were analyzed in cases with occult HBV infection.In vitro comparative study of constructed 1.24-fold wild type and S protein mutant HBV genotype D clones was further performed.RESULTS HBV DNA was detected in 23(42.6%)of 54 patients with hematological malignancies who were HBsA g negative,but anti-HBc positive,suggesting the presence of occult HBV infection.The complete HBV genome was retrieved from 6 occult HBV patients,and P120 T and S143 L were detected in 3 and 2 cases,respectively.Site directed mutagenesis was done to produce 1.24-fold genotype D clones with amino acid mutations T120 and L143.The in vitro analyses revealed that a lower level of extracellular HBsA g was detected by chemiluminescence enzyme immunoassay(CLEIA)with the clone containing T120 mutation,compared with the wild type or the clone with S143 L mutation despite the similar levels of extracellular and intracellular HBs Ag detected by Western blot.Southern blot experiments showed that the levels of intracellular HBV DNA were not different between these clones.CONCLUSION Occult HBV infection is common in patients with hematological malignancies and associated with P120 T and S143 L mutations.120 T mutation impairs the detection of HBsA g by CLEIA.
基金the National Natural Science Foundation of China(No.81230014,No.81470341,No.81520108002 and No.81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.
基金Project supported by the National Natural Science Foundation of China(Nos.81770201 , 81730008)。
文摘The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents.In patients with COVID-19,underlying chronic diseases and comorbidities are associated with dismal treatment outcomes.Owing to their immunosuppressive status,patients with hematological malignancies(HMs)are at an increased risk of infection and have a worse prognosis than patients without HMs.Accordingly,intensive attention should be paid to this cohort.In this review,we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs.Furthermore,we briefly de-scribe customized management strategies and interventions for this susceptible cohort.This review is intended to guide clinical practice.
文摘Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymerase chain reaction （PCR） in 103 acute myeloid leukemia （AML） cases, 63 acute lymphocytic leukemia （ALL） cases, 53 chronic myelogenous leukemia （CML） cases in chronic phase （CML-CP）, 34 CML cases in blast crisis （CML-BC）, 11 chronic lymphatic leukemia （CLL） cases, 36 myelodysplastic syndrome （MDS） cases, 9 multiple myeloma （MM） cases and 13 non-hodgkin＇s lymphoma （NHL） cases with marrow infiltration. Results： The expressions of FLT3/ITD gene mutations were detected in 22.3% AML cases, in 6.5% CML-BC cases, in 5.6% MDS cases and in 2.6% ALL cases. The two ALL cases with FLT3/ITD mutation were diagnosed as ALL-L2 with morphology and both with myeloid antigen expression, but finally were diagnosed as acute mixed-lineage leukemia after immunology examination. FLT3/ITD gene mutations were not detected in CML-CP, MM, NHL and CLL cases. In the 23 AML patients with FLT3/ITD gene mutation, including 2 of 8 M1 （2.5%）, 8 of 33 M2 （24.2%）, 7 of 24 M3 （29.3%）, 2 of 11 M4 （18.2%）, 3 of 21 M5 （14.3%）, 1 of 5 M6 （20%）, and 0 of 1 M7 cases, and there were no significant differences in the positive rates of FLT3/ITD mutations between the FAB subtypes （P 〉 0.05）. Statistical analyses showed that in AML patients, FLT3/ITD was associated with a higher peripheral blood white cell （WBC） counts [（41.23 ± 32.56） x 109/L vs （11.36 ± 9.89） × 10^9/L （P 〈 0.01 ）], higher percentage of bone marrow blast cells [（72.78 ± 21.79）% vs （51.26 ± 20.78）% （P 〈 0.05）], and higher cumulative relapse rates （63.6% vs 27.7%, P 〈 0.025） than those negative. Conclusion： FLT3/ITD gene mutation mainly occurred in AML patients, and might be a strong prognostic factor which was associated with high peripheral WBC counts, bone marrow blast cell proportion and a increased relapse risk in AML. Detection of FLT3/ITD gene mutation might provide insights to explore a more accurate genotyping of leukemia, differential diagnosis between AML and ALL, subdivide risk level in AML and estimate prognosis of leukemia.
