bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zanubrutinib Plus Salvage Chemotherapy in Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for Autologous Stem Cell Transplantation: A Retrospective Study
Authors: He Sha , Sun Jie , Zhong Dani , Rong Chao , Liao Chengcheng , Tan Xiaohong 
Published: December 2023

Introduction ：Salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT) is effective for relapsed or refractory DLBCL (R/R DLBCL). However, many patients are unable to undergo auto-SCT due to age, comorbidities, tolerance, economy and other factors. R/R DLBCL has poor clinical outcomes when treated with conventional salvage chemotherapy. Zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has been shown to have modest antitumor activity in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of Zanubrutinib plus salvage chemotherapy in autologous stem cell transplantation-ineligible R/R DLBCL patients.
Methods: We retrospectively reviewed R/R DLBCL patients who were administered with Zanubrutinib 160mg*bid plus BR （Bendamustine 90mg/㎡*d1-2+Rituximab 375mg/㎡*d0）or R2 （Lenalidomide 25mg* d1-21 +Rituximab 375mg/㎡*d0）in our center between January, 2019 and July, 2023.
Results: 49 R/R DLBCL patients were enrolled,including 30 patients in the Zanubrutinib plus BR group(ZBR)and19 patients in the Zanubrutinib plus R2 group(ZR2). Median age at this study was 60 years (range, 33-80). The best overall response rate (ORR) was 57.1% and complete remission rate was 12.2%. The ORR of ZBR group and ZR2 group were 63.2% and 53.3%, respectively. The response rate was lower in elderly, patients with ≥4 line treatment, refractory patients, patients with TP53 mutations, or without MYD88 and CD79A/B mutations. TThere was a positive correlation between the number of treatment cycles and ORR. With a median follow-up of 22 months (range, 6-43), the median progression-free survival (PFS) was 6.0 months, and the overall survival (OS) was 21.0 months. For OS, univariate analysis suggested that the number of treatment cycles was an independent favorable prognostic factor for OS. In multivariate analysis, , relapsed patients had better OS compared with refractory patients, and response after treatment was an independent favorable factor for OS. The most common grade-3/4 adverse events were neutropenia (55.0%), thrombocytopenia (44.9%), and pneumonia (30.1%).
Conclusion: Zanubrutinib combined with BR or R2 showed promising efficacy and acceptable safety in R/R DLBCL patients, which may be a potential treatment option for autologous stem cell transplantation-ineligible R/R DLBCL patients.
Diverse Effects of Cryopreservation-Induced Mitochondrial Dysregulation on Cord Blood Cells
Authors: Huang Yaojin , Liu Mengyao , Xie Xiaowei , Zhang Yawen , Dong Fang , Zhang Yingchi , Cheng Tao 
Published: December 2023

Umbilical cord blood transplantation (UCBT) has been performed broadly in clinic by the specific biological and immunological characteristics of umbilical cord blood cells (UCB). UCB-based cell therapy and immune therapy also presents great application potential. UCB was usually cryopreserved for several years before using. Whether and how cryopreservation affects the function of divergent cell populations in UCB still remain to be illuminated.
Here, we firstly constructed a single-cell transcriptomic profile of Lineage - CD34 + hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) collected from fresh and cryopreserved UCB with 1, 5, 10 and 19 years. Subpopulations characterized by higher mitochondrial gene expression (Mito high) were identified in all cell populations and found to be increased during cryopreservation. Compared with the fresh group, HSC/MPP cells after cryopreservation showed more active cell cycle and lower expression of HSC/MPP signature genes, especially in the Mito high HSC/MPP cells. Consistently, colony-forming ability as well as long-term hematopoietic reconstitution of HSPCs derived from cryopreserved UCB gradually decreased within 5 years but remained stable thereafter. More importantly, we observed decreased megakaryocyte differentiation ability from cryopreserved HSPCs, which could be partially rescued by antioxidants treatment after cryopreservation. Mechanically, we revealed that the metabolic dysregulation of mitochondria including elevated mitochondrial reactive oxygen species (ROS), reduced adenosine triphosphate (ATP) synthesis and impaired mitochondrial membrane potential of cryopreserved HSPCs led to attenuated hematopoietic reconstitution. Although there was a mild increase of Mito high subpopulations after cryopreservation, the cytokine production levels of T cells and NK cells were comparable to those of fresh samples. Additionally, NK cells exhibited almost same cytotoxic function with the fresh compartments.
Taken together, we elucidated the impact of cryopreservation on UCB HSPCs and provided the strategy for rescuing itsfunctional impairment. The unaffected T and NK cells after cryopreservation also paved the way for UCB-based cell therapy and immune therapy. Our study provides important implements for the quality control of applicable UCB both in hematology and immunotherapy.
Crosstalk between NFAT and NFκB Signaling Regulates NK Cell Immunosurveillance
Authors: Märklin Melanie , Holzmayer Samuel , Mueller Martin R. , Salih Helmut R. 
Published: December 2023

One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells), controlling lymphocyte development and activity. The role of NFAT signaling is well defined in T cells, the cytotoxic lymphocytes of the adaptive immunity. However, surprisingly little is known regarding the relevance of this transcription factor family in NK cells as effector cells of the innate immunity. Available data indicate that NFAT activity is dispensable for development of NK cells, whereas effects of the immunosuppressive drugs cyclosporin A and tacrolimus, that inhibit calcineurin and consecutively NFAT, implicate an involvement of the NFAT family in NK cell function. We here employed different genetic mouse models and functional analyses to unravel the role of NFAT1 (NFATc2) and NFAT2 (NFATc1) in NK cell reactivity.
In vitro knockout (KO) of NFAT1 (NFATc2) or NFAT2 (NFATc1) enhanced NK cell degranulation and resulted in increased production of granzyme B and perforin upon stimulation of activating receptors like NK1.1 or Nkp46 or upon co-culture with different leukemia and solid tumor cells. In line, cytotoxicity assays revealed increased lysis of YAC-1 and B16F10 tumor cells by both NFAT1- and NFAT2-deficient NK cells as compared to wildtype (WT) controls. The inhibitory effect of NFAT transcription factors on NK cell effector function could also be confirmed in vivo by employing WT and NFAT KO animals in syngeneic B16F10 melanoma, RMA-S lymphoma and LL/2-luc lung carcinoma models, which revealed a significantly reduced tumor burden in NFAT1 and NFAT2 KO mice. Furthermore, we detected higher numbers of tumor infiltrating NK cells in NFAT KO mice, which suggested improved NK cell migration and homing to the tumor side. Comparative analyses with single NFAT as well as NFAT1+NFAT2 double KO and WT animals further confirmed the inhibitory effect of NFAT1 and NFAT2 and pointed to additive effects of NFAT1 and NFAT2 in NK cell tumor immunosurveillance. Proteomics analysis of NK cells from the different NFAT KO strains revealed altered expression of molecules which are regulating chemokine receptor expression as well as a decreased expression of NFκB inhibitory molecules, like NFKBIB (NFKB inhibitor beta) Commd6 (COMM domain containing 6). NFκB signaling was shown to regulate granzyme B and perforin synthesis and expression. Thus, we suggest that NFAT1 and NFAT2 inhibit NFκB signaling in NK cells, and NFAT1 and NFAT2 KO reinforce NFκB induced granzyme B and perforin expression and thereby increase NK cell cytotoxicity.
Taken together, our results identify NFAT as a negative regulator of NK cell function. In addition, we provide the first evidence for a direct functional involvement of NFAT1 and NFAT2 in NK cell antitumor reactivity by regulation tumor infiltration and cytotoxicity of NK cell.
Adding Hetrombopag to Cyclosporine a to Patients with Newly Diagnosed Transfusion-Dependent Non-Severe Aplastic Anemia-a Prospective Phase 2 Study
Authors: Shen Shupei , Zhang Zhuxin , Zhuang Junling , Hu Qinglin , Chen Miao , Han Bing 
Published: December 2023

Abstract
Objective: To investigate the efficacy and safety of adding hetrombopag to cyclosporin A (CsA) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).
Methods: This was a single center, prospective phase 2 study. Eligible patients were aged 18 years or older, were diagnosed as TD-NSAA within 6 months and treatment-naïve. Enrolled patients were treated with hetrombopag and CsA. Hetrombopag was started at 10mg/day with possible titration up to 15mg/day, and tapered gradually when the optimal response was achieved. CsA was given at 3-5mg/kg/d for at least 6 months, and tapered after the optimal response was reached. The primary endpoint was the overall response rate (ORR) and safety at 6 months. Patients who had been followed-up for at least 6 months were included in the analysis. A history cohort with compatible baseline characters treated with CsA alone were analyzed as control. The trial was registered with ClinicalTrails.gov NCT05018936.
Result: Between Oct 2021 to Oct 2022, 28 patients were enrolled, comprising 13 men and 15 women, median age 46(range: 18-81). The ORR was 68.2% at 6 months. The most frequently reported adverse events were gastrointestinal discomfort grade 1 or 2. No grade 3 or 4 treatment-emergent adverse events were reported. There were 30 patients enrolled in the history control cohort with compatible baseline characters including age, sex ratio, complete blood cell count (P&gt;0.05). After a median follow-up of 15 (range: 9-22) vs 16 (range:9-24) months(P&gt;0.05), the ORR at 3, 6 months and the end of follow-up were 57.1% vs 16.7% (P=0.001), 68.2% vs 30.0% (P=0.006) and 90.9% vs 46.6%(P&lt;0.001) in hetrombopag plus CsA group and CsA alone group, respectively. The complete response rate (CRR) at 3, 6 months and the end of follow-up were 10.7% vs 0% (P=0.068), 22.7% vs 10.0% (P=0.217) and 36.4% vs 16.6% (P=0.109) in both groups, respectively. Adverse effects were reported in 13 (46.4%) patients in hetrombopag plus CsA group and 15 (50%) patients of CsA alone group (P&gt;0.05). 1 (3.6%) vs 8 (26.6%) patient relapsed (P=0.038) at 6 month in both groups. Clone evolution were noticed in no patients in hetrombopag plus CsA group and 2 (6.7%) patients in CsA alone group at 12 and15 months, respectively (P=0.225).
Conclusion: Adding hetrombopag to CsA can improve the ORR for newly diagnosed TD-NSAA, with good tolerance and lower relapse rate.
Keywords: Transfusion-dependent aplastic anemia, Hetrombopag, Cyclosporin A, efficacy, relapse.
Targeting the Oncofetal Transcription Factor Protein SALL4 in Cancer By a Non-IMiD Degrader
Authors: Vu Kim Anh L. , Kumari Kalpana , Liu Bee Hui , Gao Chong , Li Feng , Tang Jing Ping , Maddalo Danilo , Tian Xi , Liu Miao , Bassal Mahmoud Adel , Moein Shiva , Iakovleva Viktoriia , Tan Justin L. , Stein Alicia J. , Zhou Qiling , Fischer Patrick D. , Sigua Logan H. , Qi Jun , Arthanari Haribabu , Tenen Daniel G. , Chai Li 
Published: December 2023

Sal-like protein 4 (SALL4) is a C2H2 zinc finger transcription factor (TF) with two naturally occurring isoforms; SALL4A and SALL4B. It is typically detected in fetal tissues and silenced in most normal adult tissues. It is therefore intriguing that SALL4 is aberrantly re-expressed in about one-third of almost all primary human malignancies, presumably by demethylation dependent mechanisms. Direct evidence of the causative role of SALL4 in cancer has been demonstrated in SALL4 transgenic mice, which developed myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and/or liver tumors. Loss-of-function studies by SALL4 knock-down using shRNA showed cell growth inhibition and death in leukemias and solid tumors in culture and in in vivo xenotransplants.
TF's, such as SALL4, which are critical for cancer development and survival, have historically been viewed as “undruggable”. However, rather than blocking activity, an alternative approach to target TFs is to induce protein degradation. Immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide and pomalidomide, are used in treating patients with multiple myeloma (MM), MDS with 5q deletion, mantle cell lymphoma (MCL), and other hematological malignancies. Recently, several groups have reported that IMiDs can degrade SALL4 in a proteasome-dependent manner. To that end, we sought to investigate whether IMiDS could be utilized to treat SALL4-positive/expressing cancers.
Initially, our studies observed that IMiDs had no effect on SALL4-positive cancer cells. Additional investigations thereafter demonstrated that IMiDs could only degrade SALL4A. These findings suggested that SALL4B may not be affected by IMiDs, and may be essential for SALL4-mediated cancer cell survival. Further investigation revealed that SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. Moreover, through high-throughput screening, we identified a new non-IMiD SALL4 degrader that targets SALL4B via proteasomal degradation and which exhibited potent anti-cancer activity, inhibiting cancer cell proliferation in culture and in vivotumor growth by 70%.
Our observation therefore suggest that protein degraders could possess isoform specific effects. Additionally, our results exemplify the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.
Patterns of CS1 Expression on Natural Killer Cells and Correlated Factors in Plasma Cell Dyscrasias
Authors: Li Chunrui , Wang Di , Li Chunhui , Xu Yanjie , Mao Xia , Que Yimei , Li Zhe , Yu Qiuxia , An Ning , Long Xiaolu 
Published: December 2023

Abstract
BackgroundCS1 is overexpressed on myeloma cells, making it a promising target for immunotherapy in plasma cell dyscrasias (PCDs). However, monoclonal antibody (mAb) targeting CS1 showed limited efficacy when used alone. In addition, few clinical data of anti-CS1 chimeric antigen receptor T cell (CAR-T) have been published to date, suggesting that there may be some barriers to CS1-targeted immunotherapy. From previous studies, CS1 is expressed on some normal lymphocytes and plays an immunomodulatory role, and NK cells in particular play an important role in CS1-mediated immunity against MM. However, there are few studies on CS1 expression by NK cells in patients with plasma cell disease. Therefore, we investigated the expression of CS1 on NK cells, normal lymphocytes, and plasma cells in plasma cell dyscrasias and examined factors related to the CS1 expression level of NK cells and its relationship to survival.
Methods Between January 2018 and September 2019, a retrospective analysis was performed in 236 patients with multiple myeloma (MM) and 30 patients with other PCDs, including systemic light chain amyloidosis (AL), monoclonal gammopathy of undetermined significance (MGUS), POEMS syndrome, and monoclonal gammopathy of renal significance (MGRS). CS1 expression levels in NK cells, lymphocytes, and monoclonal plasma cells were assessed in patients with plasma cell dyscrasias. Membrane-bound CS1 of these three cell types was measured by multiparameter flow cytometry. Associations of CS1 expression with clinical and laboratory features were determined by univariate and multivariate analyses. Correlations between CS1 expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots.
Results When subgroups of MM and other PCDs were compared, there were no significant differences in CS1 expression in lymphocytes and NK cells alone. MM Patients had significantly higher CS1 expression levels in monoclonal plasma cells than other PCDs patients. In both MM and other PCDs patients, CS1 expression was significantly higher on monoclonal plasma cells than on NK cells and lymphocytes. There was a significant correlation between CS1 expression of monoclonal plasma cells (r = 0.60; P &lt; 0.001) and that of NK cells (r = 0.79; P &lt; 0.001) on univariate and multivariate analysis(Figure 1). Factors such as cytogenetic abnormalities, disease progression, or survival were not associated with CS1 expression level on NK cells. Neither CS1 expression level of monoclonal plasma cells nor that of NK cells was an independent predictor of patient survival.
Conclusion We demonstrated that CS1 expression level in NK cells is consistent in plasma cell dyscrasias. CS1 expression in NK cells positively correlates with that in clonal plasma cells. This positive correlation may have implications for the development of immunotherapy targeting CS1.
The Diagnostic Value of Circulating Blasts in Patients with Myeloproliferative Neoplasms in Accelerated or Blast Phase
Authors: Yacoub Abdulraheem , Philipose Shirene 
Published: December 2023

Introduction: Myeloproliferative neoplasms (MPNs) are progressive cancers with variable propensity to transform to accelerated phase and blast phase (APBP), an acute leukemia-equivalent state. MPN in APBP is associated with very poor prognosis with shortened survival and is notorious for poor response to therapy. The only curative therapy is allogeneic stem cell transplant.
Blast phase is defined by 20% blasts or higher in the bone marrow biopsy (BMBx) or peripheral blood (PB), while accelerated phase is defined by blast percentage 10% or higher. The diagnosis, and response to therapy often requires serial BMBx and PB testing. There is recognition of excessive circulating PB blasts in MPNs that occasionally exceeds blast count in BMBs, especially in fibrotic bone marrow. The aim of this study is to investigate the correlation between PB and BMBx blasts, and if PB testing might be a more convenient and lest costly marker for diagnosis and response assessment of MPN in APBP.
Methods: This is a cross sectional study, based on single institution retrospective chart review. Subjects included all available subjects over the age of 18, diagnosed with APBP MPN between January 1, 2017, to July 1, 2022. We collected serial blast percentages in simultaneously collected BMBx and PB samples, assessed by the same hematopathologist. We also collected baseline disease characteristics upon transformation to APBP. This is reported descriptively, and statistically analyzed for significance using a paired t-test.
Results: 15 subjects and 54 paired BP and BMBx blast assessments were identified. Median age was 59 (range 30 -71) and median duration since MPN diagnosis was 48 months (1-420). Median OS of the cohort since APBP diagnosis was 10 months. BMBx fibrosis was Grade II-III in 13/15 patients. Cytogenetic and mutation profiles, and therapies delivered are listed on Table 1. Based on evaluation of the results, there was no statistical correlation between blasts in the PB and BMBx both prior to therapy, and during therapy (detailed biostatistical analysis will be provided during ASH presentation)
Conclusions: Patients with APBP MPN undergo frequent diagnostic testing, including a bone marrow biopsy, to evaluate the percentage of blasts in the bone marrow. Quantification of blast count in peripheral blood should not be as a standalone diagnostic lab test for APBP MPN. BMBx remains essential for this diagnosis, response assessment, as well as cytogenetic and molecular profiling. The outcomes on APBP remain poor despite utilization of modern targeted therapeutics.
Real World Data of Extended Venous Thromboembolism Prophylaxis with Low Dose Apixaban Following Cancer Associated Thrombosis
Authors: Lalezari Shadan , Carmiel Rivka , Budnik Ivan , Kenet Gili , Levy-Mendelovich Sarina 
Published: December 2023

Introduction:
Cancer-associated thrombosis (CAT) is a leading cause of morbidity and mortality among patients with malignancies. Direct oral anticoagulants (DOACS) are frequently used to manage CAT. Bleeding risk is higher in cancer patients influencing the risk/benefit balance of treatment. Unlike in other cases of venous thromboembolism (VTE), there are no guidelines for dose reduction and extended prophylaxis after the initial period of full-dose treatment for cancer patients. We aimed to provide efficacy and safety data on patients with CAT that received extended VTE prophylaxis with a reduced dose of apixaban for the prevention of VTE recurrence.
Aim:
To investigate the clinical outcomes of patients with CAT treated with low-dose apixaban after initial treatment with full-dose anticoagulation.
Methods:
Data of all cancer patients over the age of 18 years from Sheba medical center that were diagnosed with VTE during the years 2012-2022, and treated with low-dose apixaban were retrieved using the MD Clone platform. All demographic, laboratory, and clinical data were collected from computerized medical files and statistically analyzed. The study was approved by the local IRB committee.
Results:
One hundred and seventeen patients with CAT, treated by a reduced dose of apixaban after initial full dose treatment for at least 6 months, were followed at our center. Table 1 summarizes the demographic and clinical characteristics of our cohort.
At the time of diagnosis with CAT the median age of patients was 72 (IQR 62-78).70.1% were female and 29.9% were male. 54.7% of patients had metastatic disease. After initial treatment with full-dose anticoagulation, patients were switched to low-dose apixaban for a median of 31 months (IQR 21-44 months). Twenty-one patients (18%) had a minor bleed and four patients (3.4%) had a major bleed while treated with low-dose apixaban. During this period 7 patients (6%) had a recurrent VTE. Two-thirds of the patients died. Mortality was attributed to thrombosis in one (0.9%) patient and major bleeding in two patients (1.7%).
Conclusions:
Low-dose apixaban may be a safe and appropriate option for extended treatment of cancer patients with VTE, with low rates of recurrence and major bleeding.