bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haplo-Identical Non-Gene Editing CD7 CAR T-Cells Induced Bone Marrow and Extramedullary Remission in a Pediatric Patient with
TP53
Mutated Relapsed and Refractory Early T-Cell Precursor Lymphoblastic Leukemia/Lymphoma after Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Dai Haiping , Lin Yang , Meng Huimin , Cui Qingya , Zhu Wenjuan , Tang Xiaowen , Cui Wei , Wu Depei 
Published: November 2021

Abstract
Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 expresses in almost all blasts of T-cell lymphoma/leukemia and represents one of the most promising therapeutic targets for T-ALL/LBL by CD7 targeted chimeric antigen receptor modified T cell therapy (CD7-CART). Because of shared CD7 expression in the majority of normal T-cell surfaces, we utilized an non-gene editing strategy by co-transducing CAR-T cells with a CD7 protein expression blocker (PEBL), and successfully overcame the fratricide as well as maintain the proliferation and cytotoxicity of CD7-CART-cells. Here, we presented the efficacy and safety results of CD7-CART therapy in a pediatric patient with TP53 mutated ETP-ALL/LBL. The patient was diagnosed with ETP-ALL/LBL at 2016, achieved and maintained complete remission (CR) for 2 years with traditional chemotherapy. The disease relapsed at a month after discontinuation of chemotherapy. He underwent haploidentical HSCT at the second CR, but suffered relapse again 2 years post haplo-HSCT. TP53 mutation（VAF:96.5%） and extensive extramedullary infiltration was detected at relapse. The patient was resistant to venetoclax combined with decitabine, homoharringtonine, aclarubicin, cytarabine and granulocyte colony stimulating factor (G-CSF), high-dose cytarabine combined with cladribine, G-CSF, chidamide and CD38 CART therapy. Nanobody derived CD7-CART cells were manufactured from lymphocytes of the donor. The CART cells were negative for CD7, CD223 and CD279. 70.5% of blasts in the bone marrow aspirates were observed prior to CAR T-cells infusion. A total of 5×10 6/kg CD7-CART-cells were infused. CR was confirmed at day 30 bone marrow evaluation and maintained at the last followup at day 91. Partial remission was achieved as evaluated by PET-CT scan at day 93. Persistence of CD7-CART-cells can be detected with flowcytometry until day 96 post CAR T-cells infusion. Grade 3 cytokine release syndrome with high fever and hypotension were observed, which was relived by tocilizumab and dexamethosone. No organ dysfuction and immune effector cell-associated neurotoxicity syndrome were observed. In general, we showed for the first time that the nanobody derived CD7-CART with PEBL technology was a potent and safe salvage therapy in a relapsed/refractory ETP-ALL/LBL patient with high tumor burden.

Disclosures
No relevant conflicts of interest to declare.
Development and External Validation of a Prognostic Nomogram for Angioimmunoblastic T-Cell Lymphoma
Authors: Wang Hua , Fu Bibo , Chen Guanjun 
Published: November 2021

Abstract
Introduction: Heterogeneity exists in prognosis of Angioimmunoblastic T-cell lymphoma (AITL) patients. Thus, a personalized prognostic model is crucial for survival prediction for each AITL patient. Nomogram is a powerful mathematical tool to predict survival. In this study, we aimed to develop a prognostic nomogram for AITL based on data from a large clinical database and validate it in an independent external cohort. In addition, we compared the accuracy of the nomogram with previous prognostic models used in AITL including International Prognostic Index (IPI) and Prognostic Index of T-cell lymphoma (PIT) model.
Methods: Totally, 1071 patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort; 156 patients diagnosed from 2009-2021 in Sun Yat-Sen University Cancer Center or The First Affiliated Hospital of Guangzhou Medical University were recruited as the external validation cohort. 105 patients with IPI information in the training cohort were used to compare the nomogram and IPI. 156 patients in the external cohort were used to compare the nomogram and IPI or PIT. The Prognostic risk factors in the nomogram were identified by cox proportional hazards model. Concordance index (C-index) and calibration curves were used for internal and external validation. C-index and decision curve analysis (DCA) curves were used to compare the models.
Results: Age, sex, systematic symptoms, Ann Arbor stage and chemotherapy were risk factors finally included to develop the nomogram. C-indexes of the nomogram were 0.676 and 0.652 in the training cohort and the validation cohort. Favorable agreement of nomogram-predicted and actual probability of overall survival (OS) was detected by calibration curves in both training and validation cohorts. In the cohort of 105 patients, C-indexes of the nomogram and IPI were 0.696 vs 0.616 (P&lt;0.05); in the cohort of 156 patients, C-indexes were 0.652 vs 0.597 (P=0.08) of the nomogram and IPI while 0.652 vs 0.616 (P=0.176) of the nomogram and PIT. Decision curve analysis (DCA) showed superiority of the nomogram as compared with the IPI or the PIT model in both 105 and 156 patients' cohorts. A web calculator was published for convenient clinical application. Based on the prognostic scores calculated by the nomogram, three cut points were identified by X-tile program to establish a classification system that could significantly distinguish patients in four risk groups.
Conclusion: We establish a nomogram for survival prediction of AITL, which may assist in treatment strategy making and survival consultation.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Meta-Analysis of D-Dimer, hsCRP and Cytokines in COVID-19 Severe/Critical Patients in China
Authors: Zhang Jie , Zhao Lidong , Wang Gang , Yang Linhua 
Published: November 2021

Abstract
Objective: To analyze the relationship between D-dimer, inflammatory markers, cytokines and disease severity, and the possibility of early identification of COVID-19 critical type patients. Methods: PubMed, EMBASE and CNKI databases were searched by computer, and references of related reviews and systematic reviews were manually searched as supplements. The retrieval deadline is February 9, 2021. According to the inclusion and exclusion criteria, the literatures were screened and the quality was evaluated, and then the data were extracted for meta-analysis. The fixed/random effects model was used to calculate the weighted mean difference (WMD) and 95% CI to evaluate whether the levels of D-dimer, hsCRP, IL-6, IL-8, IL-10 and TNF-α in critical type patients were statistically different from those in severe type patients. If there were statistical differences, logistic regression analysis was used, and establish the receiver operating characteristic curve (ROC) and area under the curve (AUC) of each index for the diagnosis of critical type patients. The best diagnostic value of COVID-19 critical type patients was calculated by Youden index. Results: A total of 3519 literatures entered the screening process. According to the inclusion and exclusion criteria, 40 articles were finally included in this study, and all of them were high-quality studies after evaluation. The results of meta-analysis showed that the levels of D-dimer, hsCRP, IL-6, IL-8 and IL-10 in critical type group were significantly higher than those in severe type group (P&lt;0.05). Based on ROC curve, the AUC of D-dimer was 0.785 (95% CI: 0.671-0.899), AUC of hsCRP was 0.884 (95% CI: 0.632-1.000), AUC of IL-6 was 0.819 (95% CI: 0.700-0.939), which had diagnostic significance for critical type patients (P&lt;0.05). The optimal diagnostic threshold of D-dimer was ≥2.00 mg/L (sensitivity 89.3%, specificity 64.0%); the optimal diagnostic threshold of hsCRP was ≥64.22 mg/L (sensitivity 75.0%, specificity 100%); the optimal diagnostic threshold of IL-6 was ≥33.01 ng/L (sensitivity 68.0%, specificity 92.0%). Conclusion: The levels of D-dimer, hsCRP, IL-6, IL-8 and IL-10 in COVID-19 critical type patients were significantly higher than those in severe type patients. Our results might be helpful in identify and risk reduction of mortality in critical types patients infected with COVID-19.

Disclosures
No relevant conflicts of interest to declare.
Tanshinone Iia Inhibits Megakaryopoiesis in Immune Vasculitis
Authors: Chen Hui , Zhou Min , Shu Huiying , Su Weiqing , Yang Liuming , Li Liang , Chong Beng H , Yang Mo 
Published: November 2021

Abstract
Introduction Tanshinone IIA, an active component of Danshen (Salvia miltiorrhiza), has been used for centuries to treat hypercoagulation-related diseases, which attributed to its anti-platelet and anti-inflammatory effects. However, the role of Tanshinone IIA in megakaryocytes, the precursor of platelet within the bone marrow, remains unclear. Therefore, the present study established a rabbit model with immune vasculitis to examine the effect of Tanshinone IIA on megakaryopoiesis and to identify the underlying mechanism(s).

Methods Immune vasculitis was established in rabbits (3-4 weeks old) by two intravenous injection of 10% bovine serum albumin (2.5 ml/kg) at two-week interval. Those rabbits were randomly treated with Tanshinone IIA (5 mg/kg/d, 7 d, iv) or aspirin (100 mg/kg/d, 7 d, ig). Megakaryocyte count and CFU-MK formation were measured by Wright's and AChE staining, respectively. Human megakaryotic cell lines Meg-01 and CHRF-288-11 were used to examine the effect of Tanshinone IIA on apoptosis by Annexin V-FITC/PI, mitochondrial membrane potential/JC-1 and Caspase-3 activity assays using flow cytometry.
ResultsIn rabbits with immune vasculitis, the platelet count, platelet aggregation and the serum levels of inflammatory cytokines IL-1β, TNF-α and IL-6 were significantly increased when compared to their healthy controls. After 7 days of Tanshinone IIA treatment, all these parameters were significantly reduced, with the inhibitions comparable to those caused by aspirin. In addition, the number of megakaryocytes and the formation of CFU-MK were also statistically increased in rabbits with immune vasculitis, which could be significantly reduced by Tanshinone IIA. In vitro, Tanshinone IIA (1, 3, 10 and 30 μg/ml) also significantly inhibited the formation of CFU-MK of bone marrow cells of BALB/c mice (6-10 weeks) in a dose-dependent manner. In human megakaryocytic cell line Meg-01, Tanshinone ⅡA (10 μg/ml, 72 h) induced apoptosis; both early and late apoptotic rates were significantly increased. In another human megakaryocytic cell line CHRF-288-11, Tanshinone ⅡA (10 μg/ml, 72 h) statistically increased the proportion of depolarized cells, from 9.70% to 14.13%, according to mitochondrial membrane potential using JC-1 assay. The expression of active Caspase-3 in CHRF-288-11 was also significantly increased by Tanshinone ⅡA (10 μg/ml, 72 h) from 5.25% to 15.86%.

Conclusion The present study shows that Tanshinone IIA ameliorates immune vasculitis by inhibiting megakaryopoiesis and inducing apoptosis of megakaryocytes, which might explain the anti-platelet and anti-inflammatory effects of Tanshinone IIA.

Disclosures
No relevant conflicts of interest to declare.
A NIR-II Fluorophores for Multiple Myeloma Imaging and Photodynamic Therapy
Authors: Jiang Hongqiang , Ding Qihang , Li Qianqian , Wei Yongchang , Hong Xuechuan , Zhou Fuling 
Published: November 2021

Abstract
Background: Multiple myeloma is a hematological malignant disease in which clonal plasma cells proliferate abnormally. NIR-II fluorophores have great application prospects for cancer treatment.
Methods: Multiple detection techniques were used to evaluate effect and mechanisms of the novel small-molecule NIR-II fluorophores probe on multiple myeloma cells in vitro experiment. In vivo MM.1S Luc+ B-NSG mouse model was built to assess the role of probe in multiple myeloma treatment.
Results: The novel small-molecule NIR-II fluorophores probe shown high affinity with multiple myeloma cells and specific myeloma imaging in vivo. More importantly, the probe could effectively induce tumor death with 808 nm laser irradiation in a dose-dependent manner. Further, Confocal found that the probe was mainly distributed in mitochondria and significantly reduced the mitochondrial membrane potential with laser irradiation. Moreover, Reactive Oxygen Species (ROS) level was notably increased and the up-regulation expression of cleaved poly ADP-ribose polymerase (PARP) was detected after treated with the probe and laser irradiation. Consistent with the previous results, the disease was alleviated obviously in probe laser-treated group.
Conclusions: Our work confirm for the first time that the specific imaging and remarkable photodynamic therapy (PDT) effect of a novel NIR-II fluorophores probe to multiple myeloma. It provides the foundation for application of NIR-II fluorophores from solid tumor to non-solid tumor.

Disclosures
No relevant conflicts of interest to declare.
Development and Validation of a Gamma Globin RT-Ddpcr Exploratory Biomarker for Sickle Cell Phase 1 Clinical Trial Fis 002-2020
Authors: Roth Mark , Yang Jian , Tsavachidou Dimitra , Davis Darren W. 
Published: November 2021

Abstract
FTX-6058, a selective and potent binder of embryonic ectoderm development protein (EED), is being investigated in Sickle Cell Disease (SCD). In-vitro and pre-clinical Townes mouse studies show FTX-6058 upregulates expression of the gamma globulin gene leading to increased levels of fetal hemoglobin (HbF). In human clinical trials, as an early indicator of FTX-6058 induced gamma globulin expression, a reverse transcriptase droplet digital PCR (RT-ddPCR) assay was developed and validated by Precision for Medicine. Versus RT-qPCR, RT-ddPCR gives absolute copy number, does not require a standard curve, and is more precise and reproducible for low expressed targets 1,2. Precision for Medicine developed and validated RT-ddPCR assays for the target globin genes α, β, and γ and for the housekeeping genes TFRC and OAZ1. RNA isolated from 3 healthy and 3 SCD affected individuals was used for development and validation of the assay. The upper and lower limits of quantification were 120,000 and 10.5 copies/20μL reaction, respectively. For samples with &gt;50 copies/20μL reaction, the CV for technical replicates was &lt;20% for all transcripts. Furthermore, Precision for Medicine demonstrated SCD affected individuals express approximately 15-fold more γ globulin versus non affected individuals. Fulcrum utilized the globin RT-ddPCR assay validated by Precision for Medicine in the FTX-6058 phase 1 clinical trial FIS 002-2020.
1 Zhao Y, Xia Q, Yin Y, Wang Z (2016), Comparison of Droplet Digital PCR and Quantitative PCR Assays for Quantitative Detection of Xanthomonas citri Subsp. citri. PLoS ONE 11(7): e0159004. doi:10.1371/journal.pone.0159004
2 Taylor SC, Laperriere G, Germain H (2017), Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data. Scientific Reports 7(2409): DOI:10.1038/s41598-017-02217-x

Disclosures
Roth: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Fulcrum Therapeutics, Inc.: Consultancy. Tsavachidou: Fulcrum Therapeutics, Inc.: Consultancy. Davis: Fulcrum Therapeutics, Inc.: Consultancy.
Changes in ABC Transporter Expression during Hematopoiesis Cause Lineage-Biased Cytopenias in Patients Treated with Aurora Kinase Inhibitors
Authors: Furlong Brooke A. , Posey Ryan R. , Chou David B. , Kyprianou Christos , O'Sullivan Lucy R. , David Rhiannon , Randle Suzanne , Polanska Urszula , Urosevic Jelena , Travers Jon , Hutchinson John , Hasserjian Robert P. , Prantil-Baun Rachelle , Ingber Donald E. 
Published: November 2021

Abstract
Chemotherapy-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While they are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecule drugs and the factors that determine the hematotoxicity profiles of chemotherapies are not fully understood. Here, we explore why Aurora kinase inhibitor drugs cause preferential neutropenia when compared to the cytopenic profiles of targeted small molecule cancer drugs that are FDA approved. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing published clinical datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibitors is acquired at an early stage of differentiation and is caused by developmental changes in the expression pattern of ATP-binding cassette (ABC) transporters. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some chemotherapies affect the bone marrow.

Disclosures
David: AstraZeneca: Current Employment. Randle: AstraZeneca: Current Employment. Polanska: AstraZeneca: Current Employment. Urosevic: AstraZeneca: Current Employment. Travers: AstraZeneca: Ended employment in the past 24 months. Ingber: Emulate: Membership on an entity's Board of Directors or advisory committees; BOA Biomedical: Membership on an entity's Board of Directors or advisory committees; Freeflow Medical Devices Inc: Membership on an entity's Board of Directors or advisory committees.
Outcomes after First Rescue Treatment in Patients with Relapsed or Refractory Multiple Myeloma in Colombia
Authors: Martinez-Cordero Humberto , Abello Virginia , Mantilla Duran William Armando , Gomez Rigoberto , Reyes Jheremy , Idrobo Henry , Galvez Kenny , Casas Claudia Patricia , Solano Maria Helena , Espinosa Daniel , Amar Ivan Alfredo Perdomo , Osuna Pérez Monica , Gomez Diaz Alvaro , Saavedra Domingo , Quintero Guillermo , Abenoza Lina , Gaviria Lina , Henao-Uribe Alicia , Sossa Claudia Lucia , Rosales Carmen , Paredes Claudia , Figueroa Emiliani Jair , Munevar Isabel , Bermudez Silva Carlos Daniel , Borjas Yasmin , Guerrero Alvaro , Guerrero Paola , Herrera Juan Manuel 
Published: November 2021

Abstract
Background Proteasome inhibitors (PIs) are approved for treating newly diagnosed and relapsed multiple myeloma (MM) in Colombia. This propensity score matching (PSM) analysis using data from the real-world, was designed to establish the role PIs (bortezomib or carfilzomib) at first relapsed or refractory MM. The primary endpoint was overall response rate (ORR) and secondary endpoint included was overall survival (OS). Moreover, an analysis of OS was done regarding response attained. On Behalf of RENEHOC-GRIMMCO (Colombian Registry for Hemato-Oncological Diseases and Colombian Mieloma Múltiple study group).
Methods PSM by nearest neighbor analysis to evaluate the role of PIs used at first relapse in multiple myeloma of patients belonging to RENEHOC registry, between 2010 and 2020.
Results 390 patients were identified in the first relapse of the Colombian registry, 269 patients with PI and 121 patients without PI. One hundred and ten patients were included in each group after PSM. Patients were matched for age, ISS, extramedullary disease, and use of lenalidomide to define the influence of this immunomodulatory drug in the PI group. A difference was found in the use of lenalidomide because only 1 patient was treated with PI and lenalidomide concomitantly (0.91%) compared to 31 patients in the group without PI (28.18%), (p &lt;0, 0001).
Regarding ORR, no differences were found between the 2 groups 38.18% in PIs vs 37.27% in non-PIs group (p = 0.801). A trend towards better OS was found in the PIs group with a median of 58 months versus 39 months (p = 0.179). Overall survival in patients who achieved at least PR was better compared to those who did not reach 79 months versus 32 months in non-responders (p = 0.0001).
Conclusion In this study, we found that the use of PI has a tendency to improve overall survival in real-world in MM patients when used in the first relapse and that this effect could possibly be enhanced with the combination with lenalidomide. Regardless of the treatment used, better responses are associated with better survival.
Figure 1 Figure 1.

Disclosures
Abello: Janssen: Honoraria; Amgen: Honoraria; Dr Reddy's: Research Funding. Sossa: Amgen: Research Funding.
Metal-Ion Transporter SLC39A14 Is Required for Cardiac Iron Loading in the Hjv Mouse Model of Iron Overload
Authors: Liu Qingli , Azucenas Corbin , Mackenzie Bryan , Knutson Mitchell 
Published: November 2021

Abstract
Although iron overload-related cardiomyopathy is a leading cause of morbidity and mortality in iron-overload disorders (e.g., thalassemia major and hemochromatosis), the molecular mechanisms that mediate cardiac iron uptake and accumulation are incompletely understood. Previous studies using Slc39a14 knockout mice have revealed that SLC39A14 is required for the uptake of non-transferrin-bound iron (NTBI) by the liver and pancreas and is essential for iron loading of hepatocytes and pancreatic acinar cells. To investigate the requirement for SLC39A14 in cardiac iron accumulation, we generated cardiomyocyte-specific Slc39a14 knockout (Slc39a14 hrt/hrt) mice and crossed them with iron-loading hemojuvelin (Hjv) knockout mice to generate Hjv -/-;Slc39a14 hrt/hrt animals. At 12 and 24 weeks of age, cardiac nonheme iron levels were ~340% higher in Hjv -/- mice than in controls. By contrast, cardiac nonheme iron levels in Hjv -/-;Slc39a14 hrt/hrt mice at these ages were only ~60% higher than those than in controls, and ~65% less than those in Hjv -/- mice. Moreover, cardiac nonheme iron levels in Hjv -/-;Slc39a14 +/hrt (heterozygous conditional Slc39a14 knockout) mice were between those of Hjv -/- and Hjv -/-;Slc39a14 hrt/hrt mice, suggesting a gene-dosage effect of Slc39a14 on cardiac iron accumulation. A role for voltage-dependent calcium channels in mediating the uptake of NTBI into cardiomyocytes has been proposed based on observations of the effects of L-type calcium-channel blockers on iron uptake and accumulation in vitro and in vivo. We considered the possibility that these observations could be explained if SLC39A14 were reactive with calcium-channel blockers. To test this hypothesis, we examined the effects of blockers on the activity of SLC39A14 by using radiotracer assays in RNA-injected Xenopus oocytes expressing mouse SLC39A14. We found that 100 µM amlodipine (Amld), nifedipine, and nicardipine each afforded modest inhibition of SLC39A14-mediated 55Fe 2+. Inhibition of iron transport by Amld was dose-dependent, EC 50 = 167 µM ± (SEM) 30 µM. Our findings implicate SLC39A14 in mediating cardiomyocyte NTBI uptake in the mouse and raise doubts about the relative importance of calcium channels as a mechanism by which NTBI gains entry to the heart.

Disclosures
No relevant conflicts of interest to declare.