bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Myeloma and DALY in the USA: Insights of the Global Burden of Disease
Authors: Cuartas Maria , Pan Chun-Wei 
Published: December 2023

Introduction:
In contrast to the global trends, which indicate an escalating incidence and mortality of Multiple Myeloma (MM), the United States presents an inverse scenario. The successful development and deployment of therapeutic interventions have led to an appreciable decrease in mortality by 18%. Among the diverse array of prognostic factors associated with MM, age stands out as a significant element, typically associated with poor prognosis. With these considerations in mind, our study aimed to undertake a systematic analysis of the incidence, mortality, and Disability-Adjusted Life Years (DALY) related to MM over a decade in the United States.
Methods:
The Global Burden of Disease (2019) offers extensive assessments of the incidence, mortality, and DALY in the United States from 1990 to 2019. The data was gathered using the Global Health Data Exchange query tool. We analyzed the annual percentage change (APC) over this period and compared different age groups to enhance the current trend of incidence, mortality, and DALY in the United States between 2009-2019.
Results:
Our analysis was structured around three distinct age groups-15-49 years, 50-74 years, and 75+ years, with each category further stratified by gender. For the 15-49 years cohort, males consistently exhibited higher average Disability-Adjusted Life Years (DALYs) at 15.60 per 100,000, as compared to their female counterparts, who averaged at 10.05. Intriguingly, the Annual Percentage Change (APC) displayed a downward trajectory for DALYs, Deaths, and Incidence rates over the period under study, with respective APC values of -1.79, -1.81, and -1.95. This trend indicates a consistent improvement in health outcomes for this age group.
On the other hand, the 50-74 years age group revealed a significantly ascending trend in all health measures. Here, females and males recorded average DALYs of 98.13 and 143.33 per 100,000, respectively. The APC values for this group underscored an increasing trajectory-0.72 for both DALYs and Incidence and 0.92 for Deaths-signifying a worsening in health outcomes over the duration of observation.
Lastly, in the oldest age group of 75+ years, the DALYs surged to 235.78 for females and 379.87 for males per 100,000. Although the APC values for this age group were positive, they were relatively lower than those for the 50-74 years group, with APC values of 0.62 for DALYs, 0.44 for Deaths, and 0.39 for Incidence.
Conclusion:
New therapies in MM have decreased the average of DALY in the US over the studied decade. Between the ages 15-49 years, the study's results align with the current data correlating younger age with a better prognosis. However, when divided into age categories, the subgroup from 50-74 years showed a possible rapid deterioration in health outcomes when compared with patients above 75 years old. Additional studies are needed to better understand this underlying pathophysiology to have better results and develop further therapies.
CRM1/XPO1-FOXO1 Pathway Is Associated with Clinical Outcome and Represents a Promising Target in B-Cell Acute Lymphocytic Leukemia
Authors: Deng Shiyu , Ou Jiawang , Zihong Cai , Huang Zicong , Li Jia , Liu Qifa , Zhou Hongsheng 
Published: December 2023

Background:
Currently, a proportion of B-Cell Acute Lymphocytic Leukemia (B-ALL) patients still show no response to existing therapeutic drugs and existing therapeutic drugs cannot further improve the prognosis of refractory and relapsed B-ALL. Thus, the development of a new therapeutic target to battle this deadly disease is imperative. Exportin-1 (XPO1), also known as chromosomal region maintenance 1(CRM1), plays an important role in the progression of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in B-ALL have not been reported.
Methods:
The difference in XPO1 and Foxo1 expression between normal B cells and leukemia cells was using the Human Protein Atlas (HPA) dataset and RT-qPCR results. Correlations between XPO1 expression level and clinical outcome were analyzed using the RNA-seq data of 110 newly diagnosed B−ALL patients in Nanfang Hospital. Cell proliferation assays, apoptosis assays, and cell cycle analysis were performed to analyze the anti-tumor effects of selinexor (KPT-330) in vitro. Bioinformatics analysis, western blot, and RT-qPCR were performed to explore the underlying mechanism.
Results ：
Higher XPO1 levels or Foxo1 levels were associated with poor prognosis in newly diagnosed B-ALL patients. Using bone marrow (BM)， peripheral blood (PB) cells from B-ALL and normal people as well as B-ALL cell lines, we found that XPO1 and Foxo1 expression was significantly increased in B-ALL patients and B-ALL cell lines. And notably, there was a positive correlation between the expression of Foxo1 and XPO1, which was verified by the data in the HPA database, and the results were consistent. Foxo1 is an important transcription factor in B-ALL, mainly localized in the nucleus, and is important for leukemia cell survival. KPT-330 (Selinexor), a selective Inhibitor of XPO1, mechanistically inhibited the expression of Foxo1, a leukemia transcription factor (reduced in both the nuclear and cytoplasmic compartments), and led to a strong repression of Foxo1 target genes associated with cell cycle, DNA replication, and transcriptional regulation. This induced growth inhibition, apoptosis, and cycle arrest in B-ALL cells. Moreover, in combination with Foxo1 Inhibitor (AS1842856), the proliferation inhibition and apoptosis-inducing effects of KPT-330 on B-ALL could be significantly enhanced. Furthermore, the KPT-330 strongly triggered apoptosis in leukemic but with minimal effects on normal cells implying that drugs of this class show promise for the targeted therapy of B-ALL leukemia cells.
Conclusions:
Our findings demonstrate that XPO1 is a promising prognostic indicator and a valid target for antitumor treatment with selective inhibitor KPT-330.
This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).
Cryoprecipitate-Poor Plasma Instead of Fresh Frozen Plasma As Replacement Therapy in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis
Authors: Mafra Marcela P. , Roca Mora Maria Meritxell , Godoi Amanda , Valenzuela Andres 
Published: December 2023

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition characterized by the presence of small-vessel thrombi enriched with platelets, leading to thrombocytopenia, thrombotic microangiopathy (TMA), and on occasion, resulting in end-organ damage. The standard therapeutic plasma exchange (TPE) approach, initiated after suspicion of TTP, is done with fresh frozen plasma (FFP). Yet, the use of cryoprecipitate-poor plasma (CPP) has been suggested as alternative in recent decades given its absence of von Willebrand factor, which would benefit the pathophysiology of TTP. However, its efficacy over FFP remains unclear. Therefore, we aimed to conduct a meta-analysis to compare the safety and efficacy of CPP versus FFP in patients with TTP.
Methods: We systematically searched PubMed, Cochrane Central and Embase for clinical studies published up to June 2023, comparing CPP to FFP as replacement fluids in TPP or TMA patients. Outcomes assessed were overall mortality, relapse rate, response to treatment and number of TPE sessions. We pooled outcomes as odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). We also performed a subgroup analysis with randomized controlled trials (RCTs). Statistical analysis was performed with Review Manager version 5.4.1. Heterogeneity was assessed with I 2 statistics. The protocol was registered in PROSPERO (ID: CRD42023440665).
Results: A total of eight articles met inclusion criteria, of which three were RCTs. The combined dataset involved 290 patients, of which 144 (49.7%) were in CPP group and 146 (50.3%) in the FFP group. CPP significantly reduced overall mortality compared to FFP (OR 0.27; 95% CI 0.13-0.59; p=0.001; I 2=0%; Figure 1A). However, our subgroup analysis of RCTs showed no significant difference in overall mortality between groups (OR 0.49; 95% CI 0.13-1.84; p=0.29; I 2=0%; Figure 1B). Additionally, there were no significant differences between groups regarding relapses (OR 0.81; 95% CI 0.37-1.77; p=0.60; I 2=0%; Figure 1C), response to treatment (OR 2.20; 95% CI 0.69-7.07; p=0.18; I 2=44%; Figure 1D) or number of TPE sessions (MD 1.63; 95% CI -2.83 - 6.08; p=0.47; I 2=55%; Figure 1E).
Conclusion: Our meta-analysis shows that the safety and efficacy of CPP in TTP patients is at least similar to FFP in reducing mortality, relapse rate, and improving response to treatment. The reduced mortality with CPP found in the whole pool of studies, along with the trend towards reduced mortality found in the RCT-only analysis indicates the potential benefit of CPP over FFP. However, larger population-based randomized trials should contribute to narrow confidence intervals and decrease bias of observational studies, providing clearer conclusions for treatment efficacy in the future.
Discovery of a Novel, First-in-Class Bfl-1 BH3 Mimetic with Pro-Apoptotic Activity
Authors: Derks Maarten , Bryan Marian C. , Rockx Cindy , Schults Tamara , Verhulst Tinne , Pietrak Beth , Maehigashi Tatsuya , Robertson James C. , DeMaria Andrew H. , Holt Kimberly , Ji Shaofei , Wong Victoria , Bueters Ruud , Koo Seong Joo , Masure Stefan , Bhogal Balpreet , Kelly Christopher B. , Mitra Kaushik , Luistro Leopoldo , Shaffer Paul L. , Szewczuk Lawrence , Elsayed Yusri , Philippar Ulrike 
Published: December 2023

Background: Intrinsic apoptosis is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members, such as BCL-2, MCL-1 and BFL-1, sequester their pro-apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance leads to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic family members and as such they have become attractive targets for anti-cancer drug development. BFL-1 (‘Bcl-2 related gene expressed in fetal liver’, gene name BCL2A1) is a lesser-known anti-apoptotic family member, physiologically mainly expressed in the hematopoietic system.
BCL2A1 overexpression has been reported in many types of B cell lymphoma. Diffuse Large B Cell Lymphoma (DLBCL) patient sample analysis showed that BCL2A1 expression levels are second only to MCL1 within the anti-apoptotic family. Expression of BFL-1 was shown to be upregulated in MYC+/BCL2+ double hit lymphoma cell lines treated with the BCL-2 inhibitor, Venetoclax, in vivo. Interestingly, BFL-1 positive lymphomas are less sensitive to inhibition of BCL-2 and MCL-1. Hence, targeting BFL-1 is a rational and attractive strategy in DLBCL to improve clinical outcome.
Methods: Using hit identification screens followed by iterative structure-activity relationship (SAR) analyses and structure-based design, compound A, a first-in-class, selective BFL-1 BH3 mimetic, was identified. Compound A was evaluated using biochemical, cellular in vitro and in vivo tumor efficacy models.
Results: Compound A is a highly potent and selective compound in biochemical assays. In BFL-1 sensitive lymphoma cell lines characterized by high BFL-1 protein expression, compound A was shown to displace BAK and BIM from BFL-1, leading to downstream cleavage of caspase 3 and cell death. Interestingly, these cellular models were resistant to Venetoclax. Compound A exhibited tumor growth inhibition in an engineered BFL-1 overexpressing, MCL-1 KO human multiple myeloma xenograft model. However, in the high BFL-1 expressing SU-DHL-2 DLBCL human xenograft model, compound A did not induce significant PD (cleaved caspase 3) and efficacy in vivo.
Conclusion: First-in-class selective BFL-1 BH3 mimetics are shown to specifically inhibit cell growth of lymphoma cell lines in vitro and can induce efficacy in vivo in a BFL-1 overexpressing model. Further studies may be useful to determine whether compound A elicits anti-tumor efficacy in lymphoma alone or in combination with other anti-apoptotic agents.
Evaluation of CD70 Chimeric Antigen Receptor T (CAR-T) Cells As a Potential Treatment for Non-Hodgkin's Lymphoma: A Preclinical Study
Authors: Jiang Pengfei , Xiong Qinghui , Yuan Xiujie , Zhang Haoyu , Shen Qiushuang , Wang Yang , Gong Yiwei 
Published: December 2023

Background ：CD70 is a member of the tumor necrosis factor (TNF) superfamily. While its expression is limited in healthy tissues, CD70 highly constitutive expressed on cell surface of various malignancies. This expression profile make CD70 a promising target for cancer immunotherapy. We described a CD70 CAR-T based on a potent VHH nanobody named 11C9 in treatment of renal cell carcinoma (RCC). Recently, we received approval to initiate a phase I clinical study by Center for Drug Evaluation, National Medical Products Administration (NMPA) in China. Motivated by promising evidence that CD70 aberrantly expressed on Non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphomas, follicular lymphomas, Burkitt and mantle cell lymphomas, we conducted a preclinical evaluation of CD70 CAR-T cells as a potential treatment by preclinical model.
Method: We successfully generated CD70 CAR-T cells based on a VHH nanobody (11C9) and CD19 CAR-T cells based on murine scFv (FMC63) following the exact manufacturing protocols used for phase I and phase II clinical trial products respectively. Then, we evaluated CAR-T cell cytotoxicity, phenotype, proliferation, and cytokine production in vitro. Furthermore, we established NHL tumor cell-xenograft NOG mice models to compare their anti-tumor activity in vivo.
Result: In vitro test demonstrated two types of CAR-T cells have comparable proliferation, and cytokine production. We observed more potency for CD70 CAR-T to kill CD70 and CD19 double positive Raji cells than CD19 CAR-T cells. In vivo test showed that both CD70 CAR-T cells and CD19 CAR-T cells eradiated Raji cells xenografted NOG mice models at high dose. However, after treated at lower dose CD19 CAR-T, tumor relapsed in one week when the same lower dose CD70 CAR-T treated mice keeping tumor free statue.
Conclusion: Our results indicate that CD70 CAR-T cell is potential treatment for NHL. We will conduct an investigation of single and dual CD70 CAR-T on treatment of lymphoma especially for CD19 negative NHL.
Galician Experience with Avatrombopag: Galician Thrombosis and Hemostasis Group
Authors: Calvino-Suarez Michael , Lopez Ansoar Elsa , Lorenzo Vizcaya Alvaro , Guzman Fernandez Maria Rebeca , Dorado Lopez Andrea , Salido Toimil Fatima , Rodriguez Ruiz Matilde , Iglesias Varela Raquel , Vasco Varela Beatriz , Blanquer Blanquer Miguel , Rodriguez Lopez Manuel 
Published: December 2023

Avatrombopag, an orally administered 2nd-generation thrombopoietin receptor agonist (TPO-RA), in Spain is indicated for the treatment of primary chronic (&gt;12 months) immune thrombocytopenia (ITP) in adults with inadecuate response or intolerance to other therapies, and has been the first agonist approved for adults with chronic liver disease (CLD) scheduled for surgery. It presents some advantages in relation to the present TPO-RA that make it a very attractive drug such as oral administration, non-interference of divalent cations, no need to monitor liver function or rapidity of response.
To assess the effectiveness of Avatrombopag in patients with chronic ITP in real life, we carried out a retrospective observational study in which patients with chronic ITP and patients with secondary thrombocytopenia were included. Data are shown as percentage, median, interquartile range (IQR), and mean ± standard deviation (SD), as appropriate.
Twenty-four patients were included (mean age of 60.04 years (SD 20.38), 58.33% female). The median follow-up was 135 days (IQR 96-180). 83.33% of patients had primary ITP and in 37.5% Avatrombopag was used in second-line. The rest of the patients (62.5%) had received at least two therapies previously, a median of 3 (IQR 2-4). 37.5% was in response under other agonist when started Avatrombopag. Twenty-three patients (95.83%) started Avatrombopag at 140 mg/week, one patient at a dose of 280 mg/week. 95.83% of patients reached or maintained response (&gt;30,000 platelets/m3) with a median number of days to reach it of 7 (IQR 6-14). At the last visit, they presented a median platelet response of 102,000/mm3 (IQR 62,000 - 147,000) and marked weekly dose variability. One patient had previously received 12 lines of treatment and only one was primary refractory. Although drug tolerance was excellent, serious adverse effects include one patient with grade 2 medullary fibrosis and one pulmonary thromboembolism .
Although the sample is small and the follow-up short due to the recent approval of the drug in Spain, Avatrombopag offers an effective alternative as a TPO-RA agonist for patients on second-line treatment, as well as for subsequent lines in case of inadecuate response or intolerance to other agonists.
A Deep Learning Framework for Classification of Immature White Blood Cells in Acute Myeloid Leukemia Using Convolutional Autoencoder and Transfer-Learning Ensemble
Authors: Elhassan Tusneem Ahmed M , Mohd Rahim Mohd Shafry , Osman Ahmed Hamza , Chaudhri Naeem A. , Aljurf Mahmoud 
Published: December 2023

Acute myeloid leukemia (AML) is a type of acute leukemia that affects myeloid cells. It is characterized by uncontrolled proliferation of immature WBCs causing an accumulation of immature WBCs in the bone marrow and peripheral circulation. AML is an aggressive cancer that can be life-threatening if not treated promptly, therefore, early detection is crucial. Identification of immature WBCs and their subtypes is the first step towards AML diagnosis. Microscopic blood smear image analysis is commonly used to diagnose AML as it is less expensive non-invasive diagnostic tool compared to bone marrow biopsy and immunophenotype. Nonetheless, classifying immature WBCs presents challenges due to their high similarity and minimal interclass variation, especially for intermediate stages of myelopoiesis which make is susceptible to misclassification. The current diagnostic methods of AML are based on manual identification of immature WBCs using peripheral blood smear. These methos are time-consuming, prone to errors, and subject to inter-observer variation. Therefore, this study aims to develop a computer-aided diagnostic framework to accurately identify immature WBCs and classify them into various subtypes.
The proposed framework consists of two main components: a binary classification system to classify cells into mature versus immature cells and a multiclassification system to further classify immature cells into four subtypes including myeloblast, monoblast, and promyelocytes. The proposed framework was designed to undergo four distinct phases: the first phase involves preprocessing, which includes data augmentation techniques aimed at addressing the imbalance distribution of WBCs. Augmentation encompasses geometric transformation and generation of synthetic images using convolutional Autoencoder (CAE). Feature extraction phase involves using image embedding and transfer-learning. Image embedding representation was obtained using CAE and then utilized by two pre-trained models: VGG19 and Resnet50. Classification phase was carried out using weighted ensemble of the VGG19 and Resnet50 with the optimal weights determined through Grid search. The validation phase evaluated the model performance using overall accuracy, precision, and sensitivity. The area under the ROC curve (AUC) was used to assess model discrimination ability.
The proposed framework demonstrated excellent results, achieving an average accuracy of 99.5%, a sensitivity of 97.97%, and a precision of 94.12%. The model exhibited an excellent discriminatory capability, with an AUC of 99.9%. Furthermore, the proposed framework outperformed previous methods, showcasing improved performance.
Key word:
Acute myeloid leukemia, peripheral blood smear, immature white blood cells, deep learning, feature extraction, computer-aided diagnosis.
Real Word Data on Levels of Emicizumab and Their Correspondence with the Global Hemostatic Capacity and the Spontaneous Joint Bleeding in Patients on Emicizumab Prophylaxis
Authors: López Jaime Francisco José , Marco Rico Ana , Palomo Bravo Ángeles , Fernández-Mosteirín Núria , Nieto María del Mar , Blanquer Blanquer Miguel , Marco Vera Pascual , Fernández-Bello Ihosvany 
Published: December 2023

Introduction: Emicizumab has improved the management of patients with hemophilia A. However, few real-world data are available on drug plasma levels and their correspondence with global hemostatic capacity (GHC) and annualized spontaneous joint bleeding rate (ASJBR).
Aims: Evaluation of the correlation between emicizumab plasma levels, GHC and ASJBR in patients on emicizumab prophylaxis.
Methods: Multicenter, observational and cross-sectional study was performed in 4 Spanish hospitals. Emicizumab plasma levels and thrombin generation capacity (TGT, Genesia ®, Stago ®) of patients on emicizumab prophylaxis were determined in a central laboratory. Kinetics of clot formation was evaluated by rotational thromboelastometry (ROTEM ®, naTEM ® test, Werfen ®) in one center. Time on emicizumab prophylaxis and the number of spontaneous joint bleeds (SJB) was collected retrospectively using the clinical history. Results are expressed as median (25 th-75 th percentiles) or mean ± standard deviation depending on data distribution. A p-value &lt; 0.05 was considered statistically significant.
Results: Twenty-eight patients were included: 18 aged ≥12 years (age= 20.1 [14.7-38.9] years old) (group 1) and 10 patients aged &lt;12 years (age= 6.1 [3.2-8.9] years old) (group 2) (p&lt; 0.001). Globally, emicizumab levels were 46.3 ± 11.9 mcg/mL and similar between both groups: 45.2 ± 13.1 mcg/mL (group 1) and 45.9 ± 7.3 mcg/mL (group 2) (p=0.870) (Figure 1). No correlation was detected between emicizumab levels and TGT or ROTEM ®. Compared with healthy controls, patients presented lower values of thrombin generation: Peak (% compared to controls) = 41.4 (33.3-53.0) % and endogenous thrombin potential (ETP%) = 54.9 (38.9-73.4) %. However, on the contrary, ROTEM ® showed a similar procoagulant profile (example: CT and CT+CFT; p&gt;0.05) or even higher (example: lower CFT values in patients; p= 0.023) compared to healthy subjects (Table 1). Throughout a follow-up period of 57.0 (32.3-102.3) weeks, none of the patients presented SJB (ASJBR =0).
Conclusions: Emicizumab treatment provided excellent protection to patients throughout the study period. The wide interpatient variation on emicizumab plasma levels does not appear to have an impact on the development of SJB. TGT and ROTEM ® showed contradictory results: TGT describes lower thrombin generation capacity in patients compared to healthy controls, while ROTEM ® showed a similar or even higher procoagulant function in patients. Additional studies are required to explain these findings and their clinical significance.