bluuebunny/crossref_metadata_2025_split huggingface dataset:
Venous Thromboembolism in Hematopoietic Stem Cell Transplantation
Authors: Chiu Jodi , Ananthan Brianna , Lawrence Matthew , Aly Mohamed , Srikrishnaraj Dhuvaraha , Weichel Madeleine , Deotare Uday , Xenocostas Anargyros , Lazo-Langner Alejandro 
Published: December 2023

Background:
Venous thromboembolism (VTE) is an underappreciated complication seen amongst allogeneic and autologous hematopoietic stem cell transplant (HSCT) patients and a major cause of morbidity and mortality. Despite these challenges, VTE in HSCT remains understudied, with a paucity of established guidelines on thrombosis surveillance, prevention, and treatment. Balancing risk of bleeding and thrombosis is particularly challenging as HSCT patients are concurrently pancytopenic and coagulopathic. We aimed to describe the incidence, predictors, and adverse events of VTE amongst patients at 90 days post-HSCT.
Methods:
We conducted a retrospective cohort study of adult patients, age &gt;18-years-old, who underwent HSCT for a hematological malignancy between January 1, 2011 and December 31, 2021 at a tertiary care centre in Canada. Patients were followed from transplant until Day 90 post-transplant, or death. Baseline, transplant, laboratory, and cancer characteristics were analyzed.
Results:
Four Hundred and Seventy Six (476) HSCT patients were included (age range 18 - 74), 285 (59.9%) of our patients were male, and 191 (40.1%) were female. Three Hundred and Seventeen (317) (66.6%) patients underwent autologous transplant, and 159 (33.4%) patients underwent allogeneic transplant ( Table 1). Forty Seven (47) patients (9.8%) suffered from VTE within 90 days post-HSCT; 74.5% were catheter related. 9.43% of allogeneic, versus 10.09% autologous patients were diagnosed with VTE (p=0.820). 11.9% of allogeneic, versus 4.1% of autologous patients (p=0.001) suffered from bleed unrelated to anticoagulation. There was significant association of VTE post-HSCT with history of unprovoked DVT (p = 0.026), previous treatment with steroids (p = 0.032), infectious complications (including bacteremia (p = 0.025), and skin and soft tissue infection (p &lt; 0.001)), use of peripherally-inserted central catheters (PICCs (p &lt;0.001), left-sided CVC placement (p = 0.007), second central venous line insertion (due to complications from the first) (p &lt; 0.001), and blocked or malfunctioning central venous catheter (p = 0.003). There was no significant association of VTE post-HSCT with transplant graft (autologous versus allogeneic), underlying hematological malignancy, age, BMI, or sex. Mortality rate at 90 days amongst VTE patients was 14.89%, versus 3.27% in non-VTE patients (p &lt; 0.001) ( Figure 1).
Conclusion:
The majority of VTE post-HSCT were catheter-related and were more frequently associated with use of PICCs. VTE post-HSCT was associated with higher mortality. VTE prophylaxis or active surveillance could be considered in patients with the above-mentioned risk factors balancing the risk of bleeding, particularly in allogeneic stem cell transplant patients, and those who are concurrently thrombocytopenic.
Sickle Cell Disease-Eligibility for Curative Treatment in Indian Tribal Population-Urgent Need to Stop and Think
Authors: Pendharkar Dinesh , Nirmal Garima 
Published: December 2023

Introduction: Sickle cell disease (SCD) is one of the most common hemoglobinopathies, with nearly 40000 children born annually to the tribal population of India. Hematopoietic stem cell transplantation is currently the only curative option available. Patients eligible for transplantation according to the ASH and other guidelines are those with multiple episodes of veno-occlusive crisis, despite disease-modifying treatment, recurrent episodes of acute chest syndrome, osteonecrosis, patients who experienced overt stroke, or abnormal transcranial Doppler ultrasound, requiring frequent admissions to the hospital. Although HSCT is the sole curative treatment, only a fraction of eligible patients receive it in resource-limited settings. To understand the requirements for bone marrow transplantation, we analyzed the number of eligible patients using clinical data.
Methods: A cross-sectional prospective research design was used that involved clinical examination and personal interviews with patients and caregivers, with the completion of questionnaires on clinical characteristics and treatment options. Two hundred fifty individuals with S ,invited to outreach clinics, were analyzed
Results: Among the 251 surveyed children, 122 (48.6%) were male and 129(51.4%) were female. Among them, 160 (63.7%) children had recurrent episodes of VOC in the past 1 year, despite 116 (72.5%) receiving regular hydroxyurea. Among them, 98 (62%) required multiple admissions for VOC. Episodes of fever were observed in 51 % of the patients. The requirement for admission to a healthcare facility was recorded in 57 % of the patients. Nearly 13 % of the patients required more than three transfusions in the preceding year.
Conclusions: There is an urgent need to organize SCD care pathways, as the whooping number of patients (64%) falls within the criteria of eligibility for HSCT, a curative option. The transplant community, along with healthcare providers and non-governmental organizations, should decide on a strategy to offer this important modality of curable alternatives.
Cinobufagin Induces Apoptosis of DLBCL Cells By Targeting the Inhibition of G6PD Activity
Authors: He Sanxiu , Zhai Liuyue , Zhang Xiaomei , Fu Huihui , Jun Li , Liu Yao 
Published: December 2023

Background:Globally, there are 150,000 new cases of diffuse large B-cell lymphoma (DLBCL) each year, accounting for approximately 30% of all non-Hodgkin lymphoma cases. Although most patients can be cured with R-CHOP immunochemotherapy, 30-40% of patients progress or relapse after treatment. Therefore, there is an urgent need to find new treatments to improve the survival rate of this group of patients. Natural small molecule drugs have unique advantages as anticancer agents due to their low toxicity and multiple targets. This project aims to explore potentially effective natural compounds as new therapeutic strategies for DLBCL.
Methods:Search for suitable natural compounds through GEO database, CMAP server and bioinformatics analysis. The effects of natural compounds on the biological function of DLBCL cells were studied by IC50 assay, apoptosis assay, cell cycle assay and subcutaneous transplanted tumor model. RNA sequencing, metabolomics detection, SEA server and 3D molecular simulation docking analysis were used to explore the drug target. The drug mechanism was verified by G6PD activity assay, EdU incorporation assay, NADPH assay and ROS assay.
Results:We used GEO and CMAP databases to identify 20 natural compounds that target DLBCL prognostic genes. Cinobufagin, a natural bufodienol isolated from toad venom, became the main object of this study because of its low IC50 value. Flow cytometry analysis showed that cinobufagin can effectively induce G2 arrest and apoptosis of DLBCL cells. In addition, cinobufagin significantly inhibited the growth of tumor tissue in a mouse model of heterotopic subcutaneous tumor transplantation. The results of transcriptome sequencing suggested that cinobufagin treatment inhibited multiple metabolism-related pathways. Metabolomic analysis showed a decrease in nucleoside metabolite content and inhibition of niacinamide synthesis. Through SEA server and 3D molecular docking simulation analysis, it was found that glucose-6-phosphate dehydrogenase (G6PD) may be a potential target of cinobufagin. G6PD activity assay showed that cinobufagin could inhibit the catalytic ability of G6PD. EdU incorporation experiments showed that cinobufagin inhibited DNA synthesis in DLBCL cells. In addition, cinobufagin also promoted the up-regulation of NADP+/NADPH ratio and the increase of ROS. The addition of ROS scavengers and nucleotides partially reversed the apoptosis-inducing ability of cinobufagin.
Conclusion:G6PD is a target of cinobufagin. By inhibiting the enzyme activity of G6PD, cinobufagin can inhibit DNA synthesis and the production of reducing NADPH, thereby inducing apoptosis of DLBCL cells. This suggests that Cinobufagin has potential application as a new drug for the treatment of DLBCL.
Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results
Authors: Cao Xinxin , Jin Jie , Cheng Cheng Fu , Yi Shuhua , Zhao Weili , Sun Zimin , Yang Wei , Li Dengju , CUI Guohui , Hu Jianda , Liu Ting , Song Yongping , Xu Bing , Zhu Zunmin , Xu Wei , Zhang Mingzhi , Li Sichen , Wang Weige , Zhao Renbin , Zhou Daobin 
Published: December 2023

Background
Orelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor, approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). The previous publication of this study reported that orelabrutinib is highly active in R/R Waldenström's macroglobulinemia (WM), with a well-tolerated safety profile (EClinicalMedicine. 2022;52:101682). We present here the long-term results of this study.
Methods
This is a prospective, multicenter study of orelabrutinib in patients with WM who had at least one prior line of treatment (ClinicalTrials NO. : NCT04440059). Orelabrutinib was administered orally at a daily dose of 150 mg until disease progression or unacceptable toxicity. Genotyping using MYD88 L265P and CRCR4 S338X mutation were performed with qPCR assay. The primary endpoint was major response rate (MRR) assessed by the Independent Review Committee (IRC) according to IWWM-6 (Br J Haematol. 2013; 160: 171-176).
Results
Between August 2019 and December 2020, 66 R/R WM patients were assessed for eligibility. Forty-seven eligible patients were evaluated for efficacy at a median follow-up of 31.9 months (interquartile range: 28.0，36.5). As assessed by IRC, the MRR was 80.9%, and the overall response rate was 91.5%. The PFS rates was estimated as 72.1% at 36 months and the median PFS has not been reached. There is no significant difference in PFS across various MYD88 L265P and CRCR4 S338X genotype (P=0.69; Figure 1). The 30-months PFS rate in MYD88 L265P/CXCR4 NEG, MYD88 L265P/CXCR4 S338X, and MYD88 NEG/CXCR4 NEG were 86.2%, 75% and 75%, respectively. Most adverse events were Grades 1 or 2 (63.8%). The common grade 3 or higher adverse events occurred were neutropenia (10.6%), thrombocytopenia (8.5%), and pneumonia (6.4%). Treatment related serious adverse events were reported in 8.5% patients. Adverse events leading to discontinuation occurred in 4 patients (8.5%). One treatment-related death was reported (hepatitis B reactivation).
Conclusions
Results with longer follow-up continue to show that orelabrutinib has high, deep and durable response in patients with R/R WM. Data support the safety of long-term orelabrutinib treatment in R/R WM, with no new safety signals identified.
Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia
Authors: Zhang Wei , Chang Li-xian , Zhao Bei-bei , Shan Dan-dan , Tang Bo-hao , Yang Fan , Zhou Yue , Hao Guo-xiang , Zheng Yi , Zhang Ya-hui , Van Den Anker John , Zhu Xiaofan , Zhang Li , Zhao Wei 
Published: December 2023

OBJECTIVES: Eltrombopag (EPAG) was initially approved by the U.S. Food and Drug Administration (FDA) as first-line treatment, combined with standard immunosuppressive therapy, for patients older than two years old with severe aplastic anemia (SAA). However, the use of EPAG in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA) has been limited. Therefore, we decided to investigate the efficacy, safety, and pharmacokinetics of EPAG in children with NSAA, SAA, and very severe AA (VSAA).
METHODS: A prospective, open-label, observational study was conducted at the Institute of Hematology and Blood Diseases Hospital, Tianjin, China. The efficacy including complete response (CR), partial response (PR), and no response (NR), as well as safety was assessed every three months after the start of treatment. A non-linear mixed-effects population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of EPAG. We explored the exposure-response relationship of EPAG in patients with different types of AA. This study was registered at ClinicalTrials.gov (NCT03844360).
RESULTS: A total of 23 AA children with an average age of 7.9 (range of 3.0 - 14.0) years were enrolled in this study for efficacy, safety, and PPK analysis. Fifteen patients had a treatment response (5 had CR and 10 had PR). The response rate was 12.5% after 3 months, 50.0% after 6 months, and 100% after 12 months of treatment for patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were collected and analyzed to build the PPK model using allometric scaling with fixed exponents. Body weight significantly affected EPAG's apparent clearance and volume of distribution. The mean (range) of the area under the concentration-time curve from time zero to infinity (AUC ∞) was 316 (131 - 809) μg×h /mL. Twenty patients with genotypes were included in the genotype analysis. The apparent clearance of EPAG was significantly higher in allele-T carriers of adenosine triphosphate-binding cassette G2 (ABCG2) (rs2231142, G&gt;T) ( p=0.02). In patients with clinical response, children with NSAA exhibited lower AUC ∞, higher apparent clearance, and higher weight-adjusted apparent clearance than those with SAA or VSAA, although the differences were not significant.
CONCLUSIONS: This study enriched the efficacy and safety of EPAG in children with different types of AA. Body weight and ABCG2 genotype significantly influence EPAG clearance. The results may support further individualized treatment of EPAG in children with AA.
Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients
Authors: Klamroth Robert , Sidonio Robert F , Dargaud Yesim , Jiménez-Yuste Víctor , Ljung Rolf , Young Guy , Chowdary Pratima 
Published: December 2023

Background: Arthropathy caused by repeated joint bleeding is a major complication in patients with severe hemophilia A and is associated with long-term morbidity. Factor VIII (FVIII) prophylaxis has proven benefits for prevention of bleeding, including joint bleeding, in these patients. Alongside preservation of joint health, FVIII prophylaxis may preserve bone mineral density (BMD) and reduce the risk of fractures. Emicizumab is a bi-specific monoclonal antibody with no structural homology to FVIII and is approved for prophylaxis in hemophilia A patients. However, data on the long-term impact of emicizumab on joint and bone health are limited.
Aims: To assess the impact of long-term prophylaxis with simoctocog alfa (Nuwiq ®; a fourth generation recombinant FVIII) versus emicizumab on joint and bone health in people with hemophilia A.
Methods: PROVE is a multinational, prospective, two-arm, low-interventional study that will collect clinical data on joint and bone health in patients receiving prophylaxis with simoctocog alfa or emicizumab in routine clinical practice. Approximately 200 male participants (100 in each treatment arm) at least 12 years of age with severe hemophilia A (FVIII activity [FVIII:C] &lt;1%) will be enrolled. Written, informed consent will be obtained from each patient or their legal representative.
The primary objective of the study is to evaluate the long-term effect of simoctocog alfa versus emicizumab on joint health as measured by magnetic resonance imaging (MRI). The primary endpoint will be a between-group comparison of the change in total score on the extended MRI (eMRI) scale (Table 1). Secondary and exploratory endpoints include the impact of simoctocog alfa vs emicizumab on bleeding rates, joint and bone health, physical activity, quality of life and safety (Table 1). Study treatments will be defined by the treating physician prior to inclusion of a patient into the study. Patients will not be randomized to the treatment groups but will continue with their current prophylactic regimen (simoctocog alfa or emicizumab). Patients will be provided with an electronic diary (eDiary) in which to record study related data, including treatment-related data, bleeding event details, fracture details, concomitant medications and adverse drug reactions. Each patient will be followed for up to 4 years. An interim analysis is planned after 2 years.
Conclusion: ThePROVE study aims to generate real-world data on the long-term effects of prophylaxis with simoctocog alfa or emicizumab on joint and bone health in hemophilia A.
Non-Enzymatic Role of Platelet 12-LOX in Platelet Activation
Authors: Sharma Durga Shankar Shankar , Botta Eliana , Tsai Wan-Chen , Holman Theodore , Holinstat Michael 
Published: December 2023

Background 12-lipoxygenase (12-LOX) plays an essential role in regulation of vascular disease and human platelet function through oxylipin generation such as 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE) and 12-hydroxyeicosatetraenoic acid (12-HETE). Previous literature has demonstrated that 12-LOX enzymatic function such as oxylipin generation is important for collagen- or thrombin-mediated signaling events. However, the addition of 12(S)-HETE does not completely restore the inhibitory effect of pharmacologically or genetically inhibiting 12-LOX on platelet activation, indicating that 12-LOX may have a non-enzymatic function in platelets. Therefore, we tested the non-enzymatic role of 12-LOX in platelet activation.
Method 12 LOX was co-immunoprecipitated (co-IP) from washed human platelets following FcγRIIa or thrombin stimulation. The bound proteins were eluted by laemmli buffer and the elutes were analyzed on SDS-PAGE. Proteins co-IP with 12-LOX at various times were identified by mass spectrometry and confirmed by western blot analysis.
Result Silver-stained gel of 12-LOX co-IP indicated the presence of several protein bands in complex association with 12-LOX at different time points. These bands were analyzed by mass spectroscopy and several proteins observed in complex with 12-LOX were identified including integrin β3, Talin-1, Myh9, Nexilin, Gelsolin, Actin, cytoplasmic 2, and Actin related protein 2/3 (ARP 2/3) . To confirm the mass spectroscopy identified protein, these proteins were immunoblotted following co-IP of 12-LOX. to confirm their association with 12-LOX prior to and following platelet activation. These interactions were further confirmed with a reverse co-IP. Finally, to determine if the association pattern of these proteins with 12-LOX is disrupted in the presence of a 12-LOX inhibitor already shown to limit platelet activation and which is currently in clinical trials for treatment of HIT (ML355/VLX-1005), we were able to demonstrate that the inhibitor appears to lock the protein complex into place.
Conclusion Our study identified several proteins that are present in 12-LOX complex such as integrin β3, talin-1, Myh9 and ARP 2/3. 12-LOX interacts with Integrin β3, Talin-1 and cytoskeletal proteins. Furthermore, the dynamic movement of the proteins in this complex into and out of association with 12-LOX is essential for normal platelet activation suggesting 12-LOX plays an important non-enzymatic role in regulation of agonist-mediated platelet activation.
Analysis of Allergic Transfusion Reactions at a Children's Tertiary Care Center
Authors: Katato Ghadir Khalil , Ozgonenel Bulent 
Published: December 2023

Background: Transfusion reaction adverse events are a relatively rare occurrence in the United States. This is due to specific blood safety measures such as appropriate collection, preparation, testing, storage, and distribution of blood components as well as appropriate monitoring of patients receiving these transfusions. Several years of data have been collected by our institution's blood bank. Through our analysis, we have been able to describe the rate of transfusion- associated adverse events in pediatric patients at Children's Hospital of Michigan from 2018-2022.
Objectives: The aim of this retrospective chart review was to assess the rate of allergic blood transfusion complications and reactions among pediatric patients at Children's Hospital of Michigan in Detroit, Michigan.
Materials and Methods: An institution-based retrospective chart review was conducted for a total of 43,210 transfusions over a span of five years from 2018-2022.
Results: There were a total of 43,210 transfusions. A total of 26,669 of these products were red blood cell (RBC) transfusions, 10,447 were platelets, 4,392 were plasma, and 1,702 were cryoprecipitate (combined plasma and cryoprecipitate was 6,094). A reported reaction was encountered in 176 of the 43,210 transfusions. These reported reactions were part of the patients' underlying diseases. A true acute transfusion reaction (ATR) was encountered in 116 of the 43,210 transfusions. Of the 116 transfusions, 66 (56.9%) were classified as allergic reactions. About 61% of those reactions were skin manifestations (urticaria, itching), 9% were respiratory symptoms (dyspnea, tachypnea), and the remaining 30% were both skin and respiratory symptoms.
Of the total amount of RBC transfusions, 35 (0.131%) resulted in an allergic reaction. Similarly, 19 (0.182%) platelet and 12 (0.197%) plasma transfusions resulted in ATRs. ATRs were most associated with plasma, followed by platelets and RBC transfusions. Combining all transfusions received, these represented a total of 66 (0.153%) allergic transfusion reactions. These results are demonstrated in Figure 1.
Conclusion: ATRs were observed in 0.268% of total transfusions (allergic reactions (0.153%) and other reactions (0.115%)) that occurred over the course of five years at our institution. This is about 1 in 655 blood components transfused that was associated with an allergic reaction (more commonly with plasma &gt; platelets &gt; packed RBCs). The rate of allergic reactions is less than what was reported by National Blood Collection and Utilization Survey 2017 (0.282%). This rate is also less than what is reported for children (0.53%) and adults (0.26%) in a meta-analysis (Wang Y, Sun W, Wang X, et al. Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis. Pediatr Blood Cancer. 2022;69(9):e29842.). These lower rates could be secondary to changes in blood processing and under-reporting.