bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Genetic Variations on Thrombotic Risk in Saudis with Sickle Cell Disease
Authors: Algahtani Farjah , Alshabeeb Mohammad , Alzahrani Mohsen , Alwadaani Deemah , Alajmi Hala , Abohelaika Salah , Alsaeed Hussain , Rashid Mamoon , Alsomaie Barrak , Alzayed Abdullah , Daly Ann 
Published: December 2023

Background
Sickle cell disease (SCD) is a Mendelian disease characterised by multigenic phenotypes. Previous reports indicated a higher rate of venous thromboembolism (VTE) in SCD patients. A number of candidate polymorphisms in certain genes (e.g. FVL, PRT, and MTHFR) were previously reported as risk factors for VTE in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlay VTE in SCD patients.
Methodology
A genome-wide association study involving Saudi SCD adult patients with a history of VTE (n=65) and control patients without VTE history (n=285) was performed. Genotyping used the 10x Affymetrix Axiom array which includes 683,030 markers.
Results
No associations were identified between the targeted single nucleotide polymorphisms (SNPs) [FVL (rs6025), PRT (rs1799963), and MTHFR (rs1801133)] and VTE episodes in SCD patients. In contrast, GWAS analysis showed two genome-wide significant signals (P&lt;5×10 -8) on chromosome (Chr) 11. These SNPs, rs35390334 and rs331532, are in strong linkage equilibrium (LD, r 2=0.97). A total of 35 other markers had an association threshold of P&lt;5×10 -6. Four of these variants are located in olfactory receptor genes [OR51B5 (rs147062602), OR51V1 (rs7933549), OR51A1P (rs80034548), and OR52A5 (rs2472530)].
Conclusion
No association between FVL, PRT, and MTHFR genes and VTE episodes was seen in Saudis with SCD. In contrast, two markers (rs35390334 and rs331532) showed significant genome-wide associations and less significant associations (P&lt;5×10 -6) were identified for 35 other variants (24 of them are located on Chr 11). Further replication of these findings is needed.
Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets
Authors: Larsen Hannah , Byrne Daire , Ozpolat Hasan Tahsin , Chauhan Aastha , Bailey Shawn , Rhoads Nicole , Reed Franklin , Stolla Massiel Chavez , Adili Raymond , Holinstat Michael , Fu Xiaoyun , Stolla Moritz 
Published: December 2023

Objective Platelets for transfusion are stored for 5-7 days. During storage, platelets undergo numerous detrimental functional changes. Previous studies have shown that HETE levels in the storage bag negatively correlate with platelet performance in vivo suggesting that the dysregulation of bioactive lipid mediators may contribute to the storage lesion. In the current study, we sought to understand how genetic deletion and pharmacologic inhibition of 12-lipoxygenase (12-LOX) affects platelets during storage and after transfusion.
Approach and Results Platelets from12-LOX+/+ (wild-type [WT]) and 12-LOX-/- mice were stored for 24 and 48 hours and profiled using LC-MS/MS-MRM. Polyunsaturated fatty acids increased significantly in stored platelets from 12-LOX-/- mice, while oxylipin concentrations were significantly higher in WT platelets. Baseline αIIbβ 3 integrin activation was significantly lower before and after 24 hours of storage in 12-LOX-/- platelets than in WT platelets. Surprisingly, after transfusion to thrombocytopenic mice, we observed significantly more baseline αIIbβ3 integrin activation in 12-LOX-/- platelets than in WT platelets. Stored platelets from 12-LOX-/- mice occluded vessels significantly faster than stored WT platelets in thrombocytopenic recipients challenged with a FeCl 3-induced carotid artery injury. In hemostasis models, significantly more stored 12-LOX-/- than WT platelets accumulated at the site of venous injury leading to reduced blood loss. Inhibition of cyclooxygenase-1 (COX-1) with acetylsalicylic acid abrogated both increased integrin activation and thromboxane generation in stored 12-LOX-/- platelets, highlighting a critical role of this pathway for improved post-transfusion function.
Consistent with our mouse studies, human platelets stored with the 12-LOX inhibitor, VLX-1005, showed increased integrin activation compared to vehicle-treated platelets upon transfusion in NOD/SCID mice.
Conclusion Deleting 12-LOX improves the post-transfusion function of stored murine and human platelets by increasing thromboxane generation through a COX-1-dependent mechanism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans.
Bleeding and Thrombosis in Patients with Cancer and Acute Venous Thromboembolism Requiring Urgent Procedures
Authors: Owusu Tony , Derkach Andriy , Burge Miranda , Nemirovsky David , Zwicker Jeffrey I. 
Published: December 2023

BACKGROUND
There are limited data of outcomes in patients who require anticoagulation interruption for a surgical procedure shortly after an acute VTE, especially in patients with cancer who are at higher risk for both hemorrhage and recurrent thrombosis. Our goal was to assess the incidence of recurrent thrombosis or major hemorrhage at 60-days following an urgent surgical procedure in patients with acute VTE (within one month prior to surgery).
METHODS
We performed a retrospective cohort study of patients with cancer at Memorial Sloan Kettering Cancer Center (from January 1 st 2021 to December 31 st 2022). Patients were eligible for inclusion if they were diagnosed with a new acute deep vein thrombosis or pulmonary embolism and underwent surgical procedure within 30-days following the acute VTE diagnosis. Recurrent VTE was defined as symptomatic new deep-vein thrombosis or pulmonary embolism, incidental new deep-vein thrombosis or pulmonary embolism involving segmental or more proximal pulmonary arteries, or fatal pulmonary embolism or unexplained death for which pulmonary embolism could not be ruled out as the cause. Major hemorrhage was characterized according to ISTH definition. Competing risk framework was used to estimate cumulative incidences of major hemorrhage, VTE and death at 30 and 60-days.
RESULTS
A total of 90 patients were included in this analysis. The median age was 73 years and 62% were female (Table 1). Surgical procedures were classified by their risk of bleeding with 64 patients undergoing lower bleeding risk procedures and 26 high-risk procedures (Table 1). There were 10 recurrent or new VTE within 60-days of surgery (60-day cumulative incidence of 8.9%, 95% CI 4.1-16%). The recurrent sites were deep venous (N=7) and new PE (N=3). There were 12 major hemorrhagic events within 60 days (cumulative incidence of 12%, 95% CI 6.5-20%). The most common sites of hemorrhage were the lower gastrointestinal tract and genitourinary system. The competing risk framework is shown graphically in Figure 1. Among patients who received IVC filters the incidence of recurrent VTE was 1.1% and major hemorrhage was 2.2%. The 60-day cumulative incidence of death following surgical procedure was 19% (95% 12-28%). There were no fatal VTE and 3 fatal hemorrhagic events.
CONCLUSION
Among patients with cancer undergoing surgical procedures within 30-days of an acute VTE, the rates of recurrent VTE and major hemorrhage are substantively higher than reported in non-surgical acute VTE cohorts. Placement of temporary IVC filters may improve short-term bleeding and thrombotic outcomes.
Association of Hypomethylating Agents + Venetoclax in the Real-Life Treatment of Myeloproliferative Neoplasms in Blastic Phase
Authors: Latagliata Roberto , Cristiano Gianluca , Lame Dorela , Strazimiri Alda , Cavalca Fabrizio , Rizzo Lorenzo , De Luca Giulia , Zoletto Simone , Federico Vincenzo , Cattaneo Daniele , Biagi Annalisa , Crugnola Monica , Niscola Pasquale , Palmieri Raffaele , Piccioni Anna Lina , Mulas Olga , Esposito Vangone Beatrice , Santopietro Michelina , Carmosino Ida , Iurlo Alessandra , Di Rienzo Nicola , Binotto Gianni , Salutari Prassede , Riva Marta , Bonifacio Massimiliano , Elli Elena Maria , Curti Antonio , Poloni Antonella 
Published: December 2023

Background Association of hypomethylating agents (HMA) and venetoclax (VEN) is widely used in elderly patients (pts) with de novo Acute Myeloid Leukemia not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available in pts with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP). In this setting, the survival is dismal and at present no therapy seems to have a role.
Methods Data of 54 pts with MPN-BP treated frontline with HMA+VEN in 19 hematologic Centers in Italy outside clinical trials from 11/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed.
Results: Baseline features at evolution and starting treatment are reported in the Table. Median interval from initial MPN diagnosis to evolution was 38.4 months [interquartile range (IQR) 15.4-124.5]. Pts were treated for a median of 3 courses (IQR 2-7): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 40 pts (74.1%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN &lt; 0.5 x 10 9/l) was reported in 37 pts (68.5%). Thirty pts (55.5%) had at least one infective episode during the treatment: pulmonary infections were reported in 13 pts (24.0%). Response to treatment is shown in the Table: ORR was 62.7%, with a median response duration of 9.4 months (95%CI 5.8-12.9). After a median follow-up of 6.7 months (IQR 3.2-12.1), 35 pts (64.8%) died, 2 (3.7%) were lost to follow-up and 17 (31.5%) were alive. Median OS of the whole cohort was 10.6 months (95%CI 5.8-15.3), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [11.6 (95%CI 9.4-13.7) versus 5.4 (95%CI 2.1-8.6) months, respectively (p=0.002)] (Figure).
Conclusions: Our real-life data confirm that HMA+ VEN combination could have a role in MPN-BP, with ORR &gt; 50% in pts unfit for intensive approaches: however, this treatment is affected by severe hematologic and infective toxicities and the response duration is short, with a persistently poor median OS. Larger cohorts of pts and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while addition of other targeted therapies should be explored.
First Real-World Experience Administering Etranacogene Dezaparvovec Gene Therapy for People with Hemophilia B
Authors: Ryan Matthew L. , Miller Andrea , O'Hearn Patrick , Desai Vidhi Parikh 
Published: December 2023

Research in gene therapy for hemophilia B has been ongoing for decades. Etranacogene dezaparvovec-drlb (CSL Behring) is the first gene therapy for hemophilia B to be approved by the United States Food and Drug Administration (2022) and the European Medicines Agency (EMA) (2023). The gene therapy treatment journey is a multistep process and requires coordination between multiple stakeholders within a hemophilia treatment center (HTC). The first 2 patients to receive etranacogene dezaparvovec-drlb since approval were successfully infused at the Hemophilia Outreach Center in Green Bay, Wisconsin. Here we describe the process by which the Hemophilia Outreach Center prepared their center and patients for the administration of etranacogene dezaparvovec-drlb.
Early education, both for HTC stakeholders and patients, was critical in addressing key steps in the treatment journey, including patient eligibility, preparation, administration, and post administration monitoring and management. The education was iterative, involved multiple stakeholders (physician, pharmacist, nurse, social worker, and patient) and required an open channel of communication among the HTC stakeholders, the patients, and manufacturer when appropriate. Although no certification process was required, the manufacturer provided education to the HTC stakeholders in the format of ongoing trainings and a detailed handbook describing the gene therapy process as it relates to etranacogene dezaparvovec-drlb. This education provided a foundation for the HTC stakeholders to develop their own center-specific protocols, checklists, and worksheets. These protocols provided clear guidance on how to manage every step of the process in addition to providing a contingency plan for different scenarios (e.g., infusion reactions and transaminitis), ensuring the center's preparedness for administration.
By implementing early and iterative education and developing center-specific protocols, the Hemophilia Outreach Center was able to successfully administer etranacogene dezaparvovec-drlb. These elements are crucial to ensure smooth execution and optimal patient outcomes.
NR2F1 : A Novel Candidate for Gamma Globin Activation
Authors: Wu Ruiqiong , Yi Siqi , Li Yichao , Shrestha Dewan , Zheng Minzhang , Zhang Jingjing , Cheng Yong 
Published: December 2023

The reactivation of human gamma globin holds tremendous promise as a potential treatment for hemoglobinopathies, including sickle cell disease and beta-thalassemia. Despite identifying various repressors of fetal globin genes in adult erythroid cells over the past decade, evidence concerning stage-specific factors that activate human fetal globin prior to the switch to adult beta-globin remains inadequately understood.
In our study, we constructed an erythroid-specific gene regulatory network (GCN) by integrating multiple RNA-seq datasets from erythroid cells at different stages of differentiation and development. Our analysis unveiled both known HbF activators, like HIC2, and novel candidates. Among the novel contenders, NR2F1, a member of the steroid/thyroid hormone receptor superfamily, emerged as a prominent candidate. To validate our predictions, we overexpressed NR2F1 in Hudep2 cells and observed more than a four-fold increase (28% vs. 6%) in the proportion of F cells and a three-fold rise in HbF levels as measured by HPLC. In addition, the overexpression of NR2F1 did not appear to impact beta-globin expression or cell differentiation. Intriguingly, we observed a significant reduction in the protein level of BCL11A, a master regulator of HbF, despite no major change in the total RNA level of BCL11A. This observation suggests that NR2F1 plays a role in the post-transcriptional modification of BCL11A. Additionally, NR2F1 overexpression led to an upregulation of Lin28B expression in Hudep2 cells. Lin28B is known to directly bind BCL11A mRNA and prevent its effective translation without disturbing BCL11A transcription. Consequently, the observed upregulation of Lin28B in NR2F1-overexpressing cells implies a potential NR2F1-Lin28B-BCL11A axis involved in controlling human hemoglobin switching.
In conclusion, our findings propose NR2F1 as a novel activator of gamma globin, representing an attractive target for gamma globin reactivation. Additional investigation is required to explore the molecular mechanisms through which NR2F1 regulates gamma globin expression and its role in the NR2F1-Lin28B-BCL11A axis.
Blood Collection Workflow for Interrogation of Translational Samples with Single Cell Technologies
Authors: Walter Dagmar , Abousoud Jawad , Drennon Tingsheng , Kunihiro Connor , Martin Kelly , Li Yina , Raman Nandhini , Rodriguez Veronica , Herschleb Jill Lynden 
Published: December 2023

Blood is a valuable and easily accessible sample type for clinical researchers that provides a snapshot of the organ systems at the time of sample collection. Readouts obtained from blood help inform clinical treatments, investigate disease mechanisms, evaluate drug response, and monitor outcomes. However, the impact of existing blood collection workflows on data output from new and high resolution technologies, like single cell RNA sequencing (scRNA-seq) remains a challenge. Recent scRNA-seq studies have shown that changes in gene expression can occur in blood cells in as little as a few hours post collection1. While bulk measurements rely on sample fixation to preserve the sample during transport, this approach does not preserve intact cells and hence, is not compatible with single cell technologies. With the recent availability of fixation compatible scRNA-seq assays comes the need to preserve blood while retaining single cell information. In this study, we evaluated various PBMC isolation and blood preservation methods which preserve single cell information while easing sample logistical constraints.
Our initial experiments compared various PBMC isolation methods. scRNA seq analysis of these samples demonstrated that all isolation methods captured single cell gene expression with some variability in cell types along with user-variability. Changes in cell type proportions were observed in as little as 4 hrs post blood draw, emphasizing the need for an effective blood preservation method to retain single cells during transport and blood cell isolation.
Next, we compared different methods of blood preservation including cryopreservation and fixation. Healthy and diseased whole blood samples were collected, preserved, stored followed by isolation of blood samples at different time points. scRNA-seq analysis of the samples demonstrated that blood can be preserved, transported, and stored (weeks to months) before blood cell isolation. Blood cells isolated from these cells can then be stored long term for scRNA-seq analysis. This blood collection and preparation workflow also eases blood transportation logistical constraints, allowing for batch shipping of samples from distributed collection sites. Coupled with automatable cell isolation methods and multiplexing single cell sequencing solutions, these workflows can be adapted for large scale translational research studies.
References: Massoni-Badosa, R., Iacono, G., Moutinho, C. et al. Sampling time-dependent artifacts in single-cell genomics studies. Genome Biol 21, 112 (2020).
Keywords: single cell RNA-seq, blood preservation
Efficacy of Low Dose Vs Standard Dose of Thalidomide in Patients with Transfusion-Dependent Thalassemia (TDT): A Non-Inferiority Trial
Authors: Kakkar Shruti , Sharma Ratna , Mahajan Amita , Radhakrishnan Nita , Dewan Priyanka , Manglani Mamta , Pandey Amit , Goel Manish , Parakh Nupur , Singh Varinder , Arora J S , Chandra Jagdish 
Published: December 2023

Background
Thalidomide has been demonstrated to induce global gene expression hereby increasing the proliferation of erythroid cells. Recent studies have revealed encouraging data regarding the efficacy and safety of thalidomide in both transfusion dependent (TDT) and non-transfusion dependent (NTDT) thalassemia. However, the optimal dose of thalidomide remains unclear. The study was designed to compare the efficacy and safety of thalidomide at low-dose (1 mg/kg/d) vs standard-dose (2 mg/kg/d).
Methods
Patients with TDT &gt; 12 years of age with no recent (previous 6 months) intake of Hb enhancers were enrolled in a non-inferiority trial across 4 sites in India. Patients with hypersplenism, prior history of thromboembolism, HIV, active hepatitis B/C infection, or any other known systemic illness like neurological, renal, significant hepatopathy, and sexually-active females unwilling to use contraceptives/undergo medical termination of pregnancy in case of accidental pregnancy while on the drug were excluded. Patients were randomised to receive low-dose or standard-dose thalidomide for 6 months. Pre-transfusion Hb, transfusion frequency and volumes, and adverse effects were recorded at each visit. Response was graded based on reduction in transfusion requirement at 24 weeks: Good (&gt; 50 %), moderate (25-50 %), or minimal (&lt;25%).
Results:
A total of 188 patients with mean age of 18.1 ± 5.2 years and M:F ratio of 2.1:1 were enrolled. 85.6% (80 in low-dose and 81 in standard-dose) participants completed the study period. 14.4% discontinued thalidomide due to various reasons. The mean Hb and baseline transfusion requirement were 8.6 ± 0.98 g/dl and 35.91 ml/kg in the preceding 12 weeks. The overall response rate was 55.9%. There was no statistically significant difference in the response rates in 2 groups (63% in low-dose vs 48% in standard-dose) (p:0.135). Good, moderate, and minimal responses were seen in 19.3%, 36.6 %, and 44.1% of the participants respectively. Response rate was not affected by age, sex, transfusion requirement or serum ferritin at baseline. The commonest adverse events were somnolence (n=40), constipation (n=29), weight gain (n=25), reversible cytopenia's (n=22), and peripheral neuropathy (n=14). 3.7% participants experienced Grade 2/3 events. There were no grade 4 events.
Conclusions:
The low-dose thalidomide was as efficacious as the standard dose in reducing transfusion requirements. Thalidomide is well tolerated and can be considered as an adjunct to optimal transfusion-chelation regimen under close monitoring in a resource constrained setting.
Daratumumab Combinations in US Veterans: Patient Characteristics and Outcomes
Authors: Prasad Sonika , Yin Ming , Lynch Julie A , Madison Cecelia J , Friedman Daphne R , Schoen Martin William 
Published: December 2023

Background: Daratumumab is an anti-CD38 antibody with efficacy both in relapsed and newly diagnosed multiple myeloma (NDMM).Clinical trials evaluating daratumumab have demonstrated improved outcomes when combined with lenalidomide (DRd) or bortezomib (DVd) and with dexamethasone, as well as using all four drugs (D-VRd). We evaluated characteristics and outcomes of veterans treated with daratumumab combination in NDMM.
Methods: This retrospective, cross-sectional study analyzed electronic medical record data from the Veterans Affairs (VA) Corporate Data Warehouse (CDW). We identified veterans by evidence of daratumumab administration in prescription records in combination with a second agent within 30 days and who did not receive any anti-myeloma agents prior to 30 days. Age, race, Quan's Charlson Comorbidity Index (CCI), the time to next treatment (TTNT), and overall survival (OS) were assessed. Patient characteristics were compared using ANOVA or chi-square and overall survival was estimated using Kaplan-Meier. Analyses were conducted using SAS 9.x.
Results: There were 428 veterans who received daratumumab containing regimens. Mean age was 69.5 years and 36.2% self-identified as African American. There were 147 patients who received DRd, 190 DVd, and 91 D-VRd. Veterans who received DRd were significantly older than veterans receiving DVd (mean 73.0 vs. 69.1 years) and D-VRd(73.0 vs. 64.9 years, p&lt;0.001). Use of daratumumab combinations has increased yearly since FDA approval (see table). There was no significant difference in use of regimens by race or comorbidity, measured by CCI. TTNT displayed distinct variations among the regimens, with DRd showing the most extended duration at a median of 316 days, followed by D-VRd at 231 days, and DVd at 40 days. These observed differences in TTNT may be attributed to changes in regimen, such as starting lenalidomide after 1-2 cycles of DVd. Median overall survival with DRd at 45 months (95% CI 38-not reached (NR)) and with DVd was 28 months (95% CI 20-39). Median survival in D-VRd was not reached.
Conclusion: Daratumumab combinations are increasingly used to treat multiple myeloma in the VHA. DRd is used more commonly in older veterans and D-VRd in younger veterans. DVd is used more frequently than other combinations and veterans may transition or other treatments.