bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of an Early and Complete Examination Protocol for Women and Girls with Inherited Bleeding Disorders (WGBD)
Authors: Halimeh Susan , Daoud Mohamad Ayman , Schmitz Derya , Habermann Bjoern 
Published: December 2024

Women and girls with bleeding disorders (WGBD) share the same bleeding symptoms and limitations in quality of life (QoL) as men, but they also confront unique physical and psychological challenges.1
Physically, WGBD experience joint problems, heavy menstrual bleeding (HMB), postpartum haemorrhage, excessive postoperative bleeding, epistaxis, easy bruising, and oral bleeding, also in haemophilia carriers with factor levels ≥ 40 IU/ml.2
Psychologically, they grapple with feelings of shame regarding HMB and guilt about bearing children with haemophilia.3These challenges can severely diminish QoL, yet they remain underappreciated.4
The primary physiological challenge lies in joint problems.5 WGBD, including haemophilia carriers, are at risk for subclinical joint bleeding, necessitating early detection.6 Inflammation can cause joint dysfunction before structural damage occurs, leading to pain, altered movement, and muscle degeneration, which destabilizes joints further and exacerbates pain.7
Early identification of joint issues is therefore crucial. Although ultrasound can detect joint problems, it is limited to recognizing clinical synovitis, a sign of already advanced joint problems.8
This creates two main barriers to comprehensive diagnosis and early treatment of WGBD: a) incompleteness, as diagnoses have previously concentrated on physiological aspects alone, and b) lateness, due to the absence of tools to identify joint changes before synovitis becomes clinically evident. Consequently, many with WGBD remain undiagnosed and untreated.
To address these barriers, we are creating a comprehensive assessment protocol for WGBD, evaluating all bleeding symptoms and their QoL impact. This protocol integrates new tools with existing diagnostic tools such as the Pictorial Blood Loss Assessment Chart (PBAC), Haemophilia Joint Health Score, ISTH Bleeding Score, and Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US).
The first new tool is a psychometric QoL questionnaire for WGBD, developed collaboratively with patients and health professionals based on established scientific questionnaire methodologies.
The second tool is the Noraxon system, which employs validated sensing methods, including inertial measurement units (IMUs), electromyography (EMG), and paedobarography. This system is highly regarded in biomechanical research, with over 400 peer-reviewed publications supporting its efficacy. A 2018 literature review highlighted 11 studies on biomechanical analysis in paediatric and adult patients with hemophilia, showing significant correlations with functional tests, ultrasounds, and MRI scans.
Interim test results are already available and show promising results for a smaller sample size of 26 women. Once our new psychometric questionnaire is validated, we will correlate its results with the other assessment toosl, test the whole protocol on a larger sample size and publish the results for peer review.
Non-Factor Therapy Reduces Burden of Care for Caregivers of Children with Severe Hemophilia a: A Longitudinal Cohort Study Using the Hemophilia Family Impact Tool (H-FIT v1.1)
Authors: O'Rourke Roxy , Bouskill Vanessa , Wakefield Cindy , Carcao Manuel , Abad Audrey , Blanchette Victor , Malcolmson Caroline 
Published: December 2024

Background: A child's hemophilia diagnosis has an impact on the caregiver. Caregivers often need to administer routine prophylactic therapy to prevent bleeds. Historically, in patients with severe hemophilia A (PWH-A), this consisted of giving intravenous (IV) clotting factor concentrate (CFC) multiple times per week. With the advent of novel non-factor therapies (e.g., emicizumab), there is an option to deliver prophylaxis subcutaneously (SC) less frequently. The Hemophilia Family Impact Tool (H-FITv1.1) is a caregiver-reported questionnaire that measures the burden of caring for a child with hemophilia. This validated tool can be used to evaluate how the burden of care changes when switching from IV to SC therapy.
Aim: To evaluate the impact of emicizumab, as compared to IV clotting factor, on caregiver burden of care for PWH-A.
Methods: Caregivers of PWH-A (0-18 years) on routine prophylaxis completed the H-FIT at four time points: baseline (day of switch to emicizumab), and at 3, 6, and 12-months post-switch to emicizumab. Institutional research ethics board approval and informed consent from all participants were obtained. The H-FIT is scored from 0 to 100, with 100 representing the lowest family burden.
Results: Caregivers (N=35) of PWH-A (Mage=12.43 years, SD=4.15, 100% male, 97% infusing prophylaxis &gt;twice/week pre-switch) completed the H-FIT. There was a non-statistically significant trend of improved burden of care following a switch to emicizumab (t11=-.81, CI=-14.86-6.86). Age stratification revealed this trend was consistent in children over the age of seven; however, the trend of improvement was not seen in the &lt;7 years of age cohort.
Conclusion: There was a trend of improved burden of caring for PWH-A in caregivers following the child's switch from IV to SC therapy. This trend was not seen in the under 7 cohort, however sample size was limited, and further studies are needed to elucidate age-related differences in care.
Neurofilament Light Chain: A Potential Biomarker for Chemotherapy Induced Peripheral Neuropathy in Pediatric Adolescent Young Adults
Authors: Belsky Jennifer , Orgel Etan , Carter Allie , Lustberg Maryam , Roth Michael E. , Rhodes Steven D. , Dage Jeff , Schneider Bryan P 
Published: December 2024

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment side effect in both pediatric and adolescent young adult patients (AYAs). CIPN causes significant clinical challenges resulting in chemotherapy dose reductions in attempt to improve painful symptoms, and additionally can result in decreased health-related quality of life and potentially impacting disease outcomes. CIPN detection in children and AYAs is a challenge, and current tools for CIPN detection rely on moderate to severe CIPN phenotypes in patients &gt;12 years of age, with no patient reported outcomes (PROs) validated for younger children. Earlier, more sensitive tools for CIPN detection are need for younger patients. Neurofilament light chain (NF-L) is an emerging biomarker that has shown correlation with axonal damage in rat models, with the potential to serve as an early and sensitive biomarker of CIPN. This pilot study aimed to describe changes in NF-L in children and AYAs with CIPN.
Methods: This single-center, prospective study examined patients aged &gt;10 years with leukemia or lymphoma who received a backbone chemotherapy regimen which included a tubulin toxin. CIPN was assessed by PROs with the FACT-GOG-ntx. Outcomes were evaluated at baseline prior to chemotherapy, day 1 of each chemotherapy cycle, and 6-12 weeks after last dose of chemotherapy. Values were reported as the Normalized Protein eXpression (NPX) per OLINK standard reporting on a log2. Negative N-FL values were excluded from percent change calculations. Values were calculated at baseline, first follow up, and at 90 days or the closest visit to 90 days.
Results: A total of 11 participants (aged 12-24 years) who received tubulin toxin chemotherapy backbones including to treat B-lymphoblastic leukemia (n=3), Hodgkin lymphoma (n=7), and mature B-cell lymphoma (n=1) were analyzed. 10 participants had a median % change in baseline NF-L of 67.94%. Mean NF-L levels increased from baseline timepoint (mean 2.32, median 2.16) to time point 2 (mean= 3.28, median 3.47) and remained increased at the follow-up visit closest to 90 days (mean 3.85, median 4.38). All participants had CIPN as evidenced by FACT-GOG-ntx scores, with majority of scores changing overtime from timepoint 1 (mean=1.27, median=0) to timepoint 2 (mean=3.55, median=3.00).
Conclusions: We report the first investigation of N-FL in the pediatric and AYA cancer setting as a potential novel biomarker for early and sensitive CIPN detection. These results are hypothesis generating and serve as the foundation for larger, future studies to continue investigating N-Fl as an early and objective detection measure of CIPN in this unique patient population.
CRISPR-TOF Platform: A Single-Cell Approach for Studying Kinase-Dependent Immune-Signaling Dynamics in Human Primary T Cells
Authors: Holzem Alessandra M. E. , Rovira-Clave Xavier , Drainas Alexandros , Reinhardt Hans Christian , Sage Julien 
Published: December 2024

Introduction
Chimeric antigen receptor (CAR) T-cell therapies have improved the treatment of hematologic malignancies, but challenges such as activation and persistence limit broader application. Recent insights into the T-cell receptor (TCR) pathway revealed promising strategies for modulating activation kinetics, crucial for enhancing the efficacy of CAR T-cells. Here, we developed a single-cell approach for studying kinase-dependent signaling dynamics in primary human T cells, which unravels critical mechanisms of the T-cell activation cascade to better understand the genetic programs that determine T-cell response to (tumor) antigens.
Methods
We set up a platform called “CRISPR-TOF”, in which we combined arrayed CRISPR-Cas9 gene editing, an enhanced mass tag live-cell barcoding approach, and single-cell mass spectrometry (CyTOF). We knocked out nearly 1,000 kinases in primary human T cells and tracked the phosphorylation of 23 different proteins over 30 minutes, at 20 time points, post-stimulation with anti-CD3/CD28.
Results
The expected signaling patterns were observed in the analyzed components of the TCR pathway. Initially, proximal kinases such as SLP-76, ZAP70, and VAV1 exhibited rapid phosphorylation, which decreased after one minute. In contrast, phosphorylation of MEK1/2 and ERK1/2 emerged at 2 minutes, and the S6 ribosomal protein, peaked at nine minutes post-activation. Upon knocking out specific kinases, our study identified a range of novel targets that alter downstream TCR signaling. We categorized genes that either prolong or attenuate activation and identified those that modify signaling relationships or influence individual pathway components through independent mechanisms.
Conclusions
We have generated a dynamic, high-resolution map of T-cell signaling, facilitating targeted investigations of specific pathway components. Our results represent one of the most comprehensive assessments of T-cell signaling dynamics to date. This platform allows focusing on key signaling molecules and is thus a powerful complement to platforms such as Pertub-seq in which RNA changes are measured. It opens avenues for massively multiplexed single-cell assays for drug target discovery, delving deeper into immune signaling by studying entire signaling pathways. In the future, functional analyses of specific gene knockouts in samples will be essential to fully elucidate their roles in TCR activation, signal transduction, and resultant cellular functions. More broadly, these insights could be harnessed to optimize and expand cellular therapies.
Evaluation of the New Minion Chemistry and Duplex Basecalling for Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia
Authors: Martinez-Serra Jordi , Nastasi Julieta , Ferrer Lores Blanca , Serrano-Alcalá Alicia , Moquera Adrian , Sampol Mayol Antonia , Terol Castera Maria Jose , Gutiérrez Antonio 
Published: December 2024

Introduction:
The analysis of somatic hypermutation (SHM) in the immunoglobulin heavy chain variable region (IGHV) is crucial for managing chronic lymphocytic leukemia (CLL). Traditional methods such as Sanger sequencing (SS) or second-generation sequencing (NGS) are reliable but labour-intensive. This study aims to evaluate the efficacy and accuracy of the new MinION Kit 14 chemistry, nanopore sequencing (NS), using POD5 files and duplex basecalling with the Dorado software, compared to standard methods (SS).
Methods:
CLL patient samples were analysed using a custom pipeline that includes conversion of POD5 to BAM files with Dorado, BAM to FASTQ conversion, optional quality filtering, clustering by similarity with VSEARCH, generating consensus sequences, and querying IMGT/V-Quest for mutation status assessment. Statistical analysis for comparison between the NS and SS methods was performed using Spearman correlation test.
Results:
We included 15 CLL patient samples comparing our new NS method with SS. Results showed high concordance between NS and SS in terms of the percentage of SHM of IGHV (ρ=0.99; p&lt;0.001) and 100% agreement in mutated/unmutated status definition, with NS detecting additional productive subclones. Even using Flongle flow cells, the quality of sequencing was sufficient to identify correct rearrangements with a single sample, ensuring high accuracy. The Kit 14 chemistry, which includes the E8.2 motor protein and R10.4.1 flow cells, achieved Q12-Q16+ accuracy with simplex data, significantly improving with duplex basecalling, making it suitable for SHM IGHV testing even for rapid results from individual samples. Generating 50,000 sequences per sample ensured sufficient coverage for reliable SHM detection and subclonal analysis, unlike Additionally, we provide results in less than 24 hours including just 1 hour sequencing, enabling a low-cost procedure that compares favorably with SS or second generation NGS.
Conclusions:
The new MinION chemistry and duplex basecalling offer a precise, faster, and cost-effective alternative to traditional SHM analysis methods. This approach enhances the detection of SHM and subclonal populations in CLL in the short-term, allowing for affordable real-time clinical decisions.
A Novel Small Molecule Drug-Based Approach for Treating Beta-Globinopathies
Authors: Liu Jun , Shen Ziyang , Dong Yanhua , Yu Na , Chai Li , Tenen Daniel G. , Bauer Daniel E. , Herman Adelaide , Pate Braden , Vanuytsel Kim 
Published: December 2024

Beta-globinopathies, such as β-thalassemia and sickle cell disease, present significant global health challenges. Existing treatments, including γ-globin inducers, blood transfusions, gene therapies, and bone marrow transplantation, face hurdles of cost, efficacy, and tolerability. In addition to the known function of BCL11A, recent research underscores the crucial role of ZBTB7A/LRF, another transcriptional factor, in suppressing γ-globin during the erythroid globin switch. While transcription factors have historically been deemed “undruggable”, recent advancements in therapeutic modalities, like molecular glue degraders, have spurred interest in targeting them. Leveraging nearly two decades of expertise in transcription factor biology, access to compound libraries, and collaborations, we identified and characterized a novel small molecule drug that is capable of downregulating both ZBTB7A and BCL11A, two known γ-globin repressors.
Through in silico and phenotypic screens, we discovered SH6, which was originally characterised as a novel small molecule ZBTB7A degrader but later found to also downregulate BCL11A levels. The globin induction effect of SH6 was evaluated and validated using various erythroid cell models, including HUDEP2 cells, normal CD34 cell-derived erythroid cells and sickle cell patient iPSC models. γ-globin induction was assessed by qPCR, flow cytometry, and clinical grade HPLC analyzer. Mechanistic studies explored SH6's dependence on the proteasome machinery and the Cereblon E3 ligase system to explore the drug's mechanism of action as a molecular glue degrader. Synergistic effects with other disease-modifying agents, such as hydroxyurea, decitabine, and pomalidomide, were investigated.
Treatment with SH6 (0.25uM) led to a 6-fold increase in γ-globin expression in HUDEP2 cells compared to DMSO, surpassing other γ-globin-inducing treatments and without causing significant toxicity or erythroid differentiation. In healthy donor CD34 stem cell-derived erythroid cells, SH6 induced significant functional hemoglobin F without affecting differentiation markers at 0.25uM (11% vs 34% HbF, compared to DMSO by HPLC). Preliminary evidence suggests SH6's potential efficacy in hydroxyurea-unresponsive sickle cell patients, with increased trend of γ-globin expression observed with flow cytometry. SH6 effectively downregulated/degraded ZBTB7A/BCL11A in a proteasome-dependent manner within 24 hours of treatment, and its effect is abrogated in a CRBN-E3 ligase knockout HUDEP2 cell line. Synergistic effects with Decitabine were notable, showing a 4-fold increase in mRNA expression compared to SH6 alone and a 9-fold increase compared to Decitabine alone. Additionally, SH6 demonstrated the unique ability to reactivate more “primitive” forms of globins, epsilon and zeta globins, suggesting potential relevance for treating both alpha and beta thalassemia.
An Evaluation of Characteristics Associated with Academic Hematology-Oncology Fellowship Placement
Authors: Beltran Santiago , Matos Noboa Constangela , Yan John , Dhanaraj Nitya , Wei John X , Castellucci Enrico , Sharma Amy 
Published: December 2024

Background:
Hematology is a discipline growing rapidly with advances in research and therapeutics. Thus, engagement with research, the understanding and conduct of it, is extremely important in the education and development of future hematologists. Academic fellowship programs affiliated with medical schools traditionally promote the development of academic hematologists. And so, understanding the factors associated with placement into academic fellowship programs is essential for tailoring training and support. This study aims to explore pre-fellowship characteristics that are associated with placement into academic hematology-oncology fellowships in the United States (US).
Methods:
We conducted a sampling of graduated fellow profiles available on the public websites of US hematology-oncology programs. To minimize over-representation from programs, even sampling of all available graduated fellows by year was done with a maximum of 10 per program. Characteristics analyzed included residency type (academic vs community), sex, international medical graduate (IMG) status, and pre-fellowship research productivity (number of Google Scholar publications in the 3 years prior to fellowship). Academics was defined as training in an institution associated with a medical school. Logistic regression modeling was utilized to identify characteristics associated with higher odds of initial academic fellowship placement.
Results:
We analyzed 519 fellows who graduated between 2007 and 2023, data was available from 63 out of the 181 programs in the US, representing 35% of all programs. Fellows of academic fellowships were more likely to have graduated from academic residencies (OR 13.7, 95% CI 7.39-26.4, p &lt; 0.001). IMGs were more likely to be academic fellows compared to non-IMGs (OR 2.34, 95% CI 1.24-4.54, p = 0.010). Pre-fellowship scholarly productivity did not reach statistical significance (Tertile 2: OR 1.84, 95% CI 0.93-3.69, p = 0.081; Tertile 3: OR 1.80, 95% CI 0.86-3.80, p = 0.12). Sex did not show a significant association with fellowship placement (OR 1.14, 95% CI 0.63-2.05, p = 0.7).
Conclusions:
Our findings indicate that academic fellows had higher odds of being IMGs and coming from academic residencies. Pre-fellowship research productivity did not show a significant association with academic fellowship placement. An explanation is that the quantity of research does not necessarily imply quality; further investigation is needed to establish its significance. Additionally, IMGs might seek academic placements more frequently than community placements. These insights highlight critical areas where fellowship programs can enhance support for aspiring academic oncologists.
Hepatosplenic T-Cell Lymphoma: A SEER Stat Review of Epidemiology
Authors: Ali Hassan , Durugu Satya R , Desai Krishna , Bajwa Shammas , Sinha Shrishti , Batool Humera , Hassan Muhammad , Thirumaran Rajesh , Agrawal Shubham 
Published: December 2024

Background:
Hepatosplenic T-cell Lymphoma (HSTCL), historically known as hepatosplenic gamma/delta T cell lymphoma, is an extremely rare and highly aggressive subtype of peripheral T-cell lymphomas. Characterized by malignant proliferation of cytotoxic T cells, usually expressing gamma/delta T cell receptors but infrequently alpha/beta receptors as well, HSTCL presents with hepatosplenomegaly, thrombocytopenia, or systemic B symptoms. The aim of this study is to investigate epidemiology and survival outcomes based on independent prognostic factors in adult patients with HSTCL over the last two decades.
Method:
The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2023 Sub (2000-2021). We extracted cases of Hepatosplenic T-cell lymphoma in adults of age 20 years and above, using the ICD code 9716/3. The data was stratified on the basis of age, gender, race, primary site labelled, stage, treatment types, and median household income inflation adjusted to 2022. The analysis was further completed by comparing survival using the Log-rank test (GraphPad Prism).
Results:
From 2000 to 2021, 163 cases of HSTCL were identified in adults of age 20 years and above. 63.8% of the reported cases were males and 36.2% were females. Race-specific distribution observed in descending order was: Caucasian (57.69%), Black (20.86%), Asian/Pacific Islander (11.66%), Hispanic (9.20%) and Native American/Alaskan (0.61%). The median age of diagnosis was 48 years. Further comparison of the survival curves based on age, gender, race, primary site labelled, stage, and inflation adjusted-median household income showed no statistical significance. Survival analysis calculated for chemotherapy and radiation therapy (XRT), as the primary treatment modality, also didn't show any significant association. The sole prognostic factor in our study that showed statistically significant association with survival outcomes was surgical management. The MoS compared for surgery was 22 months and no-surgery was 7 months (CI: 2.138 - 4.621, HR 0.6412, p value 0.0207).
Conclusion:
Hepatosplenic T-cell lymphoma is an ultra-rare malignancy, accounting for &lt;1% of all non-Hodgkins lymphomas. This aggressive tumor has poor outcomes, even with standard-of-care treatment approaches. HSTCL is most commonly observed in male gender and Caucasian race. Our study showed no influence on survival outcomes based on age, race, gender, primary site labelled, stage and income. While improved survival was observed in patients treated surgically, chemotherapy/XRT had no impact on MoS. More studies are needed to better understand and aid in management of this rare but hostile neoplasm.