bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Associated with in-Hospital Mortality from Gastrointestinal Bleeding in Patients with Hemophilia
Authors: Uche Ifeanyi Nnamdi , Gold-Olufadi Shakirat , Becerra Henry , Wasifuddin Mustafa , Saparov Dosbai , Hehr Rohan , Oluwadeyi Esther Yemisi 
Published: December 2024

Introduction
Gastrointestinal bleeding (GIB) is a common complication and potential cause of mortality in hospitalized patients. Patients with hemophilia (PWH) have an increased risk of developing GIB compared to patients without hemophilia. There is a paucity of literature addressing factors that could predict GIB mortality in PWH. Our study aims to identify these factors and other clinical characteristics of GIB in PWH.
Method
Data for this study were obtained from the National Inpatient Sample (NIS) database. We identified PWH aged 18 years and older who had GIB between 2016 and 2020. Patients were categorized into hemophilia A and B. The primary outcome was in-hospital mortality. Patient demographics, clinical and hospital characteristics were compared using x2 test. The association between hemophilia type and in-hospital mortality was assessed using logistic regression controlling for other covariate. A two-sided p≤0.05 was considered statistically significant.
Results
We identified 638 PWH who had GIB, 22.1% (n=141) had Hemophilia A and 77.9% (n=497) had Hemophilia B. 77.12% (n=492) were male, and 22.88% (n=146) were female. 78.06% (n=498) were ≥40 years old and 21.94% (n=140) were &lt;40 years old. Non-Hispanic Whites (NHWs) had less patients with Hemophilia A than B (59.56% vs 74.47%) compared to non-Hispanic Blacks (NHBs) (19.12% vs 13.47%), Hispanics (12.27% vs 3.55%) and Non-Hispanic Others (6.64% vs 4.96%) who had more patients with Hemophilia A than B (p=0.003). The in-hospital mortality of GIB in PWH was 5% (n=32). More patients with Hemophilia A died from GI bleed compared to Hemophilia B (5.9% vs 2.1%), this finding was however not statistically significant. Patients with a higher comorbidity index had higher inpatient mortality than those with co-morbidity index of 0(aOR:5.26, CI95%:1.94-14.23, p=0.001). There was no association between type of Hemophilia, race, gender, income, insurance, or location of GI bleed with inpatient mortality.
Conclusion
Our study demonstrates that the presence of co-morbidities increases in-hospital mortality from GIB in patients with Hemophilia. We also observed that NHWs with Hemophilia B had more episodes of GIB than those with Hemophilia A, while the reverse was true in other racial groups. Our study was limited by a small sample size. More research is needed to identify factors that could improve survival of GIB in PWH.
Cerebral Infarction As a Complication of a Hypercoagulable State in the Setting of Hyperthyroidism: A Case Presentation
Authors: Condon Samuel 
Published: December 2024

Introduction
Studies have demonstrated a significant association between hyperthyroidism and a hypercoagulable state. Hyperthyroidism, characterized by the excessive production of thyroid hormones, can influence the hemostatic balance, leading to an increased risk of thrombosis. Additionally, hyperthyroidism is a well-known risk factor for atrial fibrillation and cardiomyopathy, both of which can contribute to the development of thromboembolic events. Although rare, cerebral infarction has been reported in patients with hyperthyroidism, particularly due to the hypercoagulable state induced by the excessive thyroid hormones. This case presentation illustrates such an instance, highlighting the complex interplay between thyroid dysfunction and coagulation abnormalities.
Case presentation
A 23-year-old male with a history of Type 1 Diabetes Mellitus, uncontrolled hyperthyroidism due to Graves' disease, and asthma presented with decreased consciousness and possible seizure activity. He was diagnosed with diabetic ketoacidosis (DKA), thyrotoxicosis, cardiogenic shock, a large middle cerebral artery (MCA) infarction, and pulmonary infarction. Transesophageal echocardiogram showed no vegetations. He was initiated on propranolol, methimazole, and hydrocortisone. Hypercoagulable panel, including PT/INR, aPTT, antithrombin III activity, protein C/S, factor V Leiden, G20210A, lupus anticoagulant, homocysteine, and anticardiolipin, was unremarkable. With normalization of thyroid function, cardiac function steadily improved, and no further progression of pulmonary embolism or cerebral infarction was observed. Due to the significant MCA infarction, long-term rehabilitation was required.
Discussion
A hypercoagulable state associated with hyperthyroidism is not commonly recognized but has been documented in several cases. The proposed mechanisms include the upregulation of clotting factors, increased platelet activation, endothelial dysfunction, a hyperadrenergic state, and reduced fibrinolysis. Clinicians should maintain a high index of suspicion for hyperthyroidism as a potential cause of thromboembolic events. Prompt treatment of hyperthyroidism is essential to prevent complications.
No Sickle Cells in Sickle Cell Disease: Possible Effect of Hydroxyurea
Authors: Kim Stanley 
Published: December 2024

Peripheral blood smears of 7 adult patients with sickle cell disease who were admitted to Kern Medical Hospital during the period of March 2024 to July 2024 were examined. Six patients had sickle cell SS disease and 1 patient hemoglobin SC disease. All had acute vasoocclusive painful episodes. All patients have been taking hydroxyurea except one patient who was nursing her baby after recent delivery by cesarean section. She did not take the hydroxyurea for prior 10 months.
Total 14 slides of the 7 patients were examined under the high power field and their pictures photographed. About 5% of all red blood cells (RBCs) had abnormal morphologies. None of the patients who were taking hydroxyurea had the typical elongated crescent-shaped sickle cells. The abnormal RBCs seen in the blood smears have the shapes of canoe or spindle (20%), thick lips (20%), coffee bean (20%), pea pod (20%), rod (10%), and others such as fragmented helmets or teardrops (10%). However, the patient who had not been taking hydroxyurea had a few atypical sickle cells. The disappearance of the typical sickle cells and appearance of various abnormal shapes of RBCs may be the effect of hydroxyurea which increases the level of the hemoglobin F and subsequently reduced degree of polymerization. Conclusion: The peripheral blood smears of patients with sickle cell disease who were taking hydroxyurea showed various shapes of RBCs, but not the typical elongated crescent-shaped sickle cells. However, one patient who was off hydroxyurea for prior 10 months had a few atypical sickle cells. The disappearance of the typical sickle cells and appearance of RBCs of various abnormal morphologies may be due to hydroxyurea therapy.
Screening and Validation of Natural Product with Anti ETP-ALL Activity Using a Novel ETP-ALL Cell Line
Authors: Li Fenglin , Zhuang Haihui , Pei Renzhi , Jin Jie , Lu Ying 
Published: December 2024

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) was first identified in 2009 and was classified as a distinct subtype of T-cell acute lymphoblastic leukemia (T-ALL) by the WHO in 2016. Patients with ETP-ALL frequently face higher rates of relapse and treatment resistance, leading to poorer outcomes compared to individuals with other forms of T-ALL. As of now, there are no established treatment guidelines specifically for ETP-ALL.
Method: The ETP-ALL cell line was established by using continuous culture methods. Cell proliferation inhibition experiments were applied to screen the inhibitory effects of 2541 natural products from the Selleck natural product library on ETP-ALL cells. This screening occurred in three rounds with concentrations set at 1,000 nM, 100 nM, and 10 nM. Natural products that achieved an inhibitory concentration of ≥50% were advanced through subsequent rounds. Finally, natural products with an inhibition rate of ≥ 50% at a concentration of 10nM were selected for validation. In the final validation stage, we focused on products that demonstrated an inhibition rate of ≥50% at a concentration of 10 nM to confirm their efficacy against ETP-ALL.
Results: The novel ETP-ALL cell line, named ZYXY-T1, was successfully established from an ETP-ALL patient. ZYXY-T1 exhibited robust proliferation both in vitro and in vivo. The results from Flow cytometry analysis confirmed that ZYXY-T1 presents the typical characteristics of ETP-ALL, showing negative expression for CD1a, CD8, and CD5, along with positive expression for CD34, CD13, and CD33. Based on multiple diagnostic scoring systems, ZYXY-T1 met the criteria for ETP-ALL diagnosis, achieving maximum scores in four out of six scoring systems. In contrast, the Loucy cell line failed to meet ETP-ALL diagnostic criteria. RNA sequencing analyses identified six fusion genes in ZYXY-T1, including MLLT10::PICALM, AC068756.1::AC108690.1, PICALM::MLLT10, PCAT18::KCTD1, LINC02284::TMEM260, AC123912.1::ZNF493.
In the initial screening, 76 natural products demonstrated a half-maximal inhibitory concentration (IC50) of ≤1,000 nM against ETP-ALL. Following a second round of screening, 38 products exhibited IC 50 values below 100 nM. After the third round, 13 natural products were identified with IC50 values under 10 nM. Among these, natural product #1823 exhibited exceptional efficacy against ETP-ALL, with an IC50 of 0.2 nM-at least ten times lower than the other 12 compounds tested .
Conclusions: We successfully established a novel ETP-ALL cell line that reflects the typical ETP-ALL phenotype. Leveraging this cell line, we identified a potent natural product with significant anti-ETP-ALL activity through systematic screening of a natural product library.
Overcoming Barriers to Novel Combination Therapy in Multiple Myeloma (MM): Oncocollective Insights into Improving Patient Outcomes in Europe
Authors: Shih Ya-Chen Tina , Morgan Gilberto , Biru Yelak , Dietrich Eva Susanne , Ehlers Lars Holger , Eriksson Lise-Lott , -Goñi Manuel García , Greiner Wolfgang , Levin Lars-Ake , Postma Maarten , Fernandez Celine , Paranjpe Krupa , Hansen Hilary , Galnares Alvaro Lopez , Caschetta M. B. , Goeckeler Randi , Lee Edwin 
Published: December 2024

Background
Access to novel combination therapies for multiple myeloma (MM) remains limited in Europe partly due to health technology assessment (HTA) processes and formal reimbursement mechanisms.1,2 To address issues of access barriers, Sanofi convened OncoCollective (OC), a multi-disciplinary stakeholder collaborative of global experts, to explore solutions.
Methodology
The OC Novel Combination Therapy Working Group developed an illustrative case study to map two hypothetical patient journeys in a specific European country (Sweden), a journey that faces barriers to receiving novel combination treatment for MM versus one with fewer barriers.3−5 The group reviewed existing outcomes data to estimate the potential impact on progression-free survival (PFS) to explore if improved access to novel combination therapies could significantly improve patient outcomes and quality of life.3−5
Results
The illustrative patient journeys demonstrated that an optimized therapeutic course with few barriers to combination therapy enabled more advanced care and extended PFS across multiple lines of therapy. In contrast, a journey facing limited access to combination therapy could result in suboptimal treatment sequencing and shorter PFS.
Conclusion
These findings highlight that current healthcare systems may not be equipped to adequately handle the value of combination therapies, and different reimbursement requirements may create inequalities in MM across countries or regions within the same country. Solutions proposed by the OC include a) advocating for mandatory national guidelines, b) encouraging real-world evidence collection and methodologically sound modelling studies, c) appealing for healthcare funding as an investment, and d) working towards a holistic vision of clinical benefit leading to meaningful improvements in outcomes for all patients with MM.
References EFPIA Report on Access to Oncology Combination Therapy in Europe, April 2023. OECD. Analytical Report, 2020. Latimer N, et al. BMC Health Serv Res. 2021;21(1):412. Moreau P, et al. Ann Oncol. 2017;28(suppl 4):iv52−61. Wålinder G, et al. CancerReports.2022;5:e1614.
Arginine Deprivation Induces a Dormient Phenotype in Neoplastic Plasma Cells: The Seed and Soil in Multiple Myeloma
Authors: Scandura Grazia , Dulcamare Ilaria , La Spina Enrico , Dieni Caterina , Cambria Daniela , Giallongo Cesarina , Tibullo Daniele , Di Raimondo Francesco , Romano Alessandra 
Published: December 2024

Our previous research has demonstrated that a reduction in arginine (Arg) concentration within the bone marrow microenvironment BMME induces metabolic reprogramming in multiple myeloma (MM) plasma cells (PCs), enhancing their survival both in vitro (Romano, 2020) and in vivo (Trudu, 2022).
To explore how PCs adapt to both acute and chronic arginine deprivation, we employed a combination of mRNA-sequencing (RNA-seq), ribosome profiling (Ribo-seq), in vitro assays, and FACS analysis to evaluate two human myeloma cell lines, U266 and NCI-H929, cultured under arg-deprived conditions to mimic BMME.
Arg deprivation induced oxidative stress as confirmed by the expression and nuclear translocation of HO-1 protein in U266 cell line but not in NCI-H929 cell line. The antioxidant system upregulation reflects a lower sensitivity to treatment with proteasome inhibitors, Bortezomib and Carlfizomib in U266 cell line. Integrative amino acid profiling revealed that, while the H929 cell line maintained intracellular arginine levels after 10 days of arginine deprivation, the U266 cell line exhibited arginine auxotrophy under the same conditions.
The direct pairwise comparison of RNA-seq data revealed 888 differentially expressed genes in both cell lines, disclosing a dormant phenotype for NCI-H929 cell line, confirmed by the up-regulation of Axl gene important for the retention of MM cells in the dormant state (Khoo et al. 2019), and in the autotrophic cell line U266 the acquisition of a senescence-associated secretory phenotype, associated to accumulation of DNA damage, micronuclei and heterochromatin.
Ribosome profiling provided that U266 cells, but not NCI-H929 cells, preferentially translated shorter mRNA fragments, with ribosome footprint lengths centered around 27 nt and 28 nt after 48h of arg deprivation. The ribosome translation frame analysis revealed a preference for the first codon in 28 nt fragments and the second codon in 27 nt fragments, confirming alterations in translation. Applying AS-Quant we identified novel alternative splicing events, common in both cell lines, occurring in the skipped exons (leading to a significant increase in the expression of ASNS, ATF5, Caspase 4-6-8) and in mutually exclusive exons (leading to increased translation of CD74, a transmembrane glycoprotein involved in MHC II protein formation and transport, responsible of downstream translation of genes involved in apoptosis, immune response, and cell migration).
Taken together, our findings suggest that arg deprivation in TME conveys a complex transcriptional and translational response, leading to peptides translated from short-coding or noncoding regions of the genome, providing a basis for subsequent further functional studies, including the evaluation of potential new ne-antigens for further immunotherapy development.
Thirdhand Smoke As a Risk Factor for Pediatric Lymphoblastic Leukemia: Accelerated Leukemia in Female Pax5-P80R Mice
Authors: Zhou Mi , Snijders Antoine M , Mao Jian-Hua , Wiemels Joseph L. , Kogan Scott C 
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. The development of ALL involves genetic and epigenetic processes, but how these factors are influenced by prenatal and early life exposures is poorly understood.
Epidemiologic studies of tobacco smoke and childhood leukemia have suggested that smoking may increase risk for some children. Thirdhand smoke (THS) has gained wide attention in recent years as a newly described health risk. THS includes tobacco smoke residues in indoor environments that remain long after smoking has ended, and which then react and/or re-emit from materials and/or from surfaces. Infants can be exposed to THS through directly contacting these surfaces as well as exposure to house dust and indoor air. We hypothesize that THS exposure interacts with underlying genetics to place children at risk for the development of ALL.
We performed a pilot study to assess whether THS exposure can accelerate the development of ALL in C57BL/6J mice expressing a Pax5P80R allele, a genetic change that efficiently initiates leukemia. Mutations to the PAX5 locus are common abnormalities in human pediatric ALL. These mice therefore provide a model of the situation in humans in which a child acquires a mutation that, in combination with additional lesions, leads to leukemia. A cohort of Pax5WT/P80R animals was established that resulted from exposure of sires to THS for at least 6 weeks, mated with dams exposed at the onset of mating, and with exposure of pups continued until weaning at 3 weeks of age.
Results: In our experimental design, we pre-planned to analyze survival in all pups, in female pups, and in male pups. Pooled analysis with all female and male mice showed the median time to leukemia/lymphoma in Sham-exposed mice was 151 d. vs.140.5 d. for THS-exposed mice (p&gt;0.1). Analysis of females showed the median time to leukemia/lymphoma in Sham-exposed mice was 156 d. vs. 134 d. for THS-exposed mice (p=0.02 by log-rank test). Analysis of males showed the median time to leukemia lymphoma in Sham-exposed mice was 143.5 d. vs. 151 d. for THS-exposed mice (p&gt;0.1 by log-rank test). The results described above indicate that THS can influence the initiation of leukemia in Pax5P80R mice and can promote leukemia, which is remarkably specific for female mice.
Conclusion: Our results unexpectedly showed a sex-bias in the leukemia-promoting effect of THS. Exposure of Pax5WT/P80R animals to THS provides a model for testing hypotheses regarding how THS and sex may interact in leukemogenesis.
Targeted Treatment Additions Ibrutinib + Bortezomib + R-CHOP for Higher-Risk DLBCL: Efficacy, Feasibility and Molecular Signatures for Future Treatment Decisions
Authors: Denker Sophy , Bittner Aitomi , Kase Julia , Frick Mareike , Hoffmann Jörg , Trenker Corinna , Keller Ulrich , Bogner Christian , Hüttmann Andreas , Dürig Jan , Janz Martin , Mathas Stephan , Marks Reinhard , Krohn Ulrike , Na Il-Kang , Richter-Pechanska Paulina , Bhattacharya Animesh , Gebauer Bernhard , Savic Lynn , Hübner Norbert , Akalin Altuna , Eils Roland , Bullinger Lars , Schmitt Clemens 
Published: December 2024

Introduction
Targeted treatment additions to R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) did fail to improve outcome in recent phase III trials. However, there are molecular subgroups that benefit, in retrospect. We have conducted an explorative single-arm open-label phase I/II study from 2017-2024, investigating ibrutinib + bortezomib + R-CHOP as proximal and distal BCR/NF-κB double-targeting strategy for higher-risk DLBCL patients with no molecular pre-selection and collected repeated lymphoma biopsies for multi-omics profiling in the course of therapy to identify molecular signatures indicative of lasting responsiveness.
Methods
Within the investigator-initiated trial (IIT) ImbruVeRCHOP, 38 newly diagnosed DLBCL patients with IPI ≥ 2 and 61-80 years of age were treated with six 21d-cycles of R-CHOP plus ibrutinib (420 mg/d p.o.) and bortezomib (1.3 mg/m2 s.c. d1 + 8) followed by two subsequent applications of single-agent rituximab (ClinicalTrials.gov identifier NCT03129828, EudraCT number 2015-003429-32). Lymphoma and liquid biopsies were obstained pre treatment, once during cycle 1 and, in case of a residual and reasonably accessible tumor manifestation, once again at interim CT imaging prior to cycle 3.
Results
The follow-up phase of the study ends in 2024. Some multi-omics results such as WES and RNA seq are already available; liquid biopsy for detection of minimal residual disease as well as spatial transcriptomics and spatial proteomics are currently being processed. The study cohort with patients from Germany and Austria has a median age of 71 and reached a high R-CHOP dose adherence of 91% (compared to 73% in patients over 60 years in the PHOENIX trial, RCHOP + ibrutinib) under strongly recommended quadruple prophylaxis (G-CSF, ciprofloxacine, acyclovir, cotrimoxazole). The median follow-up is currently 18 months and the CT-based overall response rate is 73%. The primary endpoint is 2-year progression-free-survival. The toxicity profile is moderate with mostly grade 1-3 adverse events, 53% of the patients had grade 4 toxicities. 6 fatal events were observed during follow-up due to infections, secondary malignancy and lymphoma relapse.
Conclusions
The targeted treatment addition of R-CHOP with ibrutinib + bortezomib for elderly high-risk patients with DLBCL is effective and feasible. Our study will give an updated analysis of treatment outcome and insights into candidate molecular response signatures identifying patients benefiting from this therapy optimization.