Blood Disorders Research Articles

Early differential diagnosis of pancytopenia related diseases based on serum surface-enhanced Raman spectroscopy

Pancytopenia is a common blood disorder defined as the decrease of red blood cells, white blood cells and platelets in the peripheral blood. Its genesis mechanism is typically complex and a variety of diseases have been found to be capable of causing pancytopenia, some of which are featured by their high mortality rates. Early judgement on the cause of pancytopenia can benefit timely and appropriate treatment to improve patient survival significantly. In this study, a serum surface-enhanced Raman spectroscopy (SERS) method was explored for the early differential diagnosis of three pancytopenia related diseases, i.e., aplastic anemia (AA), myelodysplastic syndrome (MDS) and spontaneous remission of pancytopenia (SRP), in which the patients with those pancytopenia related diseases at initial stage exhibited same pancytopenia symptom but cannot be conclusively diagnosed through conventional clinical examinations. The SERS spectral analysis results suggested that certain amino acids, protein substances and nucleic acids are expected to be potential biomarkers for their early differential diagnosis. In addition, a diagnostic model was established based on the joint use of partial least squares analysis and linear discriminant analysis (PLS-LDA), and an overall accuracy of 86.67 % was achieved to differentiate those pancytopenia related diseases, even at the time that confirmed diagnosis cannot be made by routine clinical examinations. Therefore, the proposed method has demonstrated great potential for the early differential diagnosis of pancytopenia related diseases, thus it has significant clinical importance for the timely and rational guidance on subsequent treatment to improve patient survival.

Early diagnosis of sickle cell retinopathy by using ocular coherence tomography in pediatric population (7-18 years) in central India.

Sickle cell disease (SCD) is the commonest inherited blood disorder leading to complications occurring due to vaso-occlusion including sight-threatening retinopathy. Retinopathy can be managed if diagnosed early and vision loss can be prevented. Since, very less data are available from India, hence, this study was conducted in children (7-18 years) with SCD to diagnose retinopathy by using ocular coherence tomography (OCT) in subclinical stages. This cross sectional single-center study was performed in 7-18 years age group children with SCD without any visual symptoms. Enrolled participants underwent complete ophthalmological examination including macula and optic disc thickness measurements using Cirrus HD-OCT and results were analyzed. Among 55 participants, none had visual impairment. Significant fundoscopy finding (nonproliferative sickle cell retinopathy/NPSR) was found in three patients (5.4%), thinning of central macula in four patients (7.27%), inner macula thinning in eight patients (14.5%), outer macula thinning in one patient (1.81%), retinal nerve fiber layer thinning in five patients (9%), ganglion cell layer to inner plexiform layer thinning in eight patients (14.54%). Overall NPSR was found in 5.4% patients detected with fundoscopy, whereas retinal layer thinning was found in 14 patients (25.4%) using OCT. Despite of the significant prevalence of SCR, it is still underdiagnosed complication, leading to thinning of the retina from early ages; thus, its early diagnosis by regular screening using newer diagnostic methods can prevent progression to sight-threatening complications and provide better quality of life for these patients.

Isolation and Characterization of Fibroblast from Normal and Thalassemia Foreskin

Thalassemia is a genetic blood disorder impacting hemoglobin production, varies in severity, and requires lifelong treatments. The advancement in somatic cell reprogramming through induced pluripotent stem cells (iPSCs) represents a personalized medicine approach that holds promise as a treatment for individuals with thalassemia. One source that could be reprogrammed into iPSCs can be generated from foreskin fibroblast cells. This study aimed to isolate and characterize human fibroblast cells from normal (NFF) and thalassemia (TFF) foreskin surface markers (CD44, CD90, CD105, CD73), and negative lineage (CD45, CD34, CD11b, CD19, HLA-DR). Fibroblast cells were isolated out of normal and thalassemia foreskin using the explant method. Characterization of NFF and TFF isolates was carried out using flow cytometry to disclose the expression of CD90, CD44, CD73, CD105, and negative lineage. Isolation of fibroblast cells from normal and thalassemia foreskin was successfully carried out using the explant method with NFF and TFF characterized as expressing CD90, CD44, CD105, CD73, and negative lineages (CD45, CD11b, CD34, CD19, and HLA-DR). This result could lead to a continuation of reprogramming into iPSCs. HIGHLIGHTS Isolation of fibroblast cells from normal and thalassemia foreskin was successfully carried out and cultured within 21 days The surface marker (CD44, CD73, CD90, CD105), and negative lineage (CD45, CD34, CD11b, CD19, HLA-DR) showed similarity to MSCs Fibroblast cells from the foreskin of normal and thalassemia patients were detected expressing CD90, CD105, CD73, CD44, and negative lineages (CD34, CD11b, CD45, CD19, HLA-DR) GRAPHICAL ABSTRACT

Efficacy, Safety, and Quality of Life of Pegcetacoplan in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria Treated within the Phase 3 PEGASUS Trial

Plain Language SummaryParoxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening blood disorder where an acquired genetic mutation causes a patient’s complement system (a part of the immune system) to attack and destroy red blood cells, which can lead to symptoms including anemia and the formation of blood clots. For many years, the standard treatment for PNH has been complement 5 (C5) inhibitors, which target a downstream part of the complement signaling pathway. However, many PNH patients on C5 inhibitors continue to experience symptoms of the disease, including anemia and impaired quality of life (QoL). Recently, pegcetacoplan, a novel complement inhibitor targeting the complement 3 protein (an upstream part of the complement system) was shown to be superior to a C5 inhibitor in key patient outcome measures in the phase 3 clinical trial PEGASUS, including raising hemoglobin levels and improving QoL. Japanese patients with PNH are known to have different clinical and pathological features from non-Asian PNH patients. Here, we report findings of a post-hoc analysis which evaluated the efficacy, safety, and QoL in Japanese patients treated with pegcetacoplan in PEGASUS. Consistent with findings in the overall study population, our results show that Japanese PNH patients treated with pegcetacoplan derived durable treatment benefits across key outcome measures, including increasing hemoglobin levels and improving QoL scores. The safety outcomes were also similar between Japanese patients and the overall study population. Together, these findings indicate that Japanese PNH patients can be effectively and safely treated with the newly approved C3 inhibitor pegcetacoplan.

Empirically derived profiles of neurocognitive functioning in youth and young adults with sickle cell disease.

Sickle cell disease (SCD) is an inherited blood disorder associated with neurocognitive deficits. In contrast to variable-centered approaches, no known research has utilized person-centered strategies to identify multidimensional patterns of neurocognitive functioning of an individual with SCD. The purpose of the present study was to create empirically derived profiles and identify predictors of neurocognitive functioning subgroups among youth and young adults with SCD. Individuals with SCD (N = 393, mean age 14.05 years, age range 8-24, 50.4% female/49.6% male) completed neurocognitive assessments. Latent profile analysis derived subgroups/classes of neurocognitive functioning and determined relations with demographic and medical variables. Three latent classes emerged: average functioning (n = 102, 27%), low average functioning (n = 225, 60%), and exceptionally low functioning (n = 46, 12%). Older age was associated with membership in the low average and exceptionally low functioning groups (relative to the average group). Being prescribed hydroxyurea was associated with membership in the average functioning group (relative to the low average group) and absence of hydroxyurea use was associated with membership in the exceptionally low group (relative to the low average group). Lower social vulnerability was associated with membership in the average functioning group compared to the low average and exceptionally low groups. Clinicians can help reduce disparities in cognitive development for individuals with SCD by promoting early treatment with hydroxyurea and implementing methods to reduce social vulnerabilities that can interfere with access to evidence-based care.

Management of multiple cerebral embolisms due to polycythemia vera with acquired von Willebrand syndrome

AbstractPolycythemia vera (PV) is a rare blood disorder associated with thrombosis or acquired von Willebrand syndrome (AvWS); however, their coexistence is unusual. Here, we report about a 59‐year‐old man with PV who developed both ischemic stroke (IS) and AvWS. Although the patient had no history of thrombosis, he had refractory epistaxis 2 years prior. Brain magnetic resonance imaging and angiography (MRI and MRA) revealed new IS and mural thrombi at the left distal carotid artery. Laboratory investigations showed elevated hemoglobin and hematocrit levels with mild leukocytosis and thrombocytosis, corresponding to PV. Additionally, suppressed platelet aggregation and activity despite normal antigen of von Willebrand factor indicated AvWS. Appropriate repeated phlebotomies successfully resolved the MRA abnormalities and prevented IS recurrence, although the patient refused the recommended treatment with hydroxyurea. This case highlights the need for careful management to prevent recurrent IS and major bleeding in patients with PV who develop IS accompanying AvWS.

Detection of sickle cell disease using deep neural networks and explainable artificial intelligence

Abstract Sickle cell disease (SCD), a blood disorder that transforms the shape of red blood cells into a distinctive sickle form, is a major concern as it not only compromises the blood’s oxygen-carrying capacity but also poses significant health risks, ranging from weakness to paralysis and, in severe cases, even fatality. This condition not only underscores the pressing need for innovative solutions but also encapsulates the broader challenges faced by medical professionals, including delayed treatment, protracted processes, and the potential for subjective errors in diagnosis and classification. Consequently, the application of artificial intelligence (AI) in healthcare has emerged as a transformative force, inspiring multidisciplinary efforts to overcome the complexities associated with SCD and enhance diagnostic accuracy and treatment outcomes. The use of transfer learning helps to extract features from the input dataset and give an accurate prediction. We analyse and compare the performance parameters of three distinct models for this purpose: GoogLeNet, ResNet18, and ResNet50. The best results were shown by the ResNet50 model, with an accuracy of 94.90%. Explainable AI is the best approach for transparency and confirmation of the predictions made by the classifiers. This research utilizes Grad-CAM to interpret and make the models more reliable. Therefore, this specific approach benefits pathologists through its speed, precision, and accuracy of classification of sickle cells.

Screening for thalassemia carriers among the Han population of childbearing age in Southwestern of China.

Thalassemia is a severe hereditary blood disorder that poses a significant threat to human health and leads to mortality and disability. It is one of the most prevalent monogenic diseases worldwide. The aim of this study was to analyze the molecular epidemiological data of individuals of childbearing age from the Han ethnic group with thalassemia in Southwest China and to explore the application of next-generation sequencing (NGS) technology in screening thalassemia carriers. The participants were Han males and females of childbearing age who sought medical advice at the West China Second University Hospital, Sichuan University from June 2022 to June 2023. We detected α- and β-thalassemia mutations using full-length capture of the thalassemia genes and NGS technology. In a cohort of 1,093 participants, 130 thalassemia carriers were identified, with an overall detection rate of 11.89% (130/1,093). Among these, 0.91% (10/1,093) had mutations that could not be detected using traditional PCR techniques. The proportions of carriers with α-, β-, and α-complexed β-thalassemia gene mutations were 7.68% (84/1,093), 3.93% (43/1,093), and 0.27% (3/1,093), respectively. We identified a novel HBA2 c.166del variant that has not been previously reported. Using NGS technology, we found that the mutation-carrying rate of thalassemia genes was 11.89% in the Han population of childbearing age in Southwest China. Compared with the results of traditional PCR techniques, NGS detected an additional 0.91% (10/1,093) rare genetic variants. NGS technology should be utilized as the primary screening method for thalassemia carriers among Han nationality people of childbearing age in Southwest China.

ALL classification using neural ensemble and memetic deep feature optimization.

Acute lymphoblastic leukemia (ALL) is a fatal blood disorder characterized by the excessive proliferation of immature white blood cells, originating in the bone marrow. An effective prognosis and treatment of ALL calls for its accurate and timely detection. Deep convolutional neural networks (CNNs) have shown promising results in digital pathology. However, they face challenges in classifying different subtypes of leukemia due to their subtle morphological differences. This study proposes an improved pipeline for binary detection and sub-type classification of ALL from blood smear images. At first, a customized, 88 layers deep CNN is proposed and trained using transfer learning along with GoogleNet CNN to create an ensemble of features. Furthermore, this study models the feature selection problem as a combinatorial optimization problem and proposes a memetic version of binary whale optimization algorithm, incorporating Differential Evolution-based local search method to enhance the exploration and exploitation of feature search space. The proposed approach is validated using publicly available standard datasets containing peripheral blood smear images of various classes of ALL. An overall best average accuracy of 99.15% is achieved for binary classification of ALL with an 85% decrease in the feature vector, together with 99% precision and 98.8% sensitivity. For B-ALL sub-type classification, the best accuracy of 98.69% is attained with 98.7% precision and 99.57% specificity. The proposed methodology shows better performance metrics as compared with several existing studies.

Consequence of Red Blood Cells Deformability on Heat Sink Effect of Blood in a Three-Dimensional Bifurcated Vessel.

Several diseases like Sickle Cell Anemia, Thalassemia, Hereditary Spherocytosis, Malaria, and Micro-angiopathic Hemolytic Anemia can alter the normal shape of red blood cells (RBCs). The objective of this study is to gain insight into how a change in RBC deformability can affect blood heat transfer. The heat sink effect in a bifurcated vessel with two asymptotic cases (case 1: deformable and case 2: nondeformable RBCs) is being studied during hyperthermia treatment in a three-dimensional bifurcated vessel, whose wall is being subjected to constant heat flux boundary condition. Euler-Euler multiphase method along with the granular model and Kinetic theory is used to include the particle nature of RBCs during blood flow in the current model. To enhance the efficiency of the numerical model, user-defined functions (UDFs) are imported into the model from the C++ interface. The numerical model used is verified with the experimental results from (Carr and Tiruvaloor, 1989, "Enhancement of Heat Transfer in Red Cell Suspensions In Vitro Experiments," ASME J. Biomech. Eng., 111(2), pp. 152-156; Yeleswarapu et al. 1998, "The Flow of Blood in Tubes: Theory and Experiment," Mech. Res. Commun., 25(3), pp. 257-262). The results indicate that the deformability of RBCs can change both the flow dynamics and heat sink effect in a bifurcated vessel, which subsequently affects the efficacy and efficiency of the thermal ablation procedure. Both spatial and transient Nusselt numbers of blood flow with deformable RBCs are slightly higher compared to the one with nondeformable RBCs.

An Epidemiological Survey on the Assessment of Risk Factors during Pregnancy

Pregnancy is described as a condition or a state from the time of conception up to the time of delivery. The ‘high-risk’ pregnancy means a woman has one or more things that raise her-or her baby’s chances for health problems or preterm (early) delivery. High blood pressure, obesity, diabetes, epilepsy, thyroid disease, smoking, alcohol, using illegal drugs, heart or blood disorder, poorly controlled asthma, malnutrition anemia, multiple pregnancy, pregnancy history and infection can increase the risk of pregnancy. This study was basically a descriptive type of epidemiological study based on the concept of active surveillance. The elements involved to study were risk factors involved during pregnancy like Pre-eclampsia, Gestational Diabetes, Thyroid, delivery related complications and weight gain during pregnancy. The data obtained was categorized and analyzed using graphical representations as charts, graphs and other means. The descriptive responses were analyzed individaually. Out of 100, 27 women were suffering from complications during late age pregnancy include Gestational Diabetes, Thyroid, complications due to High Blood Pressure, Cyst in Uterus, Bed Rest due to previous Miscarriage, Bleeding in Second Trimester, Acute Body Pain, Acute Rise in Blood pressure. Premature delivery was seen due to late age pregnancy. 16 out of 100 women had premature delivery i.e in 33 to 35 weeks of pregnancy or 7th and 8th month of pregnancy. In late age pregnancy, there were total 59 responses out of 100, 27(45.7%) women facing problems due to late age pregnancy like high BP, stillbirth, death of fetus in womb, thyroid, gestational diabetes and complications during delivery and 54.20% women were not having any problems. Women who suffered pregnancy induced hypertension, out of 57women 17(29.82%) were facing problems like depression, anxiety, miscarriage, weakness, vomiting, nausea. Out of 100 women, 9 women suffered from gestational diabetes and 10 women had prolonged diabetes. So from above results, it is considered that women who are 35 years and above are considered to be at “high risk” for pregnancy. Women who were aged 22-30 years didn’t suffer from such diseases but gestational diabetes was observed in some cases. Women who were aged 28-35 years suffered miscarriage and abortion due to reasons unknown.

Therapeutic efficacy of Punarnavadi mandura against phenylhydrazine-induced hemolytic anemia in rats

Background & aimHemolytic anemia is a blood disorder whose incidence is increasing in the world in recent years especially after the pandemic. Conventional treatments include use of steroids and immunosuppresants that are accompanied by numerous adverse effects. With growing interest in using complex multi-component formulations for multi-targeted therapy, the present study aims to investigate the therapeutic efficacy of a traditional Ayurvedic herbomineral preparation, Punarnavadi Mandura, which has been traditionally used as a supplement in iron-deficiency anemia, against phenylhydrazine-induced hemolytic anemia in rodent models. Experimental approachesWe employ a combination of in vivo and in silico methods in this work to study the therapeutic potential and to understand the possible molecular targets of this traditional formulation. Conventional drugs prednisolone and ferrous sulphate were used for comparison. Results and conclusionThe in vivo studies confirm the ability of Punarnavadi Mandura to reverse pathological changes associated with hemolytic anemia at 100 mg/kg and 200 mg/kg concentration. It restored hemoglobin, bilirubin and white blood cell levels to normal and reduced reticulocytes, hemosiderin and Gamna Gandy bodies in the liver, spleen and kidney. In silico studies suggested that the key constituents in Punarnavadi Mandura interact with high affinity to erythropoietic receptor which could contribute to erythropoiesis. The in silico study also predicted that the phytoconstituents of Punarnavadi Mandura could inhibit TNF-α activity which was validated using gene expression studies.

Natural Anticoagulant Protein Levels in Patients With Beta-Thalassemia Major: A Case-Control Study.

β-thalassemia is a group of inherited blood disorders that affect the production of β-globin chains, leading to the reduction or absence of these chains. One of the complications observed in patients with β-thalassemia major (β-TM) is thrombosis, especially in those who receive frequent blood transfusions. This may be due to a decrease in the levels of the natural anticoagulants: protein C (PC), total protein S (PS), and antithrombin (AT). In this case-control study, patients with β-TM, who had received at least 20 packed cell transfusions during their lifetime, were included. Patients with other underlying diseases like bleeding or thrombotic disorders were excluded. Totally, 118 patients with β-TM and 120 healthy individuals were included. The mean level of PC and AT was significantly lower in patients with β-TM (48.2 ± 65.4 and 57.42 ± 13.6, respectively) compared to the control group (97.1 ± 21.46 and 81.79 ± 14.3, respectively), with P value of 0.001 and 0.01, respectively. Although the difference was not statistically significant (P = 0.1), a similar trend was observed for total PS (61.12 ± 21.12 for patients versus 72.2 ± 35.2 for the control group). Of note, the decrease in PC, AT, and total PS levels compared to the control group was 50.36%, 27.5%, and 15.34%, respectively. It seems that β-TM patients who receive prolonged blood transfusions frequently are at an increased risk of decreased in natural anticoagulants levels and therefore potentially are at risk of thrombosis.

An Immunological and Molecular Study to Investigate the Genes (β-globin and HBA1F) in Patients with Thalassemia in Najaf Governorate

Abstract BACKGROUND: Thalassemia, a hereditary blood disorder, poses a significant health challenge globally. This study delves into the prevalence and characteristics of thalassemia, emphasizing the need for enhanced awareness and diagnostic measures, particularly in regions with high prevalence. The primary objective is to comprehensively investigate thalassemia, focusing on genetic mutations and hemoglobin (Hb) dynamics. The specific goals include identifying gene mutations through conventional polymerase chain reaction (PCR) and exploring the correlations between different Hb types. METHODS: Blood samples, totaling three milliliters for ethylenediaminetetraacetic acid tubes and 2 ml for gel tubes, were collected from thalassemia patients and a control group. Genomic DNA was extracted for conventional PCR analysis targeting α and β-globin (HBB) genes. The specific primers were designed, and PCR products were electrophoresed for the gene detection. Demographic characteristics were recorded, and Hb electrophoresis was performed to assess HbA, HbA2, and HbF levels. RESULTS: The study revealed the presence of the HBB gene in 100% of thalassemia patients causing beta-thalassemia, contrasting with the control group. The absence of the HBA1-F gene in alpha-thalassemia patients was observed. Demographic analysis showed no significant age or gender differences between the two groups. Thalassemia patients, analyzed alongside the control group, exhibit elevated HbA2 levels (2.7%–6.6%) and increased HbF levels (2%–12.1%), surpassing normal ranges (HbA2: 2%–3%, HbF: 0.8%–2%). CONCLUSION: The study confirms HBB gene association and proposes HBA1-F absence as an alpha-thalassemia diagnostic marker. Distinctive Hb patterns in thalassemia patients, highlighted by robust negative correlations (HbA-HbA2) and moderate correlations (HbA-HbF), advance diagnostic and management strategies for beta-thalassemia.

Psycho-Social Challenges and Coping Strategies of Caregivers of Thalassemia Patients in District Gujrat

Psycho-Social Challenges and Coping Strategies of Caregivers of Thalassemia Patients in District Gujrat

Generating human bone marrow organoids for disease modeling and drug discovery.

The bone marrow supports and regulates hematopoiesis, responding to physiological requirements for blood cell production over ontogeny and during pathological challenges. Interactions between hematopoietic cells and niche components are challenging to study mechanistically in the human context, but are important to delineate in order to explore the pathobiology of blood and bone marrow disorders. Organoids are proving transformative in many research settings, but an accurate human bone marrow model incorporating multiple hematopoietic and stromal elements has been lacking. This protocol describes a method to generate three-dimensional, multilineage bone marrow organoids from human induced pluripotent stem cells (hiPSCs), detailing the steps for the directed differentiation of hiPSCs using a series of cytokine cocktails and hydrogel embedding. Over 18 days of differentiation, hiPSCs yield the key lineages that are present in central myelopoietic bone marrow, organized in a well-vascularized architecture that resembles native hematopoietic tissues. This presents a robust, in vitro system that can model healthy and perturbed hematopoiesis in a scalable three-dimensional microenvironment. Bone marrow organoids also support the growth of immortalized cell lines and primary cells from healthy donors and patients with myeloid and lymphoid cancers, including cell types that are poorly viable in standard culture systems. Moreover, we discuss assays for the characterization of organoids, including interrogation of pathogenic remodeling using recombinant TGF-ß treatment, and methods for organoid engraftment with exogenous cells. This protocol can be readily adapted to specific experimental requirements, can be easily implemented by users with tissue culture experience and does not require access to specialist equipment.

Abstract 6480: In-hospital mortality risk factors for uveal melanoma patients in the emergency department

Abstract Purpose: A considerable amount of uveal melanoma patients present to the emergency department (ED) for a complication related to their primary tumor. However, there is not much research into the primary reasons for these patients to present to the ED and their outcomes. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of in-hospital death. Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a secondary diagnosis of uveal melanoma. Most patients were at least 65 years of age (43.5%), male (52.5%), and a Medicare beneficiary (44.2%), or belong to a family in the 3rd income quartile (25.6%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.8%), with a Trauma Level I designation (47.2%), and to a metropolitan teaching hospital (72.6%). The most common diagnosis for presentation to the ED were the following general clinical categories: blood disorders (7.1%), genitourinary tract disorders (5.1%), infections (6.0%), respiratory diseases (9.0%), nervous system disorders (4.8%), endocrine/nutrition disorders (4.3%), and vascular disorders (8.3%). The rate of metastatic uveal melanoma was 5.8%. The rate of in-hospital mortality was 3.6%. In a multivariable logistic regression identified the following clinical categories as factors associated with a higher risk of in-hospital death: infections (odds ratio [OR]=10.22; p<0.001), metastases (OR=10.22; p<0.001), genitourinary tract disorders (OR=7.05; p<0.001), respiratory diseases (OR=3.31; p=0.031), and vascular disorders (OR=3.14; p=0.044). Nervous system, blood, and endocrine/nutrition disorders were not associated with a higher rate of in-hospital mortality. The only demographic variable associated with a higher risk of in-hospital death was being part of the top income quartile (OR=3.10; p=0.14). Conclusion: Physicians have to be mindful of different complications associated with uveal melanoma that can lead to presentation to the ED and possible in-hospital death. Specifically, physicians need to be mindful of infections, metastases, genitourinary tract disorders, respiratory diseases, and vascular disorders in these patients. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. In-hospital mortality risk factors for uveal melanoma patients in the emergency department [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6480.

Abstract 6242: A workflow execution system in a data fabric for integrative cancer analyses

Abstract Cancer researchers are increasingly conducting multi-omic research and performing integrative analyses on combinations of genomic, proteomic, transcriptomic, imaging, single cell and other data modalities. However, it is quite challenging for a researcher to effectively access, aggregate and analyze data and metadata from different data sources in a scalable and reproducible manner, as the individual datasets may be disconnected from each other, and have separate authentication and authorization requirements. We developed a workflow execution system in a data fabric called the Biomedical Research Hub (BRH) to overcome these challenges for academic researchers. The BRH is powered by the Gen3 technology, an open-source Kubernetes based software stack that allows cancer researchers to create their own data fabric and interoperate with data from multiple data sources. The workflow execution system utilizes nextflow and allows researchers to run containerized applications in the cloud in a secure and isolated environment. Data from multiple resources can be combined for analysis using convenient pay models including NIH STRIDES. We plan to demonstrate the application of our system on a scientific use case involving Clonal Hematopoiesis of Indeterminate potential (CHIP), a phenomenon that has been associated with aging, cancer, cardiovascular diseases, infection and all-cause mortality. We run containerized CHIP workflows on the cloud, utilizing two datasets accessible through BRH: i) The Genomic Data Commons, the world’s largest source of harmonized cancer data and ii) BioDataCatalyst, an NHLBI ecosystem that drives discovery and innovation for heart, lung, blood and sleep disorders. Our system is ideally suited for machine learning on large aggregated cancer datasets and federated learning tasks. Citation Format: Aarti Venkat, Pauline Ribeyre, Jawad Qureshi, Sai Shanmukha Narumanchi, J Montgomery Maxwell, Bill Winslow, Sara Volk Garcia, Chris Meyer, Tzintzuni Garcia, Peter Vassilatos, Clinton Malson, Zhenyu Zhang, Robert Grossman. A workflow execution system in a data fabric for integrative cancer analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6242.

Abstract 3853: T cell ferroptosis attenuates antitumor immune responses in sickle cell disease

Abstract Background: Sickle cell disease (SCD) is the most common inherited blood disorder and arises from homozygosity for the HbS mutation (GAG>GTG: βGlu6Val) leading to the production of abnormal hemoglobin that cause sickle shaped red blood cells (RBCs). Individuals with SCD are at higher risk than the general population for developing hematologic malignancies or solid tumors such as renal medullary carcinoma (RMC). Although relatively rare, RMC is one of the most aggressive kidney cancers and is the third most common kidney cancer among children and young adults who harbor sickle hemoglobinopathies such as SCD or sickle cell trait (SCT) which occurs due to heterozygosity for the HbS mutation. Molecular profiling studies have shown that most cases involve biallelic inactivation of the SMARCB1 gene, either through simultaneous hemizygous loss and translocation or by homozygous loss. The loss of SMARCB1 and subsequent dysregulation of chromatin remodeling are key factors contributing to the development and progression of renal medullary carcinoma. Despite manifesting an inflamed tumor immune microenvironment, RMC consistently demonstrates resistance to conventional immune checkpoint inhibitors (ICI). Ameliorating the efficacy of immunotherapy of RMC is vital for research and potential therapeutic interventions by targeting CD8+ T cells. Methods: CyTOF was performed by using the spleen of WT mice and SCD mouse model. mRNA was isolated from CD8+ T cells of Peripheral Blood Mononuclear Cell (PBMC) collected from healthy donors and SCD patients followed by bulk RNA sequencing. Hi-C was conducted using CD8+ T cells isolated from PBMC of healthy donors and SCD patients. We employed DNA FISH (Fluorescence in Situ Hybridization) to examine alterations in gene architecture within CD8+ T cells under varying conditions. Results: RMC tumors exhibit accelerated tumor growth and reduced numbers of tumor resident CD8+ T cells in SCD mice model compared with WT control. CD8+ T cells in the SCD associated tumor microenvironment (TME) are subjected to ferroptosis by downregulation of SLC7A11; however, SMARCB1 loss promotes the resistance of RMC tumor cells to ferroptosis. Genomic architecture of CD8+ T cells is altered under SCD conditions, potentially contributing to immune dysfunction. Conclusions: Our research has identified significant alterations in the 3D genome architecture of CD8+ T cells in individuals with SCD. These alterations lead to transcriptional inhibition of SLC7A11, resulting in CD8+ T cell ferroptosis and a hindered anti-tumor immune response in RMC. These findings elucidate the mechanistic relationship of SCD with ICI resistance in cancers such as RMC and provide novel avenues for therapeutically sensitizing tumors to immunotherapies in individuals with SCD. Keywords: Sickle Cell Disease, Renal Medullary Carcinoma, SMARCB1, Ferroptosis, Genomic Architecture Alteration, Hi-C, SLC7A11 Citation Format: Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Giannicola Genovese, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin. T cell ferroptosis attenuates antitumor immune responses in sickle cell disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3853.

The TTP specialist nurse: an advocate for patients and professionals.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening blood disorder with a mortality rate of over 90% if left untreated, multiple long-term complications for survivors, and a lifelong risk of relapse. There is a valuable role for the clinical nurse specialist in both the acute and long-term care of patients with TTP. Historically part of the team caring for patients with TTP, specialist nurses have played a vital role in co-ordinating and facilitating treatment for patients, promoting patient advocacy, supporting continuous service improvement, and delivering education to the wider clinical team to disseminate best practice. In 2021, the TTP specialist nurse role was commissioned within the NHS England National Service Framework for TTP Specialist Centres. This article aims to appraise the role of the TTP specialist nurse and share the multidimensional reach of the role in achieving better outcomes for patients with TTP.