ABSTRACT
Acute myeloid leukemia with antecedent hematologic disorder (AHD-AML) and therapy related AML (t-AML) constitute a heterogenous disease with inferior outcomes. It is often characterized by high-risk cytogenetic and molecular alterations associated with AHD or prior cancer therapy. Historically, the standard of care treatment has been intensive induction with "7â¯+â¯3", with an improved overall response rate and survival with CPX-351. Results from large registry-based studies suggested that allogeneic hematopoietic stem cell transplant is preferable to consolidation chemotherapy alone for achieving long-term survival in patients with AHD-AML. Prevalence of high-risk genetic features and advanced age and comorbidities in patients make AHD-AML and t-AML clinically challenging subgroups to treat with intensive approaches. Recent reports on less intensive treatment options, particularly the hypomethylating agent-venetoclax combination, have shown encouraging response rates in these patients. However, emerging resistance mechanisms compromise duration of response and overall survival. Several novel agents targeting apoptotic machinery, signaling pathways, and immune checkpoints are under clinical investigation, with an aim to truly improve overall outcomes in this subgroup. We reviewed updates in biology, classification, and clinical data comparing safety and efficacy of intensive and less intensive treatment options, and summarized ongoing studies with promising novel therapies in AHD-AML and t-AML.
ABSTRACT
Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.
Subject(s)
Aorta, Thoracic , Aortic Valve , Humans , Aorta, Thoracic/abnormalities , Aorta, Thoracic/pathology , Aortic Valve/abnormalities , Aortic Valve/pathology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Bicuspid Aortic Valve Disease/genetics , Pulmonary Valve Stenosis/genetics , Mutation , Receptor, Notch1/genetics , Aortic Valve Disease/genetics , Heart Valve Diseases/genetics , Heart Valve Diseases/pathology , Calcinosis/genetics , Calcinosis/pathology , Hematologic Diseases/genetics , Hematologic Diseases/pathology , Vestibular Diseases/genetics , Vestibular Diseases/pathologyABSTRACT
The ELN gene encodes tropoelastin which is used to generate elastic fibers that insure proper tissue elasticity. Decreased amounts of elastic fibers and/or accumulation of bioactive products of their cleavage, named elastokines, are thought to contribute to aging. Cellular senescence, characterized by a stable proliferation arrest and by the senescence-associated secretory phenotype (SASP), increases with aging, fostering the onset and progression of age-related diseases and overall aging, and has so far never been linked with elastin. Here, we identified that decrease in ELN either by siRNA in normal human fibroblasts or by knockout in mouse embryonic fibroblasts results in premature senescence. Surprisingly this effect is independent of elastic fiber degradation or elastokines production, but it relies on the rapid increase in HMOX1 after ELN downregulation. Moreover, the induction of HMOX1 depends on p53 and NRF2 transcription factors, and leads to an increase in iron, further mediating ELN downregulation-induced senescence. Screening of iron-dependent DNA and histones demethylases revealed a role for histone PHF8 demethylase in mediating ELN downregulation-induced senescence. Collectively, these results unveil a role for ELN in protecting cells from cellular senescence through a non-canonical mechanism involving a ROS/HMOX1/iron accumulation/PHF8 histone demethylase pathway reprogramming gene expression towards a senescence program.
Subject(s)
Cellular Senescence , Fibroblasts , Gene Expression Regulation , Heme Oxygenase-1 , Iron , Tropoelastin , Animals , Humans , Mice , Fibroblasts/metabolism , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Histone Demethylases/metabolism , Histone Demethylases/genetics , Iron/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Tropoelastin/metabolism , Tropoelastin/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND OF THE STUDY: AML classification tools have been developed to stratify the risk at AML diagnosis. There is a need to evaluate these tools in the current therapeutic era. COHORT CHARACTERISTICS: In this retrospective study, we compared five classifiers: ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil et al. classifier, and Lindsley et al. classifier, in a real-life cohort of 281 patients newly diagnosed for AML in Nice University Hospital. In our cohort median age was 68 years old, sex ratio was M/F 56%/44%, performance status was lower than 2 in 73.1% of patients, AML subtype was "De novo" in 71.5%, "secondary" in 22.4%, and "therapy-related" in 6.0% of patients. Intensive chemotherapy was used in 53.0% of patients, and non-intensive chemotherapy in 40.6% of patients. Molecular analysis was available in a large majority of patients and the main mutations found were NPM1 (22.7%), DNMT3A (17.4%), TP53 (13.1%), TET2 (12.4%), and FLT3-ITD (12.4%). RESULTS: In our findings, the comparison of overall survival between the three prognostic groups in the global cohort was statistically significant in all classifiers: ELN 2017 p < 0.0001, ELN 2022 p < 0.0001, ALFA classifier p < 0.0001, Papaemmanuil classifier p < 0.0001, Lindsley classifier p = 0.001. ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil classifier, and Lindsley classifier were calculated respectively in 99%, 99%, 89%, 90%, and 89% of patients. CONCLUSIONS: Using Akaike's information criteria (AIC) to compare all five classifiers, ELN 2022 is the best classifier into younger and older patients and for prognosis.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Aged , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Nucleophosmin , Retrospective Studies , Prognosis , Mutation , Risk AssessmentABSTRACT
BACKGROUND: Proliferative diabetic retinopathy (PDR) is a major cause of irreversible blindness in the working age population. The dysfunction of retinal vascular endothelial cells (RVECs) is the primary cause of PDR. Extracellular matrix (ECM) accumulation promotes intracellular signaling required for RVEC proliferation, migration, survival, and tube morphogenesis. OBJECTIVES: This study aimed to investigate the role of lysyl oxidase (LOX) in the cellular function of RVECs and PDR pathogenesis and to identify the underlying mechanisms. MATERIAL AND METHODS: Protein expression was determined with western blot. The interaction between LOX and elastin (ELN) was detected using a co-immunoprecipitation (Co-IP) assay, and the Cell Counting Kit-8 (CCK-8) assay evaluated cell viability. A colony formation assay was employed to assess the proliferation of human RVECs (hRVECs), and a transwell assay to determine their migration ability. Streptozotocin was used to establish PDR in mice in vivo. A histological analysis was conducted using hematoxylin and eosin (H&E) staining. RESULTS: The results showed that LOX was overexpressed in PDR patients. The LOX knockdown suppressed ECM formation and hRVEC proliferation and migration. Additionally, LOX upregulated ELN expression. However, overexpressed ELN promoted hRVEC proliferation and migration. In vivo experiments showed that curcumin-mediated LOX deficiency restored retinal tissue structure. CONCLUSIONS: The LOX-knockdown suppressed ECM formation and hRVEC proliferation and migration by inactivating ELN. Therefore, LOX/ELN signaling may be a potential PDR biomarker.
Subject(s)
Cell Movement , Cell Proliferation , Diabetic Retinopathy , Elastin , Endothelial Cells , Protein-Lysine 6-Oxidase , Up-Regulation , Humans , Protein-Lysine 6-Oxidase/metabolism , Protein-Lysine 6-Oxidase/genetics , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/enzymology , Animals , Elastin/metabolism , Diabetic Retinopathy/pathology , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/genetics , Mice , Male , Retina/metabolism , Retina/pathology , Middle Aged , Cells, Cultured , FemaleABSTRACT
Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.
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BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
Subject(s)
Aortic Stenosis, Supravalvular , Williams Syndrome , Humans , Williams Syndrome/genetics , Genome-Wide Association Study , Proteomics , Rare Diseases , Aortic Stenosis, Supravalvular/genetics , Aortic Stenosis, Supravalvular/metabolism , Aortic Stenosis, Supravalvular/surgeryABSTRACT
Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT. In patients with persistent undetectable measurable residual disease (uMRD) before transplant (n = 83), overall survival (OS) was similar across the groups. However, auto-HSCT showed a trend of increased disease-free survival (DFS) compared to AD-HSCT (HR 2.85, P = 0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n = 38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P = 0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first 2 years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P = 0.015) and AD-HSCT (P < 0.001). Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Siblings , Propensity Score , Tissue Donors , Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Hematopoietic Stem Cell Transplantation/methods , Retrospective StudiesABSTRACT
BACKGROUND: Elastin-driven genetic diseases are a group of complex diseases driven by elastin protein insufficiency and dominant-negative production of aberrant protein, including supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. Here, a Chinese boy with a novel nonsense mutation in the ELN gene is reported. CASE PRESENTATION: We report a 1-year-old boy who presented with exercise intolerance, weight growth restriction with age, a 1-year history of heart murmur, and inguinal hernia. Gene sequencing revealed a novel nonsense mutation in the ELN gene (c.757 C > T (p.Gln253Ter), NM_000501.4). Due to severe branch pulmonary artery stenosis, the reconstruction of the branch pulmonary artery with autologous pericardium was performed. The inguinal hernia repair was performed 3 months postoperatively. After six months of outpatient follow-up, the child recovered well, gained weight with age, and had no special clinical symptoms. CONCLUSION: We identified a de novo nonsense mutation in the ELN gene leading to mild SVAS and severe branch pulmonary artery stenosis. A new phenotype of inguinal hernia was also needed to be considered for possible association with the ELN gene. Still, further confirmation will be necessary.
Subject(s)
Aortic Stenosis, Supravalvular , Hernia, Inguinal , Stenosis, Pulmonary Artery , Male , Child , Humans , Infant , Elastin/metabolism , Codon, Nonsense , Hernia, Inguinal/genetics , Aortic Stenosis, Supravalvular/diagnosis , Aortic Stenosis, Supravalvular/genetics , Aortic Stenosis, Supravalvular/metabolism , MutationABSTRACT
PURPOSE: To develop a nomogram to predict the cancer-specific survival of patients with local-regionally advanced oropharyngeal squamous cell carcinoma after cervical lymph node dissection. METHODS: The clinical variables of patients confirmed as having oropharyngeal squamous cell carcinoma between 2008 and 2015 were retrieved from the Surveillance, Epidemiology and End Results database. Univariate and multivariate analysis were performed, followed by the construction of nomograms for CSS. Nomogram' accuracy was evaluated through the concordance index, calibration curves and decision curve analysis. RESULTS: A total of 1994 oropharyngeal squamous cell carcinoma patients who underwent surgery were included in this study. Sex, T-stage, American Joint Committee on Cancer-stage, positive lymph nodes, positive lymph node ratio, log odds of positive lymph nodes, and postoperative radiotherapy were selected to establish the nomogram for oropharyngeal squamous cell carcinoma. The concordance index of the nomogram was 0.747 (95% CI 0.714-0.780) in the training calibration cohort and 0.735 (95% CI 0.68-0.789) in the validationcohort and the time-dependent Area under the curve (> 0.7) indicated satisfactory discriminative ability of the nomogram. The calibration plot shows that there is a good consistency between the predictions of the nomogram and the actual observations in the training and validation cohorts. In addition, decision curve analysis showed that the nomogram was clinically useful and had a better ability to recognize patients at high risk than the American Joint Committee on Cancer tumor-node-metastasis staging. CONCLUSION: The predictive model has the potential to provide valuable guidance to clinicians in the treatment of patients with locoregionally advanced OPSCC confined to the cervical lymph nodes.
Subject(s)
Head and Neck Neoplasms , Nomograms , Humans , Squamous Cell Carcinoma of Head and Neck/surgery , Squamous Cell Carcinoma of Head and Neck/pathology , Neoplasm Staging , Lymph Node Excision , Lymph Nodes/surgery , Lymph Nodes/pathology , Head and Neck Neoplasms/pathology , PrognosisABSTRACT
The retinal pigment epithelium (RPE) and choroid are located behind the human retina and have multiple functions in the human visual system. Knowledge of the RPE and choroid cells and their gene expression profiles are fundamental for understanding retinal disease mechanisms and therapeutic strategies. Here, we sequenced the RNA of about 0.3 million single cells from human RPE and choroids across two regions and seven ages, revealing regional and age differences within the human RPE and choroid. Cell-cell interactions highlight the broad connectivity networks between the RPE and different choroid cell types. Moreover, the transcription factors and their target genes change during aging. The coding of somatic variations increases during aging in the human RPE and choroid at the single-cell level. Moreover, we identified ELN as a candidate for improving RPE degeneration and choroidal structure during aging. The mapping of the molecular architecture of the human RPE and choroid improves our understanding of the human vision support system and offers potential insights into the intervention targets for retinal diseases.
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INTRODUCTION: Careful and precise dissection of the gland, away from the typical trajectory of the recurrent and external laryngeal nerves, poses a minimal or similar risk of nerve injuries compared to directly visualizing and identifying the nerves. MATERIALS AND METHODS: In a randomized controlled study involving 150 patients with various thyroid disorders who underwent different surgical procedures (total, near total, and hemi thyroidectomy), the patients were randomly assigned into two groups using a coin toss. The first group (G1) consisted of 75 patients who underwent thyroidectomy with nerve visual identification, while the second group (G2) comprised 75 patients without the requirement of nerve visualization. The aim was to determine the method with a lower risk of complications. RESULTS: The incidence of external laryngeal nerve palsy (ELNP) was found to be higher in G1 patients compared to G2 patients (5.3% vs 2%), while no cases of permanent recurrent laryngeal nerve (RLN) palsy were observed in either group. The frequency of total nerve injury was higher in G1, with 14 patients (10.2%), compared to G2, with eight patients (5.3%). However, there was no significant association between nerve identification and the rate of nerve injury (P value = 0.452). Among the different surgical procedures, total thyroidectomy for toxic goiter was the most common operation associated with transient external laryngeal nerve (TELN) injury and permanent external laryngeal nerve (PELN) injury. CONCLUSION: By employing meticulous dissection techniques in proximity to the thyroid capsule, experienced surgeons can effectively reduce the risk of nerve injury, even in the absence of direct nerve visualization.
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Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to "intermediate" risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.
Subject(s)
Ferroptosis , Leukemia, Myeloid, Acute , Humans , Ferroptosis/genetics , Prognosis , Leukemia, Myeloid, Acute/genetics , CD8-Positive T-Lymphocytes , Algorithms , Protein Serine-Threonine KinasesABSTRACT
Elastin (ELN) fibers are essential constituents of the tumor microenvironment of gastric cancer (GC). However, few studies have investigated the clinical prognostic significance of ELN in GC. We screened for molecular markers that were highly related to distant metastasis by transcriptome sequencing. The Cancer Genome Atlas (TCGA) and Harbin Medical University (HMU) validation cohorts were used to validate ELN expression and to explore molecular mechanisms. Immunohistochemistry for ELN, vimentin (VIM), and fibroblast activation protein, and elastic fiber-specific staining were used to evaluate the relationship between ELN and prognosis. R studio was used to construct a nomogram prognostic model. In this study, we found that ELN mRNA levels were significantly higher in cancer tissues and were associated with poor prognosis in TCGA and HMU patients. Gene set enrichment analysis showed that ELN was mainly enriched in the epithelial-mesenchymal transition (EMT) pathway. The mRNA expression of ELN was positively correlated with fibroblast molecular markers, especially VIM. For validation, we collected a tissue microarray containing 180 pairs of samples. We found that ELN was positively correlated with VIM expression in cancer tissue but not in paracancerous tissues by immunohistochemistry staining. Univariate and multivariate analyses showed that the expression of ELN and lymph node metastasis rate were independent predictors for overall survival. Moreover, a nomogram model was used to evaluate the risk of death by combining the expression of ELN and lymph node metastasis rate. ELN may play an important role in the progression of GC by regulating EMT and is a useful prognostic indicator in predicting the prognosis of GC.
Subject(s)
Epithelial-Mesenchymal Transition , Stomach Neoplasms , Humans , Stomach Neoplasms/genetics , Prognosis , Lymphatic Metastasis , Fibroblasts , RNA, Messenger/genetics , Tumor MicroenvironmentABSTRACT
This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.
Subject(s)
Myelodysplastic Syndromes , Humans , Flow Cytometry , Myelodysplastic Syndromes/diagnosisABSTRACT
Multiparameter flow cytometry (MFC) is one of the essential ancillary methods in bone marrow (BM) investigation of patients with cytopenia and suspected myelodysplastic syndrome (MDS). MFC can also be applied in the follow-up of MDS patients undergoing treatment. This document summarizes recommendations from the International/European Leukemia Net Working Group for Flow Cytometry in Myelodysplastic Syndromes (ELN iMDS Flow) on the analytical issues in MFC for the diagnostic work-up of MDS. Recommendations for the analysis of several BM cell subsets such as myeloid precursors, maturing granulocytic and monocytic components and erythropoiesis are given. A core set of 17 markers identified as independently related to a cytomorphologic diagnosis of myelodysplasia is suggested as mandatory for MFC evaluation of BM in a patient with cytopenia. A myeloid precursor cell (CD34+ CD19- ) count >3% should be considered immunophenotypically indicative of myelodysplasia. However, MFC results should always be evaluated as part of an integrated hematopathology work-up. Looking forward, several machine-learning-based analytical tools of interest should be applied in parallel to conventional analytical methods to investigate their usefulness in integrated diagnostics, risk stratification, and potentially even in the evaluation of response to therapy, based on MFC data. In addition, compiling large uniform datasets is desirable, as most of the machine-learning-based methods tend to perform better with larger numbers of investigated samples, especially in such a heterogeneous disease as MDS.
Subject(s)
Myelodysplastic Syndromes , Humans , Flow Cytometry/methods , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/pathology , Antigens, CD34 , Granulocytes/pathology , Monocytes/pathology , ImmunophenotypingABSTRACT
BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.
Subject(s)
Myelodysplastic Syndromes , Humans , Flow Cytometry/methods , Myelodysplastic Syndromes/diagnosis , Reference Standards , Biological Assay , Fluorescent DyesABSTRACT
Modern investigations in biology often require the efforts of one or more groups of researchers. Often these are groups of specialists from various scientific fields who generate and share data of different formats and sizes. Without modern approaches to work automation and data versioning (where data from different collaborators are stored at different points in time), teamwork quickly devolves into unmanageable confusion. In this review, we present a number of information systems designed to solve these problems. Their application to the organization of scientific activity helps to manage the flow of actions and data, allowing all participants to work with relevant information and solving the issue of reproducibility of both experimental and computational results. The article describes methods for organizing data flows within a team, principles for organizing metadata and ontologies. The information systems Trello, Git, Redmine, SEEK, OpenBIS and Galaxy are considered. Their functionality and scope of use are described. Before using any tools, it is important to understand the purpose of implementation, to define the set of tasks they should solve, and, based on this, to formulate requirements and finally to monitor the application of recommendations in the field. The tasks of creating a framework of ontologies, metadata, data warehousing schemas and software systems are key for a team that has decided to undertake work to automate data circulation. It is not always possible to implement such systems in their entirety, but one should still strive to do so through a step-by-step introduction of principles for organizing data and tasks with the mastery of individual software tools. It is worth noting that Trello, Git, and Redmine are easier to use, customize, and support for small research groups. At the same time, SEEK, OpenBIS, and Galaxy are more specific and their use is advisable if the capabilities of simple systems are no longer sufficient.
ABSTRACT
BACKGROUND: Mid-aortic syndrome (MAS) is characterized by the congenital coarctation of the abdominal aorta, abdominal and limb claudication, and hypertension. The etiology of this disorder is very diverse and often manifests in conjunction with Takayasu's arteritis, Williams-Beurens syndrome, and neurofibromatosis. The isolated mid-aortic syndrome is very rare with only a few cases reported in the literature. CASE PRESENTATION: A 45 years old man was admitted to the Emergency Department with sudden muscle weakness and facial paralysis on the left side. Imaging studies reveal right middle cerebral artery infarction at the M1 section. Incidental findings include multiple moderate to severe stenoses in the right internal carotid artery, and total abdominal aorta occlusion. A variant at the ELN gene (Elastin, OMIM*130,160): c.1768G > A/wt (p.Ala590Thr) was identified. CONCLUSION: This is the first reported case of ELN related mid-aortic syndrome in Vietnam which was diagnosed through careful clinical and genetic workup. The finding of mid-aortic syndrome, in this case, was incidental and the decision to reverse the occlusion was postponed as there was no immediate risk of renal failure or reduced blood flow to the lower limb.