scholarly journals The Role of OMICS Research in Understanding Phenotype Variation in Thalassaemia: The THALAMOSS Project

2014 ◽  
Vol 4 (3) ◽  
pp. 81-85
Author(s):  
Roberto Gambari
Keyword(s):  
Gene Therapy ◽  
Globin Gene ◽  
B Cell Lymphoma ◽  
Great Promise ◽  
Product Portfolio ◽  
Treatment Regimens ◽  
Therapeutic Protocols ◽  
The Impact ◽  
Novel Therapeutic

The β-thalassaemias are a group of severe and rare anaemias with monogenic inheritance, a complex systemic phenotype and several treatment-related complications, caused by more than 300 mutations of the β-globin gene. Novel therapeutic protocols, most of which are based on still experimental treatments, show great promise but significant variability of success between patients. These strategies include chemical/molecular induction of the endogenous β-like γ-globin gene or the restoration of clinically relevant β-globin levels by gene therapy. A small number of modifiers with significant impact on disease penetrance, severity and efficacy of treatments are known, but most remain elusive. Improvements of existing treatment regimens and optimization and application of novel treatments will critically depend on the characterization of additional disease modifiers and the stratification of patients for customized treatment regimens. This requires extensive analyses based on “OMICS”, an English-language neologism which refer to different but connected fields in molecular biology and biochemistry, such as genomics, transcriptomics, exomics, proteomics, metabolomics. The major objective of OMICS is a collective characterization of pools of biological molecules (gene sequences, transcripts, proteins and protein domains) controlling biological structures, functions and dynamics, including several involved in pathological conditions. One of the most interesting observations of genomics in β-thalassaemias is the association between genomic sequences and high fetal haemoglobin (HbF) levels, in consideration of the fact that high HbF levels are usually associated with milder forms of β-thalassaemia. Related to this issue, is the possibility to predict response to different therapeutic protocols on the basis of genomic analyses. For instance, three major loci (Xmn1-HBG2 single nucleotide polymorphism, HBS1L-MYB intergenic region on chromosome 6q, and BCL11A) contribute to high HbF production. Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production in a collection of β-thalassemia and sickle cell disease (SCD) patients allowed the identification of genomic signatures associated with high HbF. Therefore, it can hypothesized that genomic studies might predict the response of patients to treatments based on hydroxyurea, which is at present the most used HbF inducer in pharmacological therapy of β-thalassaemia. Transcriptomic/proteomic studies allowed to identify the zinc finger transcription factor B-cell lymphoma/leukemia 11A (BCL11A) as the major repressor of HbF expression. The field of research on g-globin gene repressors (including BCL11A) is of top interest, since several approaches can lead to pharmacologically-mediated inhibition of the expression of g-globin gene repressors, leading to gglobin gene activation. Among these strategies, we underline direct targeting of the transcription factors by aptamers or decoy molecules, as well as inhibition of the mRNA coding g-globin gene repressors with shRNAs, antisense molecules, peptide nucleic acids (PNAs) and microRNAs. In this respect, the THALAMOSS FP7 Project (THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia, www.thalamoss.eu) aims develop a universal sets of markers and techniques for stratification of β-thalassaemia patients into treatment subgroups for (a) onset and frequency of blood transfusions, (b) choice of iron chelation, (c) induction of fetal hemoglobin, (d) prospective efficacy of gene-therapy. The impact of THALAMOSS is the provision of novel biomarkers for distinct treatment subgroups in β-thalassaemia (500–1000 samples from participating medical centres), identified by combined genomics, proteomics, transcriptomics and tissue culture assays, the development of new or improved products for the cell isolation, characterization and treatment of β-thalassaemia patients and the establishment of routine techniques for detection of these markers and stratification of patients into treatment groups. Translation of these activities into the product portfolio and R&D methodology of participating SMEs will be a major boost for them as well as for the field. THALAMOSS tools and technologies will (a) facilitate identification of novel diagnostic tests, drugs and treatments specific to patient subgroups and (b) guide conventional and novel therapeutic approaches for β-thalassaemia, including personalized medical treatments.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

The Impact of Immunophenotypic Subtypes and Treatment Regimens on Patient Outcomes in Monomorphic Post-Transplant Lymphoproliferative Disorders (Diffuse Large B-Cell Lymphoma)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4449-4449 ◽  
Author(s):  
Dejan Radeski ◽  
Daniela Hoehn ◽  
Francesca Montanari ◽  
Bachir Alobeid ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
B Cell ◽  
B Cell Lymphoma ◽  
Refractory Disease ◽  
Cell Of Origin ◽  
Post Transplant ◽  
Treatment Regimens ◽  
Large B Cell Lymphoma ◽  
Stage Disease ◽  
Germinal Center B Cell ◽  
The Impact

Abstract Introduction : Post-Transplant Lymphoproliferative Disorders (PTLD) are a group of heterogeneous disorders that arise as a consequence of iatrogenic immunosuppression for solid organ or allogeneic bone marrow/stem cell transplantation. Though they all arise in a common clinical context, different types of PTLD differ with respect to their underlying biology, clinical presentation and treatment. The aims of this study were to: (1) Define the cell of origin (COO) of monomorphic Diffuse Large B-cell Lymphoma (DLBCL) PTLD and evaluate their impact on clinical presentation and survival and (2) assess the impact of different Rituximab containing treatment regimens on survival outcomes in monomorphic DLBCL PTLD patients. Methods : We conducted a retrospective review of our institutional databases to identify all the cases of monomorphic PTLD (DLBCL) diagnosed and treated at our medical center from 2000-2013. COO classification into germinal center B-cell like (GCB) and non-germinal center B-cell like (non-GCB) type was performed by immunohistochemistry using the Hans algorithm. Results : Cell of origin: 40 cases of monomorphic PTLD (DLBCL) were diagnosed during the study interval. Tissue material for COO subtyping was available for 25 patients. By immunohistochemistry 16/25 (64%) were non-GCB and 9/25 (36%) were GCB subtype, median age of presentation being 46 years (range 3-75) and 48 years (range 3-64), respectively. A trend towards EBV positivity (by in situ hybridization for EBV encoded RNA) was noted in the non-GCB group (75% vs. 33%) [p=0.09]. Non-GCB DLBCL PTLD presented earlier post-transplant at a median 1.5 years (range 0.2-15) vs. 3.9 years (range 0.7-17) for GCB cases. When comparing immunosuppressive therapy at the time of PTLD presentation, an association between Tacrolimus therapy and non-GCB phenotype was identified [p=0.03]. Non-GCB DLBCL PTLD demonstrated a trend towards higher rates of extra nodal involvement (88% vs. 44%) [p=0.06] and advanced stage disease (Stage III/IV 75% vs. 33%) [p=0.09]. No significant differences in organ transplanted, LDH, ECOG performance and IPI were observed. While acknowledging the heterogeneity of therapies administered, no significant differences in Progression Free Survival (PFS) (median PFS non-GCB = 17 months vs. GCB = 15 months [p=0.36]) and Overall Survival (OS) (median OS non-GCB = 33 months vs. GCB = 27 months [p=0.22]) were identified. Impact of Treatment: 35 adults (age≥18) were treated at our center. The four most common first line therapies administered were R-CHOP (14), R-EPOCH (7), Palliative Care (5) and Rituximab monotherapy (4). Five patients were given 4 other different therapies. In patients given Rituximab monotherapy, two patients presenting with stage I disease responded while two with stage IV disease progressed. When focusing on patients who commenced R-CHOP or R-EPOCH as their initial therapy, no significant differences in age, stage, LDH, extra nodal disease, ECOG performance status, IPI and immunosuppression therapy was identified between the groups. The complete response (CR) rate for R-CHOP was 50% vs. 71% for R-EPOCH. Primary refractory disease was present in 29% of patients receiving R-CHOP vs. 14% with R-EPOCH. Death during first line therapy occurred equally in both groups (14%). All four primary refractory disease patients in the R-CHOP arm died, while the one patient who was primary refractory to R-EPOCH is alive 3 years post autologous stem cell transplant. R-EPOCH demonstrated prolonged PFS (median PFS R-CHOP = 15 months vs. R-EPOCH not reached [p=0.049]) and prolonged OS (Figure 1) [p=0.036]. Conclusions : (1) In monomorphic PTLD (DLBCL), the non-GCB subtype predominates and is associated with the use of Tacrolimus. It commonly presents with advanced stage disease and extra nodal involvement however, no difference in PFS and OS was noted when compared to GCB DLBCL PTLD. (2) R-EPOCH demonstrated prolonged PFS and OS when compared to R-CHOP. The survival differences reflect the higher rates of primary refractory disease in the R-CHOP group and the inability to salvage patients once they become relapse/refractory. Given the retrospective nature of our analysis, further studies in a larger cohort of patients are ongoing to validate these results. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Analyses of Learning Strategies in English as a Second Language: Theoretical Classification and Measurement Test

2020 ◽  
Vol 4 (2) ◽  
pp. 118-129
Author(s):  
Asti Gumartifa ◽  
◽  
Indah Windra Dwie Agustiani
Keyword(s):  
Language Learning ◽  
Learning Outcomes ◽  
Learning Strategies ◽  
Learning Process ◽  
English Learners ◽  
English Language ◽  
Point Of View ◽  
Effective Learning ◽  
The Impact

Gaining English language learning effectively has been discussed all years long. Similarly, Learners have various troubles outcomes in the learning process. Creating a joyful and comfortable situation must be considered by learners. Thus, the implementation of effective learning strategies is certainly necessary for English learners. This descriptive study has two purposes: first, to introduce the classification and characterization of learning strategies such as; memory, cognitive, metacognitive, compensation, social, and affective strategies that are used by learners in the classroom and second, it provides some questionnaires item based on Strategy of Inventory for Language Learning (SILL) version 5.0 that can be used to examine the frequency of students’ learning strategies in the learning process. The summary of this study explains and discusses the researchers’ point of view on the impact of learning outcomes by learning strategies used. Finally, utilizing appropriate learning strategies are certainly beneficial for both teachers and learners to achieve the learning target effectively.

scholarly journals Modulation of Gut Microbiota and Oxidative Status by β-Carotene in Late Pregnant Sows

2020 ◽  
Vol 7 ◽  
Author(s):  
Xupeng Yuan ◽  
Jiahao Yan ◽  
Ruizhi Hu ◽  
Yanli Li ◽  
Ying Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Supplementation ◽  
Basal Diet ◽  
Fecal Microbiota ◽  
Control Group ◽  
Metabolic Activities ◽  
The Impact ◽  
Positive Effect ◽  
Β Carotene

Recent evidences suggest that gut microbiota plays an important role in regulating physiological and metabolic activities of pregnant sows, and β-carotene has a potentially positive effect on reproduction, but the impact of β-carotene on gut microbiota in pregnant sows remains unknown. This study aimed to explore the effect and mechanisms of β-carotene on the reproductive performance of sows from the aspect of gut microbiota. A total of 48 hybrid pregnant sows (Landrace × Yorkshire) with similar parity were randomly allocated into three groups (n = 16) and fed with a basal diet or a diet containing 30 or 90 mg/kg of β-carotene from day 90 of gestation until parturition. Dietary supplementation of 30 or 90 mg/kg β-carotene increased the number of live birth to 11.82 ± 1.54 and 12.29 ± 2.09, respectively, while the control group was 11.00 ± 1.41 (P = 0.201). Moreover, β-carotene increased significantly the serum nitric oxide (NO) level and glutathione peroxidase (GSH-Px) activity (P < 0.05). Characterization of fecal microbiota revealed that 90 mg/kg β-carotene increased the diversity of the gut flora (P < 0.05). In particular, β-carotene decreased the relative abundance of Firmicutes including Lachnospiraceae AC2044 group, Lachnospiraceae NK4B4 group and Ruminococcaceae UCG-008, but enriched Proteobacteria including Bilophila and Sutterella, and Actinobacteria including Corynebacterium and Corynebacterium 1 which are related to NO synthesis. These data demonstrated that dietary supplementation of β-carotene may increase antioxidant enzyme activity and NO, an important vasodilator to promote the neonatal blood circulation, through regulating gut microbiota in sows.

scholarly journals Exploring the Characteristics and Influencing Factors of Leisure Walking Based on the Demand of Behavior

2021 ◽  
Vol 13 (8) ◽  
pp. 4105
Author(s):  
Yupei Jiang ◽  
Honghu Sun
Keyword(s):  
Health Benefits ◽  
Health Benefit ◽  
Public Health Research ◽  
Space Time ◽  
Time Behavior ◽  
Walking Behavior ◽  
Face To Face ◽  
Residential Neighborhood ◽  
The Impact

Leisure walking has been an important topic in space-time behavior and public health research. However, prior studies pay little attention to the integration and the characterization of diverse and multilevel demands of leisure walking. This study constructs a theoretical framework of leisure walking behavior demands from three different dimensions and levels of activity participation, space-time opportunity, and health benefit. On this basis, through a face-to-face survey in Nanjing, China (N = 1168, 2017–2018 data), this study quantitatively analyzes the characteristics of leisure walking demands, as well as the impact of the built environment and individual factors on it. The results show that residents have a high demand for participation and health benefits of leisure walking. The residential neighborhood provides more space opportunities for leisure walking, but there is a certain constraint on the choice of walking time. Residential neighborhood with medium or large parks is more likely to satisfy residents’ demands for engaging in leisure walking and obtaining high health benefits, while neighborhood with a high density of walking paths tends to limit the satisfaction of demands for space opportunity and health benefit. For residents aged 36 and above, married, or retired, their diverse demands for leisure walking are more likely to be fulfilled, while those with high education, medium-high individual income, general and above health status, or children (<18 years) are less likely to be fulfilled. These finding that can have important implications for the healthy neighborhood by fully considering diverse and multilevel demands of leisure walking behavior.

scholarly journals Size-resolved characterization of organic aerosol in the North China Plain: new insights from high resolution spectral analysis

2021 ◽  
Author(s):  
Weiqi Xu ◽  
Chun Chen ◽  
Yanmei Qiu ◽  
Conghui Xie ◽  
Yunle Chen ◽  
...  
Keyword(s):  
Radiative Forcing ◽  
North China Plain ◽  
North China ◽  
Fine Particles ◽  
Large Fraction ◽  
Organic Aerosol ◽  
Size Distributions ◽  
The North ◽  
The Impact

Organic aerosol (OA), a large fraction of fine particles, has a large impact on climate radiative forcing and human health, and the impact depends strongly on size distributions. Here we...

scholarly journals SUPPORT FOR MANAGING PARTLY CONFIGURABLE MODULAR SYSTEMS

2021 ◽  
Vol 1 ◽  
pp. 2791-2800
Author(s):  
Jarkko Pakkanen ◽  
Teuvo Heikkinen ◽  
Nillo Adlin ◽  
Timo Lehtonen ◽  
Janne Mämmelä ◽  
...  
Keyword(s):  
Portfolio Management ◽  
Product Variety ◽  
Added Value ◽  
Modular System ◽  
Product Management ◽  
Design Decision ◽  
Product Portfolio ◽  
Modular Systems ◽  
Engineer To Order ◽  
The Impact

AbstractThe paper studies what kind of support could be applied to the management of partly configurable modular systems. The main tasks of product management, product portfolio management and product variety management are defined. In addition, a partly configurable product structure and modular system are defined. Because the limited support in the literature for managing partly configurable modular systems, the article reviews previous product development cases in which authors have been involved on lessons learnt basis, i.e., if the methods and tools used in the cases could provide support for the research objective. As a result, the existing definition of the modular system should be extended by the concepts of non-module and design decision sequence description when dealing with partly configurable modular systems. This is because engineer-to-order should be made possible in cases where it brings clear added value to the customer compared to completely pre-defined solutions that may limit the customer's interest in the offering. Tools to assess the impact of changes to the product offering are required. These should be taken into account in frameworks that are used in method and tool development.

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