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Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials.

The heterogeneous nature of human CD34 + hematopoietic stem cells (HSCs) has hampered our understanding of the cellular and molecular trajectories that HSCs navigate during lineage commitment. Using various platforms including single cell RNA-sequencing and extensive xenotransplantation, we have uncovered an uncharacterized human CD34 + HSC population. These CD34 + EPCR + (CD38/CD45RA) − (simply as EPCR + ) HSCs have a high repopulating and self-renewal abilities, reaching a stem cell frequency of ~1 in 3 cells, the highest described to date. Their unique transcriptomic wiring in which many gene modules associated with differentiated cell lineages confers their multilineage lineage output both in vivo and in vitro. At the single cell level, EPCR + HSCs are the most transcriptomically and functionally homogenous human HSC population defined to date and can also be easily identified in post-natal tissues. Therefore, this EPCR + population not only offers a high human HSC resolution but also a well-structured human hematopoietic hierarchical organization at the most primitive level. The trajectories of hematopoietic stem cells (HSCs) during lineage commitment are complex. Here, the authors use single cell RNA-sequencing and xenotransplantation to uncover CD34 + EPCR + (CD38/CD45RA)- HSCs, which high repopulating and self-renewal properties.

Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34 + CD38 − CD45RA − CD90 + CD49f + HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.

Myelodysplastic syndrome disease (MDS) is caused by the successive acquisition of mutations and thus displays a variable risk for progression to AML. Mutations in CEBPA are commonly associated with a high risk of disease progression, but whether they are causative for AML development is unclear. To analyse the molecular basis of disease progression we generated MDS patient-derived induced pluripotent stem cells from a low risk male patient harbouring RUNX1 / SRSF2 mutations. This experimental model faithfully recapitulates the patient disease phenotypes upon hematopoietic differentiation. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain in cells from low-risk stages mimicks disease progression by reducing clonogenicity of myeloid cells, blocking granulopoiesis and increasing erythroid progenitor self-renewal capacity. The acquisition of this mutation reshapes the chromatin landscape at distal cis-regulatory regions and promotes changes in cellular composition as observed by single cell RNAseq. Mutant C/EBPα is therefore causative for MDS disease progression. Our work identifies mutant CEBPA as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies. In Myeloiddysplastic syndromes, CEBPA mutations are linked to disease progression and AML. Here, the authors use somatic reprogramming and genome editing to generate isogenic cell lines from an MDS patient, identifying CEBPA bZIP domain disruption as causative for disease progression.

Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor–recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex‐specific engraftment levels with significant differences observed in the lineage output of normal CD34+ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre‐clinical research.

The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs. Scaffolds coated with human mesenchymal stromal cells (hMSCs) proved to be superior in terms of HSC engraftment and long-term maintenance when implanted in vivo. Moreover, we found that hMSC-coated scaffolds can be modulated to form humanized bone tissue, which was also able to support human HSC engraftment. Importantly, hMSC-coated humanized scaffolds were able to support the growth of leukemia patient cells in vivo, including the growth of samples that would not engraft the BM of immunodeficient mice. These results demonstrate that an s.c. implantation approach in a 3D carrier scaffold seeded with stromal cells is an effective in vivo niche model for studying human hematopoiesis. The various niche components of this model can be changed depending on the context to improve the engraftment of nonengrafting acute myeloid leukemia (AML) samples.

Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with −7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with −7). Patients with del(7q) or −7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in −7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0–8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with −7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated −7 or del(7q).

Additive manufacturing is a recent trend in production processes owing to its many benefits. It can be defined as the process of producing parts through the deposition of material in a layer-by-layer fashion. It has been a topic of intense study and review by many researchers. In this work, a comprehensive review pertaining to additive manufacturing has been accomplished. The evolution of additive manufacturing as a prominent technology and its various phases are discussed. The importance of part orientation, build time estimation, and cost computation has also been reviewed. The remarkable aspect of this work is the identification of problems associated with different additive manufacturing methods. Because of the imperfections in additive manufacturing, its hybridization with other methods, such as subtractive manufacturing, has been emphasized. This review will help readers understand the different aspects of additive manufacturing and explore new avenues for future research.

The emergence of Industry 4.0, also referred to as the fourth industrial revolution, has entirely transformed how the industry or business functions and evolves. It can be attributed to its broadening focus on automation, decentralization, system integration, cyber-physical systems, etc. Its implementation promises numerous benefits in terms of higher productivity, greater volatility, better control and streamlining of processes, accelerated enterprise growth, sustainable development, etc. Despite the worldwide recognition and realization of Industry 4.0, its holistic adoption is constrained by the requirements of specific skills among the workforce. The personnel are expected to acquire adaptive thinking, cognitive and computational skills, predominantly in the area of information technology, data analytics, etc. Thus, the universities that laid the foundation for future talents or trends in society have to adapt and modernize the existing programs, facilities, and infrastructure. This reshaping of higher education in consonance with the vision of Industry 4.0 possesses its opportunities and challenges. There are, of course, a multitude of factors involved and they need a reasonable assessment to strategically plan this metamorphosis. Therefore, this work aims to explore and analyze the different factors that influence the progression and enactment of Industry 4.0 in universities for sustainable education. For this purpose, a systematic approach based on a questionnaire as well as a SWOT (strengths (S), weaknesses (W), opportunities (O), and threats (T)) integrated with the analytic hierarchy process (AHP) is adopted. The questionnaires are administered to university employees and students (or stakeholders) to assess their viewpoint, as well as to estimate the priority values for individual factors to be included in SWOT. The AHP is implemented to quantify the different factors in terms of weights using a pairwise comparison matrix. Finally, the SWOT matrix is established depending on the questionnaire assessment and the AHP weights to figure out stakeholders’ perspectives, in addition to the needed strategic scheme. The SWOT implementation of this research proposes an aggressive approach for universities, where they must make full use of their strengths to take advantage of the emerging opportunities in Industry 4.0. The results also indicate that there are fundamental requirements for universities in Industry 4.0, including effective financial planning, skilled staff, increased industrial partnerships, advanced infrastructure, revised curricula, and insightful workshops. This investigation undoubtedly underlines the importance of practical expertise and the implementation of digital technologies at the university level to empower novices with the requisite skills and a competitive advantage for Industry 4.0.