bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal inspection of hybrid nanofluid flows over a stretched cylinder at an oblique stagnation point with variable characteristics
Authors: Li Shuguang , Shahmir Nazia , Ramzan Muhammad , Ahammad N. Ameer , Alhuthali Abdullah M. S. , Saleel C. Ahamed , Kadry Seifedine
Published: April 2024

The enhanced thermal characteristics of hybrid nanofluids make them more versatile compared to conventional fluids. These improved thermal properties render hybrid nanomaterials highly practical for a wide range of applications, including solar systems, energy production, and cooling processes. In line with this perspective, the current study concentrates on evaluating the thermal performance of two unique hybrid nanofluid flows that impinge obliquely on a stretched cylinder. Two base fluids, FC‐77 and a binary mixture of water and ethylene glycol (50:50)%, have been considered, with the addition of nanoparticles such as single‐walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs). The said model's novelty is enhanced by the temperature dependent viscosity and thermal conductivity. Appropriate transformations are applied to derive a system of ordinary differential equations (ODEs), which are then solved numerically using the bvp4c method. A thorough examination is conducted on the physical phenomenon of pertinent parameters, accompanied by graphical representations. The results revealed that, for the FC‐77 coolant‐based hybrid nanofluid, mounting the particle volume fraction leads to a significant reduction in temperature distribution. Additionally, it is perceived that the presence of a variable viscosity parameter causes a reduction in the surface drag coefficient as well as the axial and tangential velocities. The validity of the proposed flow model is demonstrated by comparing the results with those from an earlier study.
Clinical and Biological Concepts for Mastering Immune Reconstitution After Hematopoietic Cell Transplantation: Toward Practical Guidelines and Greater Harmonization
Authors: Kuball Jürgen , Greco Raffaella , Nierkens Stefan , Boelens Jaap Jan
Published: April 2024

Not only the underlying mechanisms driving a long-term cure but also life-threatening side effects after hematopoietic cell transplantation (HCT) are primarily mediated by reconstitution of the immune repertoire. The composition and dynamics of reconstitution are influenced by the conditioning regimen, cell dose, graft composition, and age and type of immune suppression. However, our understanding of these mechanisms is limited due to many variations in clinical programs, including the specific type of transplantation procedure, and the absence of standardized immune monitoring after HCT. While the process of donor selection has seen significant advancements based on new biological insights, little attention has been given to optimizing cell product design in terms of numbers and composition to minimize inter-patient variability. In addition, the high inter-patient disparities in the clearance of agents used during the conditioning are rarely investigated. The lack of prospective clinical studies addressing these concepts, coupled with limited pharmaceutical company interest, fosters a consensus discussion. Our goal is to harmonize HCT interventions by exploring how individual patient differences and overall transplantation strategies impact the final effector mechanisms of HCT, specifically aiming for timely and well-balanced immune reconstitution.
Selection of Stem Cell Source
Authors: Horgan Claire , Valcárcel David
Published: April 2024

Selection of stem cell source is an important consideration for any physician planning an allogeneic haematopoietic cell transplant (HCT) and has evolved considerably since bone marrow (BM) was used as the stem cell source in the first successful allogeneic HCT in 1968 (Gatti et al. 1968). BM remained the only source of stem cells for the two decades that followed until experimental work demonstrating that peripheral blood (PB) stem cells can be enriched by pre-treatment with certain chemotherapy agents and haematopoietic growth factors (Richman et al. 1976; Socinski et al. 1988; Duhrsen et al. 1988) resulted in the first peripheral blood stem cell transplant in 1986 (Korbling and Freireich 2011). Alongside this, the recognition of cord blood (CB) as a rich source of stem cells (Prindull et al. 1978) led to the successful use of cord blood as a third stem cell source in allogeneic HCT in the late 80s (Gluckman et al. 1989).
Mobilization and Collection of HSC
Authors: Worel Nina , Bilgin Yavuz M. , Wuchter Patrick
Published: April 2024

The intravenous infusion of patient’s own HSC (autologous SCT) to restore BM damage is the basic principle of high-dose chemotherapy, since otherwise the patient would expect long-lasting aplasia with life-threatening infections. Therefore, a sufficient collection of HSC before application of high-dose therapy is mandatory. Since HSC expresses CD34 on their surface, the number of CD34+ cells in the transplant material is considered as an indicator of the HSC content.

The aim of infusion of HSC from a donor (allogeneic SCT) is to restore BM damage and to treat the patient’s disease. It represents a permanent cellular immunotherapy by adding a graft versus tumor effect in malignant diseases.
Graft Manipulation
Authors: Lang Peter , Schumm Michael , Pierini Antonio , Handgretinger Rupert
Published: April 2024

Graft manipulation is performed to define and to optimize the volume and cellular composition of stem cell sources like apheresis products, bone marrow, or umbilical cord blood.
Short- and Long-Term Controls After HCT
Authors: Suárez-Lledó Maria , Rovira Montserrat
Published: April 2024

Patients undergoing HCT (mainly allo-HCT) have a risk of developing complications related to pre-, peri-, and post-HCT. The resulting morbidity of the HCT process makes it necessary for patients to adopt a healthy lifestyle that promotes health and contemplate preventive measures for the detection and treatment of possible complications.
Vaccinations
Authors: de la Cámara Rafael , Meisel Roland
Published: April 2024

Vaccination should be considered a routine practice for all HCT receptors, either autologous or allogeneic, adults or children. It should be implemented in all HCT programs. Adult cover is particularly important as they represent 90% of HCTs.
The Roles of the HCT Nurse
Authors: Kenyon Michelle , Murray John
Published: April 2024

Haematopoietic cell transplantation (HCT) is undoubtedly one of the most challenging and complex forms of treatment for malignant and non-malignant blood disorders as well as autoimmune disease. As a result, nursing in the field of HCT and cellular therapy offers a wealth of opportunities to make a positive difference to patient experience through high-quality specialist nursing care and the unique role of nursing within the transplant MDT. In this section, we will describe the nursing roles that surround the patient pathway and offer an overview the particular aspects of patient care that they encompass.
Neutropenic Fever
Authors: Mikulska Malgorzata
Published: April 2024

Fever during neutropenia is almost universal after an HCT. In neutropenic HCT recipients, clinicians are faced with a unique combination of issues: (1) high incidence of bacterial bloodstream infections, (2) high mortality in case of infections due to Gram-negative bacteria unless effective antibiotic treatment is provided promptly, and (3) numerous causes of fever other than bacterial infection.
Invasive Fungal Diseases
Authors: Maertens Johan A.
Published: April 2024

Invasive fungal diseases are potentially life-threatening infectious complications following HCT and CAR-T cell treatment. The successful introduction of azole-based antifungal prophylaxis has dramatically changed the fungal epidemiology and resistance patterns in many institutions. Timely and accurate diagnosis remains a challenge, especially for mould infections, and relies nowadays heavily on the detection of fungal biomarkers, fungal DNA, and sensitive imaging. Various antifungal strategies are in place, and recommendations regarding drugs of choice are available.
Viral Infections
Authors: Ljungman Per , Piñana Jose Luis , Cesaro Simone , de la Cámara Rafael
Published: April 2024

Viral infections are important and possibly serious complications to cellular therapies especially allogeneic hematopoietic stem cell transplantation. The most important virus infections are caused by the herpesviruses, adenovirus, and community acquired respiratory viruses including SARS-CoV-2, but also other more rare infections require attention. This chapter discusses some of these infections and their management
Other Life-Threatening Infections
Authors: Martino Rodrigo
Published: April 2024

Toxoplasma gondii is a protozoan that commonly infects animals and birds. Primary T. gondii infection in humans and other mammals is usually asymptomatic but leads to lifelong latent infection. Transmission to humans occurs by ingesting tissue cysts from undercooked meat or oocysts (released in the feces of cats). Latent cysts can give rise during immunosuppression to a severe localized reactivation producing, for example, toxoplasma encephalitis or chorioretinitis, with dissemination being common (Martino, et al.Clin Infect Dis 2000;31:1188–95; Martino et al. Clin Infect Dis 2005;40:67–78; Tomblyn et al., Biol Blood Marrow Transplant 2009;15:1143–23; Martino, et al., Clin Infect Dis 1996;23:419–20.).

Very detailed guidelines for the management and diagnosis of toxoplasmosis following HCT have been recently finalized for the European Conference of Infections in Leukemia 9th Meeting (ECIL-9) conference and are being considered for publication as of June 2023 (Aerts et al., Under peer-review, 2023).
Bleeding and Thrombotic Complications
Authors: Shah Rahul , Savani Bipin N. , Chaturvedi Shruti
Published: April 2024

Bleeding and thrombotic complications are an important cause of morbidity and mortality in patients undergoing hematopoietic cell transplantation (HCT). The major thrombotic complications include venous thromboembolism (VTE) including catheter-related thrombosis (CRT), sinusoidal obstruction syndrome (SOS), and transplant-associated thrombotic microangiopathy (TA-TMA), while bleeding commonly involves the gastrointestinal or respiratory tracts and is most common in thrombocytopenic patients or those with graft-versus-host disease (GVHD). HCT is associated with multiple risk factors for both thrombosis and bleeding including the underlying malignancy, thrombocytopenia, high-dose myeloablative chemotherapy (MAC) and immune-modulatory drugs, GVHD, infections, indwelling vascular catheters, and prolonged immobilization (Chiu and Lazo-Langner 2023; Gerber et al. 2008; Chaturvedi et al. 2016; Nadir and Brenner 2007). In addition, HCT is also associated with alterations in the coagulation system with activation of endothelium-dependent coagulation factors, increase in von Willebrand factor (vWF) and platelet adhesion, increased thrombin generation, decreased antithrombin levels, and decreased levels of anticoagulant proteins such as protein C (Vannucchi et al. 1994). Collectively, major patient-, disease-, and therapy-related factors contribute to hemostatic complications in HCT patients. Thrombotic and bleeding complications in HCT are discussed separately in the following section.
Graft Failure
Authors: Valcárcel David , Sánchez-Ortega Isabel , Sureda Anna
Published: April 2024

The current definition for hematological recovery includes neutrophil recovery, defined as the first of three consecutive days with an absolute neutrophil count ≥0.5 × 109/L and platelet recovery which is defined as a platelet count of ≥20 × 109/L in the absence of platelet transfusion for 7 consecutive days.
Early Complications of Endothelial Origin
Authors: Carreras Enric , Diaz-Ricart M. , Jodele S. , Penack O. , Vasu S.
Published: April 2024

During HCT, the vascular endothelium is affected by conditioning, IS agents, inflammatory molecules released by injured cells and tissues, endotoxins translocated across injured mucosal barriers, the complex process of engraftment, and in allo-HCT immune alloreactivity. This endothelial damage can affect the entire vascular endothelium or that of specific organs and be the triggering event for several of the early complications grouped under denomination vascular endothelial syndromes of HCT.
Acute Graft-Versus-Host Disease
Authors: Holler Ernst , Greinix Hildegard , Zeiser Robert
Published: April 2024

Acute graft-versus-host disease (GvHD) remains a major course of short term (100 days and 1 yr) mortality and morbidity after allogeneic stem cell transplantation. The pathophysiology of GvHD is described as a 3 step process starting with initial tissue damage by conditioning followed by host antigen presenting cell activation by damage and pathogen associated molecular patterns and finally resulting in activation of alloreactive T cells and proinflmmatory cytokines inducing target cell apoptosis. This activating cycle elicits multiple regulatory mechanisms and cells such as regulatory T cells and myeloid derived suppressor cells. Besides the disturbed balance between immune activation and immune tolerance, a disturbed capacity of tissue repair contributes to clincal damage.
Chronic Graft-Versus-Host Disease
Authors: Wolff Daniel , Peric Zinaida , Lawitschka Anita
Published: April 2024

Chronic GVHD (cGVHD) is the most relevant cause of late non-relapse morbidity and subsequent mortality (approximately 25%) following allo-HCT (Grube et al. 2016). Its incidence is approximately 50% among all patients following allo-HCT and has increased during the last two decades due to increasing patient age and increasing use of unrelated and/or mismatched donors, RIC regimens, PBSC with application of standard GVHD prophylaxis (calcineurin inhibitor [CNI] + MMF or MTX) only (Arai et al. 2015). While the incidence of cGVHD is lower (6–40%) in children, its incidence rises to 60% as age increases (Baird et al. 2010; Sobkowiak-Sobierajska et al. 2022).
Haemorrhagic Cystitis and Renal Dysfunction
Authors: Cesaro Simone
Published: April 2024

Haemorrhagic cystitis is a frequent complication after haematopoietic cell transplantation. Supportive measures (analgesics, antispasmodics, blood product transfusions and hyperhydration) are the main mode of treatment, with or without antivirals or experimental approaches (hyperbaric oxygen therapy, fibrin-glue or platelet-rich plasma application, adoptive immunotherapy).
Noninfectious Pulmonary Complications
Authors: Bergeron Anne , Cooke Kenneth R.
Published: April 2024

Lung injury occurs frequently following HCT and significantly contributes to morbidity and mortality in the immediate posttransplant period and in the months and years that follow. In each setting, infectious and noninfectious etiologies must be considered.
Monitoring Measurable Residual Disease in ALL and AML
Authors: Bader Peter , Kreyenberg Hermann , Ossenkoppele Gert
Published: April 2024

In ALL evaluation of molecular treatment response, assessment of minimal residual disease, nowadays named measurable residual disease (MRD), is a substantial independent predictor of outcome, as proven by randomized studies (Conter et al. 2010; Gökbuget et al. 2012; Bassan and Spinelli 2015). Consequently, MRD is implemented in virtually all clinical protocols in order to supplement or to redefine multifactorial risk stratification with optional customized treatment intensity. The detection of leukemic cells below the limit of classical cytomorphology is feasible by either disease-specific alterations of the immune phenotype or unique genetic features. Several competing and complementing MRD methods have been developed with preference application according to clinical protocols (Van der Velden et al. 2007; van Dongen et al. 2015).
Delayed Transfer of Immune Cells or the Art of Donor Lymphocyte Infusion (DLI) 2.0
Authors: Falkenburg J. H. Frederik , Schmid Christoph , Kolb Hans Joachim , Kuball Jürgen
Published: April 2024

In the context of an allogeneic hematopoietic cell transplantation (HCT), the interplay between host and donor immune cells is considered to be the primary mechanism responsible for graft-versus-leukemia (GVL) reactivity and also able to mediate graft-versus-host disease (GVHD) (Schmid et al. 2021). The tissue specificity of the immune response determines the balance between GVL and GVHD, as well as tropism of GVHD. The main population for success and failure of HCT and DLIs originates from αβT cells. Other subsets are also key modulators of efficacy. For example, NK cells most likely provide acute control of leukemia and of infections like CMV. However, NK cells become rapidly educated over time (Orr and Lanier 2010) and lose their antileukemia activity. Thus, donor transfer of NK cells is obsolete and needs additional, for example, genetic modification to engineer long-term efficacy (Laskowski et al. 2022; Liu et al. 2020). Other subsets, like γδT cells, appear to have a more prolonged antileukemia effect (Handgretinger and Schilbach 2018; Sebestyen et al. 2020) and are also helpful in controlling CMV reactivation (Scheper et al. 2013; de Witte et al. 2018). However, also, donor γδT cells can lose activity over time, and sustainable activity requires, outside the context of an HCT, most likely further modifications (Sebestyen et al. 2020; Li et al. 2023). NKT cells, like regulatory T cells, have been mainly reported to influence GVHD. While an increase in NKT cells in the graft associates with a reduced GVHD incidence (Malard et al. 2016), depletion of regulatory T cells in donor lymphocyte infusions (DLI) improves GVL effects, although it augments the risk of GVHD (Maury et al. 2010). Thus, lymphocyte infusions as part of the graft at the time of transplantation, or delayed as DLI, have multiple effector cells that need to be considered in terms of different alloreactive effects (for review see also (Schmid et al. 2021)).
Mechanisms of Immune Resistance
Authors: Vago Luca , Dazzi Francesco
Published: April 2024

Relapse represents one of the main unsolved issues in allogeneic HCT, prompting research on its underlying mechanisms. Growing evidence support the hypothesis that in many patients relapse is driven by immune changes in cancer cells and in the supporting microenvironment, abrogating the graft-versus-tumor effect.
At-Home HCT
Authors: Fernández-Avilés Francesc
Published: April 2024

The main indications for autoHCT are lymphoid malignancies (90%) with plasma cell disorders (MM and others) comprising 55% of all autoHCT (Passweg et al. 2021). Toxicity and mortality associated with autoHCT have been reduced significantly with the use of mobilized peripheral blood HSC, the extended use of cryotherapy associated with MEL, and the improvements in prophylactic antibiotic and antiemetic regimens. Besides this, outpatient parenteral antimicrobial treatment has been proven feasible and safe, thanks to modern CVC and infusion devices. All these advances have led to the development of outpatient autoHCT programs, and several studies have demonstrated their feasibility and safety (González et al. 2021).
Haploidentical HCT
Authors: Bacigalupo Andrea , Lankester Arjan , Ciceri Fabio , Bertaina Alice
Published: April 2024

We will discuss two platforms of haploidentical HSCT(haplo-HSCT): ex vivo T cell depletion and unmanipulated in vivo T-cell depletion. The former has evolved from positive selection of CD34+ cells to selection of CD34+ cells associated with alpha/beta T cell and CD19 B cell depletion. We will outline the outcome of these procedures in children and adults. More recently selective add back of Treg Tcon has also been developed and will be discussed. The second platform is unmanipulated haplo-HSCT: PTCy and ATG have been used alone or in combination to optimize prevention of GvHD. We will discuss the outcome in patients with hematologic malignancies as well as in patients with non-malignant disorders, such as aplastic anemia, hemoglobinopathies, and immune deficiencies.
Acute Myeloid Leukaemia in Children
Authors: Gibson Brenda E. S. , Sauer Martin G. , Ramanathan Subramaniam , Amrolia Persis J.
Published: April 2024

The outcome for children with acute myeloid leukaemia (AML) continues to improve although not at the pace of acute lymphoblastic leukaemia (ALL). The current 3-year EFS and OS are 65–70% and 75–80%, respectively. The improved survival is attributed to better supportive care, refinement in risk stratification (particularly directing patients to allogeneic HCT in CR1), and improved salvage in relapsed/refractory AML (R/R AML). The enhanced understanding of the genomic landscape of paediatric AML has lead to the strategic use of novel treatments. The future of AML treatment lies in optimising the therapeutic potential of new treatments, including CAR T-cells, in combination with conventional chemotherapy and allogeneic HCT.
Myelodysplastic Neoplasms/Syndromes (MDS)
Authors: Robin Marie , Gurnari Carmelo
Published: April 2024

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by peripheral cytopenias and dysplastic features in blood and bone marrow.
Myelodysplastic/Myeloproliferative Neoplasms
Authors: Onida Francesco , Chalandon Yves
Published: April 2024

The myelodysplastic syndrome-myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative clinical, laboratory, and morphological overlapping features, both in marrow and in blood. MDS/MPNs include chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation (in its absence with ringed sideroblasts) and thrombocytosis (MDS/MPN-SF3B1-T), and MDS/MPN not otherwise specified (MDS/MPN-NOS). Prognosis of MDS/MPN is highly variable, being dismal in the majority of patients with CMML, MDS/MPN with neutrophilia and MDS/MPN-NOS. In the absence of disease-modifying treatment options, allo-HCT represents the only curative option for eligible patients. With regard to allo-HCT indication in CMML patient, a number of prognostic systems have been developed over the years.  As far as pre-transplant phase, in high-risk patients with MDS/MPN and low blast count (<10%), upfront transplantation is the most frequently preferred strategy. In patients with high blast count, pre-transplant treatment with HMAs, or combination of HMAs with other new agents in clinical trials may be considered. In case of rising leukocytosis and/or organ infiltration, hydroxyurea is the drug of choice.  In MDS/MPN patients, the choice of conditioning regimen depends on many different conditions, the major ones being comorbidities, patient age, disease phase at transplant, type of donor, and HSC source. In general, myeloablative regimens may be advisable in young patients without comorbidities aiming to reduce the relapse risk, while reduced-intensity regimens are preferred for patients with older age or comorbidities. As disease recurrence represents the major cause of transplant failure in MDS/MPN, there is a growing interest toward possible post-transplant treatment strategies, both as preemptive and as prophylactic modalities.
Acquired Bone Marrow Failure: Severe Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
Authors: de Latour Régis Peffault , Risitano Antonio , Kulasekararaj Austin , Dufour Carlo
Published: April 2024

Severe aplastic anemia (SAA) is an autoimmune disorder due to the attack of autoreactive cytotoxic T lymphocytes to the hematopoietic component of the bone marrow. SAA might be associated with PNH, resulting from the clonal expansion of hematopoietic stem cells that have somatic mutations in the X-linked gene PIG-A. This review is summarizing the management of SAA from the diagnosis, where inherited disorders need to be excluded, to the overall treatment algorithm of this disease, including immunosuppression and bone marrow transplantation.
Hemoglobinopathies (Sickle Cell Disease and Thalassemia)
Authors: Cappelli Barbara , Gluckman Eliane , Corbacioglu Selim , de la Fuente Josu , Abboud Miguel R.
Published: April 2024

Hematopoietic cell transplantation (HCT) using an HLA-matched sibling donor is a well-established curative therapy for pediatric patients with sickle cell disease (SCD) and transfusion-dependent thalassemias (TDT). In order to expand the donor pool, new approaches such as related haploidentical donor HCT have been used with encouraging results. These approaches aim for a higher overall survival, an effective reduction of acute and chronic GvHD and a reduced toxicity. Due to these alternative approaches and adult patients being increasingly transplanted, the number of HCT has dramatically increased in the last decade. Furthermore, different gene therapy and gene editing strategies are being developed in clinical trials, showing promising results.
Multiple Myeloma
Authors: Mohty Mohamad , Bruno Benedetto , Gagelmann Nico , Mateos Maria-Victoria
Published: April 2024

The concept of high-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (AHCT) remains the standard for treating newly diagnosed multiple myeloma in young and in select, fit, elderly patients. The introduction of ImiDs and proteasome inhibitors administered before and/or after HDT/AHCT gave way to the groundbreaking achievement of stringent complete response (sCR), immunophenotypic CR, and molecular CR, in addition to significantly increased CR and CR plus very good partial response rate (VGPR; Table 81.1). In randomized studies, age of participants is limited to 65 years to avoid selection bias and limit toxicities and withdrawal from studies. However, this does not mean that AAHCT is not feasible in older patients. A study whereby the median age of patients was 72 years old concluded that elderly multiple myeloma patients should not be excluded from transplantation displaying good results with melphalan 140 mg/m2. Currently, in many centers, fit patients up to age 70, and even 75 years old, receive AHCT.
Indolent Lymphoma
Authors: Serroukh Yasmina , Montoto Silvia
Published: April 2024

Indolent lymphomas (iNHL) form an heterogenous group accounings for 1/3 of all malignant lymphomas with Follicular lymphoma (FL) being the most common subtype. iNHL are characterized by repeated relapses. Among available treatment lines, autologous (auto) and allogeneic (allo) HCT are the only curative options for relapsed disease. Nevertheless, the roles of both forms of HCT are evolving and are currently being challenged as T-cell engaging therapies emerge. The indications for auto-HCT and allo-HCT in 2023 are reviewed in this chapter.
Chronic Lymphocytic Leukemia
Authors: Schetelig Johannes , Dreger Peter
Published: April 2024

CLL is a rare indication for HCT/Cellular Therapy since it usually follows an indolent course. Allogeneic HCT is considered as standard of care in eligible high-risk patients who have failed at least two classes of modern pathway inhibitor-based therapy, and in select patients with CLL transformed in to an aggressive B-cell lymphoma (Richter transformation). Except for Richter transformation, there is no role for autologous HCT in CLL. In the absence of a labeled indication, CAR T-cells should not be used outside of clinical trials.
Large B-Cell Lymphoma
Authors: Bento Leyre , Glass Bertram , Schmitz Norbert
Published: April 2024

The most recent WHO classification of tumors of hematopoietic and lymphoid tissues (Alaggio et al. 2022) classifies large B cell lymphomas (LBCL) into diffuse large B cell lymphoma (DLBCL) NOS with distinct morphological and molecular (germinal center B-cell, activated B-cell) subtypes, high-grade B-cell lymphomas (with MYC and BCL2 rearrangements or NOS subtype), and other less frequent subtypes.
Other B- and T-Aggressive Lymphomas and Lymphomas Associated with HIV
Authors: Hübel Kai , Montoto Silvia , Güven Mustafa , Duarte Rafael F.
Published: April 2024

BL accounts for around 2% of all adult NHL with a higher incidence in patients with immunodeficiency and in patients who have HIV infection. There is an endemic pediatric subtype in equatorial Africa, which is strongly associated with EBV. The clinical course of BL usually is highly aggressive with a Ki67 expression of nearly 100% requiring prompt institution of therapy.
Inborn Errors of Immunity
Authors: Albert Michael H. , Lankester Arjan , Gennery Andrew , Neven Bénédicte
Published: April 2024

Inborn errors of immunity (IEI) comprise diseases arising from genetic defects that lead to abnormalities in immune cell development or function with a wide spectrum in severity and clinical manifestations. The number of transplants for IEI has increased significantly over the last years, elicited by better insight in the pathogenesis of the IEI (and thus the “curability” of these diseases with allo-HCT), better outcomes even with unrelated and haploidentical donors, and more differentiated approaches to HCT including reduced toxicity conditioning regimens.
Inborn Errors of Metabolism and Osteopetrosis
Authors: Wynn Robert , Schulz Ansgar
Published: April 2024

Inborn errors of metabolism (IEM) comprise a large group of inherited disease, some of which are disorders of lysosomal, peroxisomal, or mitochondrial function, and only some can be improved following HCT. The mechanism of action varies between the different metabolic disorders. In the lysosomal disorders, healthy donor cells deliver the enzyme (secretion) to residual enzyme-deficient host cells. This is a changing area of medicine, in which autologous stem cell gene therapy is changing BMT practice, and this is likely to accelerate in the immediate future.

Osteopetrosis is a disorder of bone remodelling. The defect usually lies in the osteoclast, which is involved in bone metabolism, and is a specialized tissue macrophage. HCT restores competent tissue osteoclasts and therefore corrects the disease.
CART Cells and Other Cell Therapies (ie MSC, Tregs) in Autoimmune Diseases
Authors: Greco Raffaella , Farge Dominique
Published: April 2024

Auto-immune diseases (AD) are heterogeneous conditions, characterized by polyclonal activation of the immune system with a defect of B or T lymphocyte selection and altered lymphocytic reactions to auto-antigens components (Burnet 1959a, b), although it is rare to identify a single antigenic epitope. The native immune system and its tissue environment play an important role to determine if exposure to a given antigen will induce an immune response or tolerance or anergy. The role of the genes coding for the major histocompatibility system molecules, but also of many other genes, is important in the regulation of the immune response, although this does not explain all the observed phenomena during loss of tolerance (Matzinger 1994; Rioux and Abbas 2005).
Food Loss, Food Waste, and Sustainability in Food Supply Chains
Authors: Akkerman Renzo , Cruijssen Frans
Published: April 2024

Considering that food supply chains are a major part of many discussions about sustainability, it is worrying that a lot of the food that is produced does not actually make it to consumption. This means that related environmental impacts were made in vain, while at the same time food insecurity is a main problem in many parts of the world. In this chapter, we discuss food loss and waste (FLW) in the context of sustainable supply chain management. We provide an overview of the drivers behind FLW for different supply chain stages. Subsequently, we discuss potential actions to prevent or reduce FLW in food supply chains as well as provide a brief outlook towards the future of sustainable food supply chains. Many of the FLW reduction strategies lead to the development of novel and different supply chains, dealing with redistribution of surplus food, valorization of FLW streams, management of novel processing and packaging technologies, developing intelligent pricing strategies, extending product assortments, and changing procurement practices. From an operations and supply chain perspective, these issues provide many challenges and opportunities for practitioners and researchers alike.
Australia Catches Up, and What Hope for the Future?
Authors: Sawer Marian , Maley Maria
Published: April 2024

While slow to begin, Australia has undertaken systematic standards reform since 2021. The Australian parliament is putting in place a set of interlocking new rules and institutions which aim to establish, for the first time, independent regulation and accountability in the parliamentary workplace. An authoritative cross-party body leads the reform process, providing a high level of accountability and driving consensus. The reform agenda draws on a more comprehensive review of parliamentary workplaces than seen elsewhere. The Jenkins Review framed parliament as a workplace in which rights to safety existed and it named gender inequality as a key driver of toxicity. Australian reformers drew on experiences in other Westminster parliaments, especially the UK. One of Australia’s distinctive innovations is an independent centralised Human Resources (HR) body, able to make policies and mandate professional employment practices for parliament. While formal institutions have changed across the Westminster world, informal norms such as adversarialism are resilient. There is conscious policy borrowing amongst Westminster reformers, but improving toxic parliaments will be an ongoing project, requiring sustained and committed leadership.
The cosine addition and subtraction formulas on non-abelian groups
Authors: Ajebbar Omar , Elqorachi Elhoucien , Stetkær Henrik
Published: April 2024

Let G be a topological group, and let C(G) denote the algebra of continuous, complex valued functions on G. We determine the solutions $$f,g,h \in C(G)$$

f
,
g
,
h
∈
C
(
G
)

of the Levi-Civita equation $$\begin{aligned} g(xy) = g(x)g(y) + f(x)h(y), \ x,y \in G, \end{aligned}$$

g
(
x
y
)
=
g
(
x
)
g
(
y
)
+
f
(
x
)
h
(
y
)
,

x
,
y
∈
G
,

that extends the cosine addition law. As a corollary we obtain the solutions $$f,g \in C(G)$$

f
,
g
∈
C
(
G
)

of the cosine subtraction law $$g(xy^*) = g(x)g(y) + f(x)f(y)$$

g

(
x

y
∗

)

=
g

(
x
)

g

(
y
)

+
f

(
x
)

f

(
y
)

, $$x,y \in G$$

x
,
y
∈
G

where $$x \mapsto x^*$$

x
↦

x
∗

is a continuous involution of G. That $$x \mapsto x^*$$

x
↦

x
∗

is an involution, means that $$(xy)^* = y^*x^*$$

(
x
y
)

∗

=

y
∗

x
∗

and $$x^{**} = x$$

x

∗

∗

=
x

for all $$x,y \in G$$

x
,
y
∈
G

.
Bioengineered MSCCxcr2 transdifferentiated keratinocyte-like cell-derived organoid potentiates skin regeneration through ERK1/2 and STAT3 signaling in diabetic wound
Authors: Choudhury Subholakshmi , Dhoke Neha R. , Chawla Shilpa , Das Amitava
Published: April 2024

Skin regeneration is severely compromised in diabetic foot ulcers. Allogeneic mesenchymal stem cell (MSC) transplantation is limited due to the poor engraftment, mitogenic, and differentiation potential in the harsh wound microenvironment. Thus, to improve the efficacy of cell therapy, the chemokine receptor Cxcr2 was overexpressed in MSCs (MSCCxcr2). CXCL2/CXCR2 axis induction led to the enhanced proliferation of MSCs through the activation of STAT3 and ERK1/2 signaling. Transcriptional upregulation of FGFR2IIIb (KGF Receptor) promoter by the activated STAT3 and ERK1/2 suggested trans-differentiation of MSCs into keratinocytes. These stable MSCCxcr2 in 2D and 3D (spheroid) cell cultures efficiently transdifferentiated into keratinocyte-like cells (KLCs). An in vivo therapeutic potential of MSCCxcr2 transplantation and its keratinocyte-specific cell fate was observed by accelerated skin tissue regeneration in an excisional splinting wound healing murine model of streptozotocin-induced type 1 diabetes. Finally, 3D skin organoids generated using MSCCxcr2-derived KLCs upon grafting in a relatively avascular and non-healing wounds of type 2 diabetic db/db transgenic old mice resulted in a significant enhancement in the rate of wound closure by increased epithelialization (epidermal layer) and endothelialization (dermal layer). Our findings emphasize the therapeutic role of the CXCL2/CXCR2 axis in inducing trans-differentiation of the MSCs toward KLCs through the activation of ERK1/2 and STAT3 signaling and enhanced skin regeneration potential of 3D organoids grafting in chronic diabetic wounds.
LncRNA CARMN inhibits abdominal aortic aneurysm formation and vascular smooth muscle cell phenotypic transformation by interacting with SRF
Authors: Liu Shenrong , Zhou Haobin , Han Dunzheng , Song Haoyu , Li Yuanqing , He Shangfei , Du Yipeng , Wang Kai , Huang Xingfu , Li Xin , Huang Zheng
Published: April 2024

Phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a crucial role in abdominal aortic aneurysm (AAA) formation. CARMN, a highly conserved, VSMC-enriched long noncoding RNA (lncRNA), is integral in orchestrating various vascular pathologies by modulating the phenotypic dynamics of VSMCs. The influence of CARMN on AAA formation, particularly its mechanisms, remains enigmatic. Our research, employing single-cell and bulk RNA sequencing, has uncovered a significant suppression of CARMN in AAA specimens, which correlates strongly with the contractile function of VSMCs. This reduced expression of CARMN was consistent in both 7- and 14-day porcine pancreatic elastase (PPE)-induced mouse models of AAA and in human clinical cases. Functional analyses disclosed that the diminution of CARMN exacerbated PPE-precipitated AAA formation, whereas its augmentation conferred protection against such formation. Mechanistically, we found CARMN's capacity to bind with SRF, thereby amplifying its role in driving the transcription of VSMC marker genes. In addition, our findings indicate an enhancement in CAMRN transcription, facilitated by the binding of NRF2 to its promoter region. Our study indicated that CARMN plays a protective role in preventing AAA formation and restrains the phenotypic transformation of VSMC through its interaction with SRF. Additionally, we observed that the expression of CARMN is augmented by NRF2 binding to its promoter region. These findings suggest the potential of CARMN as a viable therapeutic target in the treatment of AAA.

Graphical abstract
Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis
Authors: Czamara Darina , Dieckmann Linda , Lahti-Pulkkinen Marius , Cruceanu Cristiana , Henrich Wolfgang , Plagemann Andreas , Räikkönen Katri , Braun Thorsten , Binder Elisabeth B. , Lahti Jari , Entringer Sonja
Published: April 2024

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.
A Mathematical Framework for Quantum Hamiltonian Simulation and Duality
Authors: Apel Harriet , Cubitt Toby
Published: April 2024

Analogue Hamiltonian simulation is a promising near-term application of quantum computing and has recently been put on a theoretical footing alongside experiencing wide-ranging experimental success. These ideas are closely related to the notion of duality in physics, whereby two superficially different theories are mathematically equivalent in some precise sense. However, existing characterisations of Hamiltonian simulations are not sufficiently general to extend to all dualities in physics. We give a generalised duality definition encompassing dualities transforming a strongly interacting system into a weak one and vice versa. We characterise the dual map on operators and states and prove equivalence ofduality formulated in terms of observables, partition functions and entropies. A building block is a strengthening of earlier results on entropy preserving maps—extensions of Wigner’s celebrated theorem- –to maps that are entropy preserving up to an additive constant. We show such maps decompose as a direct sum of unitary and antiunitary components conjugated by a further unitary, a result that may be of independent mathematical interest.
Sensitivity and wave propagation analysis of the time-fractional (3+1)-dimensional shallow water waves model
Authors: Şenol Mehmet , Gençyiğit Mehmet , Demirbilek Ulviye , Az-Zo’bi Emad A.
Published: April 2024

This study investigates the exact solutions of the time-fractional (3+1)-dimensional combined Korteweg–de Vries Benjamin–Bona–Mahony (KdV-BBM) equation. The considered model describes the long surface gravity waves of small amplitude, which portrays the two-way propagation of waves. The modified generalized Kudryashov method and the exp(-$$\varphi (\xi $$

φ
(
ξ

))-expansion methods are employed to resolve the aforementioned issue because of their effectiveness and simplicity. For generality, the time fractional version is studied; more advanced solutions that do not exist in the literature were obtained. As a result, a variety of the exact wave solutions of the conformable (3+1)-dimensional KdV-BBM equation are obtained. The dynamical behaviors of some obtained solutions are represented with the proper parameter values. The used methods yield noteworthy results in obtaining the analytical solutions of fractional differential equations under various conditions. Besides, the sensitivity of regarding dynamical system is assessed to show the numerical stability effects.
Sharp corner singularity of the White–Metzner model
Authors: Evans Jonathan D. , Jones Christian A.
Published: April 2024

The stress singularity is determined using matched asymptotics for complete flow of a White–Metzner (WM) fluid around a re-entrant corner. The model is considered in the absence of a solvent viscosity, with power-law forms for the relaxation time and polymer viscosity. In this form, the model shares the same stress singularity as the upper convected Maxwell (UCM) model, but its wall boundary layers may be thinner or thicker than those for UCM depending upon the relative difference in the power-law exponents. If the exponent for the relaxation time is greater than that for the polymer viscosity, the boundary layer is narrower, whilst it is thicker if the polymer viscosity exponent exceeds that of the relaxation time. When the exponents are the same, the WM boundary layer thickness is the same size as that for UCM. A self-similar solution is derived for the stress and velocity fields and matched to both upstream and downstream boundary layers. Restrictions on the sizes of the power-law exponents are also given for validity of this solution.
Vermittlung kommunikativer Kompetenzen in der Lehre der HNO-Heilkunde
Authors: Gür Deniz , Offergeld Christian , Fabry Götz , Wünsch Alexander
Published: April 2024

Hintergrund

Kommunikative Kompetenzen gehören zu den wichtigsten Schlüsselqualifikationen der ärztlichen Tätigkeit. Inwieweit diese im medizinischen Unterricht der Hals‑, Nasen- und Ohrenheilkunde auch online erworben werden können, wird in dieser Studie untersucht.

Fragestellung

Ein freiwilliges Online-Training zur Vermittlung kommunikativer Fertigkeiten wurde mit einem entsprechenden Präsenzformat verglichen. Dabei wurde der Frage nachgegangen, inwieweit sich Akzeptanz der beiden Formate sowie die Selbsteinschätzung der Studierenden hinsichtlich ihrer kommunikativen Fertigkeiten unterscheiden.

Material und Methoden

Im Online-Training wurden die Studierenden über ein Video asynchron auf die Thematik vorbereitet. Danach konnten sie Gespräche mit Simulationspatient*innen online und synchron führen. Die Präsenzveranstaltung war in Aufbau und Dauer vergleichbar und fand in einem früheren Semester statt. Die Akzeptanz der jeweiligen Seminare wurde mit einem Fragebogen mit 19 Items erhoben, dabei wurde eine 5‑stufige Likert-Skala verwendet. Die Selbsteinschätzung der Kommunikationsfertigkeiten wurde über eine 10 cm lange visuelle Analogskala prä/post mit 16 Items erfasst.

Ergebnisse

Beide Formate erreichten eine hohe Akzeptanz mit einer Durchschnittsnote (M) von 2,08 (Standardabweichung, SD: 0,54) für das Online-Format und M = 1,97 (SD = 0,48) für die Präsenzveranstaltung. Die Selbsteinschätzungen der Studierenden zu kommunikativen Fertigkeiten haben in der Online-Gruppe (M = 1,54, SD = 0,94) einen doppelten Zuwachs gegenüber der Präsenzgruppe gezeigt (M = 0,75, SD = 0,87).

Schlussfolgerung

Diese Studie zeigt, dass die Vermittlung von kommunikativen Kompetenzen im Online-Format gut angenommen wurde und zu signifikanten Veränderungen in der Selbsteinschätzung der Kommunikationsfertigkeiten der Studierenden führte.
Square compactness and Lindelöf trees
Authors: Marun Pedro E.
Published: April 2024

We prove that every weakly square compact cardinal is a strong limit cardinal, and therefore weakly compact. We also study Aronszajn trees with no uncountable finitely splitting subtrees, characterizing them in terms of being Lindelöf with respect to a particular topology. We prove that the class of such trees is consistently non-empty and lies between the classes of Suslin and Aronszajn trees.
Asymptotic strictly pseudoconvex CR structure for asymptotically locally complex hyperbolic manifolds
Authors: Pinoy Alan
Published: April 2024

In this paper, we build a compactification by a strictly pseudoconvex CR structure for a complete and non-compact Kähler manifold whose curvature tensor is asymptotic to that of the complex hyperbolic space. To do so, we study in depth the evolution of various geometric objects that are defined on the leaves of some foliation of the complement of a suitable convex subset, called an essential subset, whose leaves are the equidistant hypersurfaces above this latter subset. With a suitable renormalization which is closely related to the anisotropic nature of the ambient geometry, the above mentioned geometric objects converge near infinity, inducing the claimed structure on the boundary at infinity.
Lefschetz-type theorems for the effective cone on Hyperkähler varieties
Authors: Baltes Jonas
Published: April 2024

In this paper we show some Lefschetz-type theorems for the effective cone of Hyperkähler varieties. In particular we are able to show that the inclusion of any smooth ample divisor induces an isomorphism of effective cones. Moreover we deduce a similar statement for some effective exceptional divisors, which yields the computation of the effective cone of e.g. projectivized cotangent bundles or some projectivized Lazarsfeld–Mukai bundles.