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Patients with precursor B-cell acute lymphoblastic leukemia (pB-ALL) who have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted chimeric antigen receptor (CAR) T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercially available autologous CD19-directed CAR T-cell product. We performed a retrospective study inviting all CAR T-cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR T-cell infusion, 71 patients (87.7%) were in complete response, and 8 (9.9%) were in nonremission. At 2 years, the probabilities of event-free survival (pEFS), relapse-free survival (pRFS), and overall survival (pOS) were 45.3%, 51.7%, and 53.2%, respectively. pEFS was not different in patients without (n = 16, 55.0%) vs with prior allo-HSCT (n = 65, 43.4%). In patients treated after allo-HSCT, the time to relapse after allo-HSCT was a strong predictor of outcome. Patients relapsing within 6 months of allo-HSCT had a disappointing pEFS of 18.4% (pOS = 16.0%); the pEFS for those relapsing later was 55.5% (pOS = 74.8%). Our study provides real-world experience in pediatric, adolescent, and young adult patients with ALL treated with Tisa-cel, where most patients were treated after having relapsed after allo-HSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that patients with ALL after allo-HSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons.

Biological specimens in natural history collections constitute a massive repository of genetic information. Many specimens have been collected in areas in which they no longer exist or in areas where present-day collecting is not possible. There are also specimens in collections representing populations or species that have gone extinct. Furthermore, species or populations may have been sampled throughout an extensive time period, which is particularly valuable for studies of genetic change through time. With the advent of high-throughput sequencing, natural history museum resources have become accessible for genomic research. Consequently, these unique resources are increasingly being used across many fields of natural history. In this paper, we summarize our experiences of resequencing hundreds of genomes from historical avian museum specimens. We publish the protocols we have used and discuss the entire workflow from sampling and laboratory procedures, to the bioinformatic processing of historical specimen data.

The electromagnetic fields (D, H) represent contravariant components of an antisymmetric 4‐tensor, while the fields (E, B) represent covariant components of the same 4‐tensor. Both sets are identical in Lorentz frames. The governing equations for them represent equations of balance for the flux of D and the flux B across open surfaces and they are invariant under arbitrary analytic transformation of space and time. This convenient property has motivated mechanicians to reformulate mechanics and thermodynamics in terms of the symmetric 4‐tensor of energy‐momentum so as to exhibit, perhaps, the same invariance as electromagnetism: general relativity. The interpretation of electromagnetism in terms of fields carries the theory a long way. But it breaks down when absorption and emission of radiation by bodies is concerned. In this case the proper view is that of a photon gas. Also the elegant union of electromagnetism and thermodynamics meets practical difficulties for bodies with internal structure, like electric and magnetic dipoles or for mixtures of charged constituents. The description of such bodies is limited to velocities much smaller than that of light. Still in those bodies the entropy inequality implies severe and interesting restrictions on the dependence of material properties on the electromagnetic fields. It will be evaluated by using the Lagrange multiplier method. In the early days of electromagnetism there was much confusion among physicists and engineers about the different formulation of the fields and about proper dimensions and units. This dilemma is also briefly explained in the article.

Patients with precursor B cell acute lymphoblastic leukemia (pB-ALL) who have relapsed subsequent to allogeneic stem cell transplantation (alloHSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted CAR-T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercial autologous CD19-directed CAR-T cell product. We performed a retrospective study inviting all CAR-T cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR-T cell infusion, 71 patients (87.7%) were in CR, and 8 (9.9%) were in NR. At two years, the probabilities of event-free, relapse-free and overall survival were 45.3% (pEFS), 51.7% (pRFS) and 53.2% (pOS), respectively. pEFS was not different in patients without (n=16, 55.0%) vs. with prior alloHSCT (n=65, 43.4%). In patients treated after alloHSCT, the time to relapse after alloHSCT was a strong predictor of outcome. Patients relapsing within 6 months of alloHSCT had a disappointing pEFS (pOS) of 18.4% (16.0%); pEFS (pOS) for those relapsing later was 55.5% (74.8%). Our study provides real-world experience in pediatric, adolescent and young adult patients with ALL treated with Tisa-cel, where the majority of patients were treated after having relapsed post-alloHSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that ALL patients post-alloHSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype.

This article is an exercise in elementary mechanics and thermodynamics. It emphasizes the basic difference between mechanics and thermodynamics which lies in the irreversibility of the latter theory. Clausius [1] (Poggendorff’s Annalen der Physik, p. 125, 1865) – the discoverer of entropy – was led to express the dichotomy in the famous slogandie Energie der Welt ist constant, anddie Entropie der Welt strebt einem Maximum zu.(Gibbs put these slogans on top of his comprehensive memoir [2] (Gibbs, On the Equilibrium of Heterogeneous Substances, pp. 108–248, 1876).)And again Clausius [3] (Über den zweiten Hauptsatz der mechanischen Wärmetheorie, A lecture given at the general session of German natural scientists and physicians in Frankfurt/M on September 23, 1867, 1867) invented the notion of the heat death as the final destiny of the world. Nowadays it has become quiet around the heat death. Says Asimov [4] (Asimov’s Biographical Encyclopedia of Science and Technology, 1975): “Though the laws of thermodynamics stand as firmly as ever, cosmologists ... [show] a certain willingness to suspend judgement on the matter of heat death.” And we, the authors of this article, might add that present-day cosmologists know so little about the universe that heat death is a tiny spot in the sea of ignorance and therefore not worthy of discussion by serious scientists. All the more reason to take a fresh look at the subject.Now, however, this article is most definitely not a contribution to formal and technical cosmology as described in the monograph [5] (Cosmology, 2008) by S. Weinberg, or the popular booklet [6] (Fundamentals. Ten Keys to Reality, 2021) by F. Wilczek. Far from it! We treat a monatomic ideal gas under adiabatic conditions in two situations: The gas in a cylinder under a locked piston which – at some instance – is released; and a homogeneous cloud of gas at rest when – at some time – gravitation is “switched on”.It is only by a big leap of imagination that the two cases may be viewed as models for the universe. We also admit that we do not know whether the universe is adiabatic and free of working. Clausius and Gibbs thought so and we follow authority and investigate the validity of the prediction of the heat death and the related idea of the big crunch under these assumptions. We shall confirm the heat death as a very hot event but refute the big crunch.

Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children ≤2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 ± 0.01 and 0.13 ± 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7–13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0–9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.

Correction to: Journal of Clinical Immunology (2021) 41:1633–1647

In the last decade, treatment using Chimeric Antigen Receptor (CAR) are largely studied and demonstrate the potential of immunotherapeutic strategies, as seen mainly for blood related cancers. Still, efficient CAR-T cell approaches especially for the treatment of solid tumors are needed. Tn- and Sialyl-Tn antigens are tumor associated carbohydrate antigens correlating with poor prognosis and tumor metastasis on a variety of tumor entities. These glycans can be recognized by CD301 (CLEC10A, MGL), which is a surface receptor found primarily on immune cells. In the present study, we hypothesized, that it is possible to use newly generated CD301-bearing CARs, enabling cytotoxic effector cells to recognize and eliminate breast cancer cells. Thus, we genetically modified human NK92 cells with different chimeric receptors based on the carbohydrate recognition domain (CRD) of human CD301. We assessed their cytotoxic activity in vitro demonstrating the specific recognition of CD301 ligand positive cell lines. These results were confirmed by degranulation assays and in cytokine release assays. Overall, this study demonstrates CD301-CARs represent a cost-effective and fast alternative to conventional scFv CARs for cancer immunotherapy.

With the advent of cloud computing, where computational resources are expensive and data movement needs to be secured and minimized, database management systems need to reconsider their architecture to accommodate such requirements. In this paper, we present our analysis, design and evaluation of an FPGA-based hardware accelerator for offloading compression and encryption for SAP HANA, SAP's Software-as-a-Service (SaaS) in-memory database. Firstly, we identify expensive data-transformation operations in the I/O path. Then we present the design details of a system consisting of compression followed by different types of encryption to accommodate different security levels, and identify which combinations maximize performance. We also analyze the performance benefits of offloading decryption to the FPGA followed by decompression on the CPU. The experimental evaluation using SAP HANA traces shows that analytical engines can benefit from FPGA hardware offloading. The results identify a number of important trade-offs (e.g., the system can accommodate low-latency secured transactions to high-performance use cases or offer lower storage cost by also compressing payloads for less critical use cases), and provide valuable information to researchers and practitioners exploring the nascent space of hardware accelerators for database engines., Proceedings of the VLDB Endowment, 15 (12), ISSN:2150-8097

During the Grand Finale stage of the Cassini mission, organic-rich ring material was discovered to be flowing into Saturn's equatorial upper atmosphere at a surprisingly large rate. Through a series of photochemical models, we have examined the consequences of this ring material on the chemistry of Saturn's neutral and ionized atmosphere. We find that if a substantial fraction of this material enters the atmosphere as vapor or becomes vaporized as the solid ring particles ablate upon atmospheric entry, then the ring-derived vapor would strongly affect the composition of Saturn's ionosphere and neutral stratosphere. Our surveys of Cassini infrared and ultraviolet remote-sensing data from the final few years of the mission, however, reveal none of these predicted chemical consequences. We therefore conclude that either (1) the inferred ring influx represents an anomalous, transient situation that was triggered by some recent dynamical event in the ring system that occurred a few months to a few tens of years before the 2017 end of the Cassini mission, or (2) a large fraction of the incoming material must have been entering the atmosphere as small dust particles less than ~100 nm in radius, rather than as vapor or as large particles that are likely to ablate. Future observations or upper limits for stratospheric neutral species such as HC$_3$N, HCN, and CO$_2$ at infrared wavelengths could shed light on the origin, timing, magnitude, and nature of a possible vapor-rich ring-inflow event., Comment: accepted in Icarus

BACKGROUND Approximately 1700 children per year with end-stage kidney disease undergo kidney transplantation in Europe and the United States of America; 30%-50% are living donor kidney transplantations. There may be immunological differences between paternal and maternal donors due to transplacental exchange of cells between the mother and fetus during pregnancy leading to microchimerism. We investigated whether the outcome of living-related kidney transplantation in young children is different after maternal compared with paternal organ donation. METHODS Using the international Collaborative Transplant Study (CTS) database, we analyzed epidemiological data of 7247 children and adolescents aged

In the domain of high-energy physics (HEP), query languages in general and SQL in particular have found limited acceptance. This is surprising since HEP data analysis matches the SQL model well: the data is fully structured and queried using mostly standard operators. To gain insights on why this is the case, we perform a comprehensive analysis of six diverse, general-purpose data processing platforms using an HEP benchmark. The result of the evaluation is an interesting and rather complex picture of existing solutions: Their query languages vary greatly in how natural and concise HEP query patterns can be expressed. Furthermore, most of them are also between one and two orders of magnitude slower than the domain-specific system used by particle physicists today. These observations suggest that, while database systems and their query languages are in principle viable tools for HEP, significant work remains to make them relevant to HEP researchers., Proceedings of the VLDB Endowment, 15 (2), ISSN:2150-8097

Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.

Concurrency control is a cornerstone of distributed database engines and storage systems. In pursuit of scalability, a common assumption is that Two-Phase Locking (2PL) and Two-Phase Commit (2PC) are not viable solutions due to their communication overhead. Recent results, however, have hinted that 2PL and 2PC might not have such a bad performance. Nevertheless, there has been no attempt to actually measure how a state-of-the-art implementation of 2PL and 2PC would perform on modern hardware. The goal of this paper is to establish a baseline for concurrency control mechanisms on thousands of cores connected through a low-latency network. We develop a distributed lock table supporting all the standard locking modes used in database engines. We focus on strong consistency in the form of strict serializability implemented through strict 2PL, but also explore read-committed and repeatable-read, two common isolation levels used in many systems. We do not leverage any known optimizations in the locking or commit parts of the protocols. The surprising result is that, for TPC-C, 2PL and 2PC can be made to scale to thousands of cores and hundreds of machines, reaching a throughput of over 21 million transactions per second with 9.5 million New Order operations per second. Since most existing relational database engines use some form of locking for implementing concurrency control, our findings provide a path for such systems to scale without having to significantly redesign transaction management. To achieve these results, our implementation relies on Remote Direct Memory Access (RDMA). Today, this technology is commonly available on both Infiniband as well as Ethernet networks, making the results valid across a wide range of systems and platforms, including database appliances, data centers, and cloud environments., Proceedings of the VLDB Endowment, 12 (13), ISSN:2150-8097

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

The Cassini spacecraft completed 22 orbits around Saturn known as the ‘Grand Finale’ over a 5 month interval, during which time the spacecraft traversed the previously unexplored region between Saturn and its equatorial rings near periapsis. The magnetic field observations reveal the presence of temporally variable low‐latitude field‐aligned currents which are thought to be driven by velocity shears in the neutral zonal winds at magnetically conjugate thermospheric latitudes. We consider atmospheric waves as a plausible driver of temporal variability in the low‐latitude thermosphere, and empirically constrain the region in which they perturb the zonal flows to be between ±25◦ latitude. By investigating an extensive range of hypothetical wind profiles, we present and analyse a timeseries of the modelled velocity shears in thermospheric zonal flows, with direct comparisons to empirically inferred angular velocity shears from the Bϕ observations. We determine the maximum temporal variability in the peak neutral zonal winds over the Grand Finale interval to be ∼ 350 m/s assuming steady‐state ionospheric Pedersen conductances. We further show that the ionospheric currents measured must be in steady‐state on ∼ 10 minute timescales, and axisymmetric over ∼ 2 hours of local time in the near‐equatorial ionosphere. Our study illustrates the potential to use of magnetospheric datasets to constrain atmospheric variability in the thermosphere region.

Background Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. Methods MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. Results HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. Conclusions The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable., Graphical abstract Unlabelled Image

Hematopoietic stem cell transplantation (HSCT) following myeloablative conditioning represents the only curative treatment option to overcome numerous hematologic malignancies. Despite the overall clinical success to achieve reconstitution of the blood system in many patients, the length of the aplastic phase until recovery response remains a critical parameter for patient survival. Fatal infections are the major risk factor for immunocompromised individuals and in many cases lead to transplant related morbidity and mortality. Therefore, we hypothesized that transplants from young donors might be beneficial for the spatiotemporal blood reconstitution in comparison to old grafts. Here we report on our multicolor-coded barcode system (BC32) to track hematopoietic stem and progenitor cell (HSPC) populations in a murine model of HSCT. By using different experimental settings of young and aged donor and recipient animals we compared the influence of age on graft composition, leukocyte recovery and more precisely, the contribution of individual HSPC subpopulations to the process. We show that blood reconstitution is substantially driven and maintained by HSCs and MPPs, while the latter accounted for higher output rates than HSCs, confirmed by FACS and NGS analyses. Reconstitution patterns were highly polyclonal and stable in all animals aside from variability between individual animals. This leads to the conclusion that HSPCs home, engraft and differentiate independently of donor and recipient age in our experimental conditions. Our findings add to ongoing efforts to expand the application of HSCT in older individuals while minimizing therapy related risks resulting from intensive myeloablative conditioning or incomplete blood reconstitution.

Immunotherapy with CD19-specific chimeric antigen receptor (CAR-) T cells has shown excellent efficacy in relapsed/refractory B-cell cancers. The in vivo expansion and persistence of CAR-T cells after infusion are important response- and toxicity-determining variables, but diagnostic tools are largely missing. We showed previously for axi-cel that digital PCR (dPCR) is excellently suited to monitoring CAR-T cells in vivo. Here, we aimed to develop an analogous dPCR assay for tisa-cel. To do so, we cloned and sequenced the CAR construct from the lentiviral tisa-cel vector and designed primers and Black hole quencher (BHQ) probes complimentary to sequences present in the FMC63 scFv part of axi-cel (assay A), tisa-cel (T), and both constructs (U = &ldquo, universal&rdquo, ). In conjunction with excellent specificity, all assays have a detection limit of one single CAR copy, corresponding to a sensitivity of approximately 1 in 5000 cells (0.02%) for 100 ng genomic DNA (for one vector copy per transduced cell). The new universal assay was first validated using patient samples previously quantified with the axi-cel-specific dPCR and thereafter applied to quantify and monitor adoptively transferred axi-cel and tisa-cel T cells in post-infusion samples (peripheral blood, bone marrow, liquor, and ascites). Actual CAR-T counts per &micro, l were calculated, taking into account vector copy and peripheral blood mononuclear cell (PBMC) numbers, and showed very good correlation with flow cytometry results. We conclude that our novel dPCR assay is optimally suited to monitoring tisa-cel and axi-cel CAR-T cells in real-time in various body fluids.

BACKGROUND Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if

Getting the best performance from the ever-increasing number of hardware platforms has been a recurring challenge for data processing systems. In recent years, the advent of data science with its increasingly numerous and complex types of analytics has made this challenge even more difficult. In practice, system designers are overwhelmed by the number of combinations and typically implement a single analytics type on one platform, leading to repeated implementation effort---and a plethora of semi-compatible tools for data scientists. In this paper, we propose the "Collection Virtual Machine" (or CVM)---an extensible compiler framework designed to keep the specialization process of data analytics systems tractable. It can capture at the same time the essence of a large span of low-level, hardware-specific implementation techniques as well as high-level operations of different types of analyses. At its core lies a language for defining nested, collection-oriented intermediate representations (IRs). Frontends produce programs in their IR flavors defined in that language, which get optimized through a series of rewritings (possibly changing the IR flavor multiple times) until the program is finally expressed in an IR of platform-specific operators. While reducing the overall implementation effort, this also improves the interoperability of both analyses and hardware platforms. We have used CVM successfully to build specialized backends for platforms as diverse as multi-core CPUs, RDMA clusters, and serverless computing infrastructure in the cloud and expect similar results for many more frontends and hardware platforms in the near future., Proceedings of the 16th International Workshop on Data Management on New Hardware, DaMoN '20, ISBN:978-1-4503-8024-9

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for II-IV (95% confidence interval [CI], 16% to 37%) and 7% for III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHDfree survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (, SCOPUS: ar.j, info:eu-repo/semantics/published

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I–IV and 26.6% for grades II–IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.