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Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS -DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL -DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS -DBA was characterized by erythroid differentiation arrest, whereas RPL -DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL -DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.

Background: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD., Methods: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available., Results: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease., Conclusion: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD., (© 2019 Wiley Periodicals, Inc.)

Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 10 9/L ) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: This is the first documented case of a patient with hemophagocytic lymphohistiocytosis in association with coeliac disease. There was complete clinical and biochemical remission of hemophagocytic lymphohistiocytosis following the introduction of a gluten-free diet., Case Presentation: A 7-year-old white girl presented with fevers and maculopapular rash with a recent history of tonsillitis. Blood tests revealed thrombocytopenia (64×10 9 /L), anemia (80 g/L), hypofibrinogenemia (1 g/L), and hyperferritinemia (71,378 μg/L). A bone marrow revealed evidence of hemophagocytosis, but the results of tests for the genetic or familial-associated hemophagocytic lymphohistiocytosis syndromes were negative. The results of screening tests for known secondary causes were negative. She was diagnosed as having hemophagocytic lymphohistiocytosis and following treatment with the hemophagocytic lymphohistiocytosis-2004 protocol these symptoms, in addition to the biochemical and hematological markers, completely resolved. She presented again 10 months later with fever, rash, and biochemical abnormalities suggestive of hemophagocytic lymphohistiocytosis. Her tissue transglutaminase was markedly raised and the results of blood tests revealed a genetic susceptibly to coeliac disease in the form of HLA-DQ2 positivity. She commenced a gluten-free diet and there was complete symptomatic and biochemical response without any further chemotherapy. She had further episodic rashes, each associated with the accidental intake of gluten., Conclusions: This is to the best of our knowledge the first documented case of hemophagocytic lymphohistiocytosis in association with coeliac disease. No other secondary cause found; she initially responded to chemoimmunotherapy specific for hemophagocytic lymphohistiocytosis but relapsed within a few months of cessation of treatment and then achieved complete remission on gluten withdrawal alone.

When dysregulated, skin fibrosis can lead to a multitude of pathologies. We provide a framework for understanding the wide clinical spectrum, mechanisms, and management of cutaneous fibrosis encompassing a variety of matrix disorders, fibrohistiocytic neoplasms, injury-induced scarring, and autoimmune scleroses. Underlying such entities are common mechanistic pathways that leverage morphogenic signaling, immune activation, and mechanotransduction to modulate fibroblast function. In light of the limited array of available treatments for cutaneous fibrosis, scientific insights have opened new therapeutic and investigative avenues for conditions that still lack effective interventions. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a hereditary blood disorder characterized by abnormal hemoglobin, leading to the sickle shape of red blood cells. It has several vascular complications and the cerebrovascular ones are among the most frequent and severe both in children and in adults. This review summarizes the main neurovascular manifestations of SCD, including acute stroke, silent cerebral infarction, large-vessel diseases (moyamoya arteriopathy and aneurysms), and brain bleeding. Both epidemiology, pathophysiology, and treatment issues are addressed and prevention of cerebrovascular events, including silent cerebral infarctions, is particularly relevant in SCD patients, being associated to poor functional outcome and cognitive complaints. Transfusions and hydroxyurea are the main available therapy at the moment, but contraindications, availability, and complications might prevent their long term use, particularly in low-income countries. The role of transcranial Doppler in monitoring the patients (mainly children) is analyzed and a practical approach has been selected in order to give the main messages from the current literature for a better management of SCD patients. [ABSTRACT FROM AUTHOR]

Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the "barcode" hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and β-arrestin recruitment, and for a synthetic biased agonist that only stimulates β-arrestin recruitment. The endogenous and β-arrestin–biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full β-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on β-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable β-arrestin–receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling. Editor's summary: The specific patterns of phosphorylation in the intracellular tail of a G protein–coupled receptor (GPCR) are thought to act as a barcode that determines whether G proteins are stimulated or β-arrestins are recruited. Gareri et al. investigated the role of phosphorylation barcodes in signaling by the angiotensin II type 1 receptor (AT1R). AT1R elicits both G protein activation and β-arrestin recruitment in response to the endogenous agonist AngII but stimulates only β-arrestin recruitment in response to a synthetic biased agonist. The authors identified patterns of serine and threonine phosphorylation that stabilized specific conformations of β-arrestin and were necessary for β-arrestin function. These findings demonstrate the importance of phosphorylation barcodes in determining the consequences of AT1R activation. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

The AA6082-T6 was experimentally studied in the present research with respect to the drilling performance. Drill diameter, cutting speed and feed rate were examined, using a full factorial design. Mathematical modelling of the process was carried out using the Response Surface Methodology (RSM) as well as the Artificial Neural Network (ANN) techniques. The output results in terms of cutting force, torque and surface roughness, revealed high levels of correlation between the experimental and the predicted data. Specifically, the Mean Absolute Percentage Error (MAPE) values using RSM compared to the ones of the experiments, were equal to 2.14%, 3.49% and 6.16% for Fz, Mz and Ra respectively. The equivalent MAPE between the ANN and the experiments were found to be 2.19%, 1.82% and 2.85% accordingly. Moreover, the most significant terms were revealed, being the interaction D × f for the thrust force and the torque with contribution percentages equal to approximately 44% and 42% respectively, and the term D² for the surface roughness with 51%. The evaluation of the machining parameters, identified their significance, enabling the selection of the optimal cutting parameters, which were obtained by the desirability function, taking into account the importance of the generated surface quality and the reduction of cost. The solutions given by this approach, pointed out the Φ9 tool, coupled with Vc = 50 m/min and f = 0.15mm/rev as a well-balanced combination, whereas the Φ9.9 tool used under the same conditions, yielded the best possible surface quality (appr. 0.2 mm). [ABSTRACT FROM AUTHOR]

The stabilization of different active conformations of G protein–coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (AT1R) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When AT1R endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor–β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor–β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V2 vasopressin receptor and a mutant β2-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds. Editor's summary: Biased agonists of GPCRs stimulate signaling through either G proteins or β-arrestins, which is clinically relevant if one pathway is therapeutic and the other produces side effects. Tóth et al. found that the endocytosis of the angiotensin II receptor AT1R and other GPCRs determined signaling strength through the β-arrestin pathway. Blocking endocytosis elicited responses from weak β-arrestin–biased agonists that resembled those generated by full agonists. As a result, ligand efficacy in β-arrestin signaling may be determined more by spatiotemporal regulation than by the induction of different receptor conformations at the plasma membrane by distinct agonists. These findings may guide the development of GPCR-targeting drugs that more effectively produce only the desired therapeutic response. —John F. Foley [ABSTRACT FROM AUTHOR]

Background: Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. Objectives: The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. Methods: We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Results: Nineteen participants (13.1 ± 1.2 years [3.3-20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Conclusion: Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT. Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837). [ABSTRACT FROM AUTHOR]

Children with sickle cell disease (SCD) may experience cognitive difficulties, including slowed processing speed. Thus, we investigated if processing speed changes over time. From 1992–2001, 103 participants with SCD aged 3–16 years (n ≤ 8.99 = 45; n ≥ 9.00 = 58) completed cognitive assessments. MRI was available for 54 participants. Between 1992–2002, 58 participants consented to one or two further assessments. A repeated measures regression using linear mixed-effects modelling determined longitudinal changes in processing speed index (PSI), examining the interaction between age (continuous variable) and timepoint (i.e., assessment 1 or 3) and controlling for MRI infarct status (i.e., no infarct, silent infarct, or stroke). Those aged ≤8.99 and ≥9.00 at first assessment experienced PSI decline. Declines were most prominent for the processing speed coding subtest, with a significant interaction between timepoint and age, t(31) = 2.64, p = 0.01. This decline may reflect a developmental delay, likely due to disease progression, with slower improvements in processing speed. Although there have been significant improvements in SCD treatments, mostly in high-income countries, processing speed still remains a target; thus, incorporating clinical monitoring of processing speed may help identify delay and allow for early intervention. [ABSTRACT FROM AUTHOR]

Erythroid cells, the most prevalent cell type in blood, are one of the earliest products and permeate through the entire process of hematopoietic development in the human body, the oxygen-transporting function of which is crucial for maintaining overall health and life support. Previous investigations into erythrocyte differentiation and development have primarily focused on population-level analyses, lacking the single-cell perspective essential for comprehending the intricate pathways of erythroid maturation, differentiation, and the encompassing cellular heterogeneity. The continuous optimization of single-cell transcriptome sequencing technology, or single-cell RNA sequencing (scRNA-seq), provides a powerful tool for life sciences research, which has a particular superiority in the identification of unprecedented cell subgroups, the analyzing of cellular heterogeneity, and the transcriptomic characteristics of individual cells. Over the past decade, remarkable strides have been taken in the realm of single-cell RNA sequencing technology, profoundly enhancing our understanding of erythroid cells. In this review, we systematically summarize the recent developments in single-cell transcriptome sequencing technology and emphasize their substantial impact on the study of erythroid cells, highlighting their contributions, including the exploration of functional heterogeneity within erythroid populations, the identification of novel erythrocyte subgroups, the tracking of different erythroid lineages, and the unveiling of mechanisms governing erythroid fate decisions. These findings not only invigorate erythroid cell research but also offer new perspectives on the management of diseases related to erythroid cells., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breakthroughs in precision cell surface engineering tools are supporting the rapid development of programmable living assemblies with valuable features for tackling complex biological problems. Herein, the authors overview the most recent technological advances in chemically‐ and biologically‐driven toolboxes for engineering mammalian cell surfaces and triggering their assembly into living architectures. A particular focus is given to surface engineering technologies for enabling biomimetic cell–cell social interactions and multicellular cell‐sorting events. Further advancements in cell surface modification technologies may expand the currently available bioengineering toolset and unlock a new generation of personalized cell therapeutics with clinically relevant biofunctionalities. The combination of state‐of‐the‐art cell surface modifications with advanced biofabrication technologies is envisioned to contribute toward generating living materials with increasing tissue/organ‐mimetic bioactivities and therapeutic potential. [ABSTRACT FROM AUTHOR]

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Allogeneic stem cell transplantation (Allo-SCT) is the only rapidly available curative treatment modality in patients with severe sickle cell disease (SCD). The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to Allo-SCT. Antibodies against donor-specific HLA (DSA) increase the risk of engraftment failure in HLA mismatched Allo-SCT. We report the results of five patients with SCD, whereas three with DSA, who underwent an unmanipulated haploidentical stem cell transplantation (Haplo-SCT) after a busulfan-based RT-MAC regimen with PT-Cy. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immune suppression (PTIS) phase was added prior to the conditioning regimen. All patients engrafted successfully. The procedure was well tolerated. None of the patients developed acute GVHD, whereas one developed moderate chronic GVHD. After a median follow-up of 5 years (range, 2.2-9), all patients are free of pain with excellent quality of life. Our report shows that Haplo-SCT after a RT-MAC regimen is feasible and safe with stable long-term engraftment and excellent disease control. The risk of graft failure can be abrogated by adding a PTIS phase prior to initiating the conditioning regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Adoptive immunotherapy utilizing natural killer (NK) cells has demonstrated remarkable efficacy in treating hematologic malignancies. However, its clinical intervention for solid tumors is hindered by the limited expression of tumor-specific antigens. Herein, lipid-PEG conjugated hyaluronic acid (HA) materials (HA-PEG-Lipid) for the simple ex-vivo surface coating of NK cells is developed for 1) lipid-mediated cellular membrane anchoring via hydrophobic interaction and thereby 2) sufficient presentation of the CD44 ligand (i.e., HA) onto NK cells for cancer targeting, without the need for genetic manipulation. Membrane-engineered NK cells can selectively recognize CD44-overexpressing cancer cells through HA-CD44 affinity and subsequently induce in situ activation of NK cells for cancer elimination. Therefore, the surface-engineered NK cells using HA-PEG-Lipid (HANK cells) establish an immune synapse with CD44-overexpressing MIA PaCa-2 pancreatic cancer cells, triggering the "recognition-activation" mechanism, and ultimately eliminating cancer cells. Moreover, in mouse xenograft tumor models, administrated HANK cells demonstrate significant infiltration into solid tumors, resulting in tumor apoptosis/necrosis and effective suppression of tumor progression and metastasis, as compared to NK cells and gemcitabine. Taken together, the HA-PEG-Lipid biomaterials expedite the treatment of solid tumors by facilitating a sequential recognition-activation mechanism of surface-engineered HANK cells, suggesting a promising approach for NK cell-mediated immunotherapy., (© 2023 Wiley‐VCH GmbH.)

G protein–coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gαq and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gαq coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation. Residue stretches in transmembrane domain 4 conferred β-arrestin bias and represented an important structural element in AT1R for functional selectivity. Furthermore, we identified allosteric small-molecule binding sites that were enclosed by communities of residues that produced biased signaling when mutated. Last, we showed that allosteric communication within AT1R emanating from the Gαq coupling site spread beyond the orthosteric AngII-binding site and across different regions of the receptor, including currently unresolved structural regions. Our findings reveal structural elements and mechanisms within AT1R that bias Gαq and β-arrestin coupling and that could be harnessed to design biased receptors for research purposes and to develop allosteric modulators. Editor's summary: The angiotensin II type 1 receptor (AT1R) exerts distinct biological effects depending on whether it couples to the G protein Gαq or the scaffolding protein β-arrestin. To identify residues that allosterically regulated effector coupling, Cao et al. characterized 359 alanine or glycine substitution mutants of AT1R. Those that affected Gαq coupling occurred throughout the receptor in multiple structural regions and were greater in number than those that modulated β-arrestin coupling, which were concentrated in transmembrane domain 4. Many residues were distal to the ligand-binding site. Moreover, AT1R contained multiple allosteric communication pathways, suggesting the possibility of identifying additional sites to allosterically modulate signaling downstream of AT1R activation. –Wei Wong [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft-versus-host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Raman spectroscopy is of course a well-established analytical technique due to its ability to provide highly specific Raman fingerprints for purposes of identifying molecular components in simple and complex samples. Coherent Raman spectroscopies can offer significant advantages over spontaneous Raman observations for some applications, as has been well established since the commercial accessibility of high-powered lasers in the visible. Central to this work is a machine learning-assisted low-frequency Raman based methodology, informed by DFT results, that can characterize the twist angle of these thin layered samples. [Extracted from the article]

The structural quality of the catalytic transition metal substrate plays a critical role in pristine graphene synthesis by chemical vapor deposition. In this work, the microstructural parameters of commercial copper foils are investigated in lieu of conventional laboratory grade crystalline copper foils. Initially, the commercial copper foils are simultaneously plasma etched and heat treated for a period of 30, 45 min, and 1 h respectively at two elevated temperature levels of 823 and 923 K under the exposure of hydrogen plasma. The experiments are carried out in a 2.45 GHz Electron Cyclotron Resonance (ECR) Plasma Enhanced Chemical Vapor Deposition (PE‐CVD) reactor, at an operating pressure of 5 × 10−2 mbar. X‐ray diffraction (XRD) results are plotted and analyzed by Williamson–Hall (W–H) method to determine microstructural parameters, e.g., micro‐strain, stress, average domain size, and energy density associated to the processed copper foils. [ABSTRACT FROM AUTHOR]

Despite significant improvements in the supportive care, sickle cell disease (SCD) leads to significant morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (HSCT), the only curative option, is limited due to matched donor availability. This could be met with T-cell-depleted haploidentical HSCT. Twenty advanced-stage SCD patients, median age 15 years, and 9 patients, median age 14 years, were transplanted with CD3/CD19- or TCRαβ/CD19-depleted grafts and from matched sibling donors (MSDs). The conditioning consisted of ATG, thiotepa, fludarabine, and treosulfan. The median follow-up in the T-haplo-HSCT and the MSD patients was 21 (9-62) and 25 (7-60) months, respectively. The OS in the T-haplo-HSCT and MSD was 90% and 100%, respectively. In the T-haplo-HSCT group, two patient succumbed to a CMV pneumonitis and a macrophage activation syndrome (MAS). One patient in the T-haplo-HSCT group requires renal replacement therapy because of BK virus nephritis. None developed grade III-IV acute GvHD. In the T-haplo-HSCT and in the MSD, 20% and 22%, respectively, developed a mild or moderate chronic GvHD. These results demonstrate the feasibility, safety, and efficacy of T-haplo-HSCT also for adult advanced stage SCD patients.

Molecular recognition at the biointerface plays a critical role in sensing molecular interactions (e.g., DNA hybridization) and extracellular changes, which can directly affect the detection performance of biosensors (e.g., sensitivity, specificity, and response dynamics). However, conventional sensing biointerfaces show low molecular recognition efficiency due to limited target accessibility. Engineering sensing biointerfaces to regulate the orientation, spacing, and density of surface‐confined molecular probes offer an effective approach to improve molecular recognition at interfaces. Over the last decades, biointerface engineering with nucleic acid materials has advanced the fundamental understanding of DNA hybridization kinetics and facilitated the design of improved biosensing platforms for monitoring cellular activities and diagnosing relevant diseases. This review summarizes the recent progress in nucleic acid‐based biointerface engineering. The development of nucleic acid materials that can be applied to specific diagnostic applications is briefly introduced. Then the roles of nucleic acids in tailoring the properties of nanosurfaces, cell surfaces, and macroscopic surfaces are discussed and their biosensing applications are comprehensively highlighted. Finally, future challenges and perspectives of emerging technologies and applications in the field are presented. [ABSTRACT FROM AUTHOR]

Secondary hemophagocytic lymphohistiocytosis (sHLH) has historically been defined as a cytokine storm syndrome (CSS) occurring in the setting of triggers leading to strong and dysregulated immunological activation, without known genetic predilection. However, recent studies have suggested that existing underlying genetic factors may synergize with particular diseases and/or environmental triggers (including infection, autoimmune/autoinflammatory disorder, certain biologic therapies, or malignant transformation), leading to sHLH. With the recent advances in genetic testing technology, more patients are examined for genetic variations in primary HLH (pHLH)-associated genes, including through whole exome and whole genome sequencing. This expanding genetic and genomic evidence has revealed HLH as a more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Rather than a simple, binary definition of pHLH and sHLH, HLH represents a spectrum of diseases, from a severe complication of common infections (EBV, influenza) to early onset familial diseases that can only be cured by transplantation., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Hematopoietic stem cell transplantation (HSCT) is a well-established curative therapy for patients with sickle cell disease (SCD) when using a human leukocyte antigen (HLA)-matched sibling donor. Most patients with SCD do not have a matched sibling donor, thereby significantly limiting the accessibility of this curative option to most patients. HLA-haploidentical HSCT with post-transplant cyclophosphamide expands the donor pool, with current approaches now demonstrating high overall survival, reduced toxicity, and an effective reduction in acute and chronic graft-vs.-host disease (GvHD). Alternatively, autologous genetic therapies appear promising and have the potential to overcome significant barriers associated with allogeneic HSCT, such as donor availability and GvHD. Here the authors each take a viewpoint and discuss what will be the future of curative options for patients with SCD outside of a matched sibling transplantation, specifically haploidentical HSCT vs. gene therapy. [ABSTRACT FROM AUTHOR]

One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is associated with severe morbidity and early mortality. Two large population studies found an increased risk for leukemia in individuals with SCD. Notably, while the relative risk of leukemia development is high, the absolute risk is low in individuals with SCD who do not receive cell-based therapies. However, the risk of leukemia in SCD is high after graft rejection and with gene therapy. Clonal hematopoiesis (CH) is a well-recognized premalignant condition in the general population and in patients after high-dose myelotoxic therapies. Recent studies suggest that CH may be more common in SCD than in the general population, outside the cell-based therapy setting. Here, we review risk factors for CH and progression to leukemia in SCD. We surmise why patients with SCD are at an increased risk for CH and why leukemia incidence is unexpectedly high after graft rejection and gene therapy for SCD. Currently, we are unable to reliably assess genetic risk factors for leukemia development after curative therapies for SCD. Given our current knowledge, we recommend counseling patients about leukemia risk and discussing the importance of an individualized benefit/risk assessment that incorporates leukemia risk in patients undergoing curative therapies for SCD. [ABSTRACT FROM AUTHOR]

The goal of curing children and adults with sickle cell disease (SCD) is to maximize benefits and minimize intermediate and long-term adverse outcomes so that individuals can live an average life span with a high quality of life. While greater than 2000 individuals with SCD have been treated with curative therapy, systematic studies have not been performed to evaluate the long-term health effects of hematopoietic stem cell transplant (HSCT) in this population. Individuals with SCD suffer progressive heart, lung, and kidney disease prior to curative therapy. In adults, these sequalae are associated with earlier death. In comparison, individuals who undergo HSCT for cancer are heavily pretreated with chemotherapy, resulting in potential acute and chronic heart, lung, and kidney disease. The long-term health effects on the heart, lung, and kidney for children and adults undergoing HSCT for cancer have been extensively investigated. These studies provide the best available data to extrapolate the possible late health effects after curative therapy for SCD. Future research is needed to evaluate whether HSCT abates, stabilizes, or exacerbates heart, lung, kidney, and other diseases in children and adults with SCD receiving myeloablative and non-myeloablative conditioning regimens for curative therapy. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) is an inherited blood disorder that is associated with developmental delays and neurocognitive deficits. This review details key findings related to neurocognitive outcomes for children and adults with emphasis on the impact of neurological correlates and disease severity. Associations between neurocognition, demographic factors and social determinants of health are also reviewed. Emerging literature has reported on the neurocognitive impact of SCD in children and adolescents in Africa and Europe, including children from immigrant communities. Neurocognitive deficits are linked to poor functional outcomes, including transition from paediatric to adult care, medication adherence and unemployment. Integrating neuropsychology into multidisciplinary care for individuals with SCD can assist with identification and management of neurocognitive concerns, intervention development, individualized care plan development and continued multidisciplinary research. [ABSTRACT FROM AUTHOR]

Introduction We present data on the impact of donor characteristics in a uniform cohort of children who underwent hematopoietic stem cell transplantation (HSCT) for thalassemia major. Patients and methods We performed a retrospective study in children undergoing matched related (MRD) or unrelated (MUD) HSCT from January 2009 to December 2019. Results We analyzed data on 250 patients (age seven months-19 years), MRD n = 187, MUD n = 63. We documented sex mismatch in 44% of HSCTs. The graft rejection rate was 3.7%; all had a sex mismatched HSCT (P value = 0.001). Graft versus host disease (GVHD) was higher when donors were above two years as compared to less than two years (23%vs.6.5%, P value = 0.006), with higher rates of mixed chimerism when donors were < two years at 33.3%vs.8.3% in > two years (P value = 0.0001). Mortality and GVHD were higher in the MUD group as compared to the MRD group (15%vs.5%, P value = 0.009; 42.9%vs. 23.4%, P value = 0.0001 respectively). Overall survival was 92.8% with a median follow up of 5.4 years, and was superior in MRD versus MUD group (9.4 years versus 4.8 years P = 0.008). Conclusion The risk of graft rejection was higher with donor-recipient sex mismatch; while initial mortality and chronic GVHD was higher with MUD HSCT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a lifesaving therapy for hematological malignancies. For years, a fully matched HLA donor was a requisite for the procedure. However, new immunosuppressive strategies have enabled the recruitment of viable alternative donors, particularly haploidentical donors. Over 95% of patients have at least two potential haploidentical donors available to them. To identify the best haploidentical donor, the assessment of new immunogenetic criteria could help. To this end, the clinical benefit of KIR genotyping in aHSCT has been widely studied but remains contentious. This review aims to evaluate the importance of KIR-driven NK cell alloreactivity in the context of aHSCT and explain potential reasons for the discrepancies in the literature. Here, through a non-systematic review, we highlight how the studies in this field and their respective predictive models or scoring strategies could be conceptually opposed, explaining why the role of NK cells remains unclear in aHCST outcomes. We evaluate the limitations of each published prediction model and describe how every scoring strategy to date only partly delivers the requirements for optimally effective NK cells in aHSCT. Finally, we propose approaches toward finding the optimal use of KIR genotyping in aHSCT for a unified criterion for donor selection. [ABSTRACT FROM AUTHOR]

This study emphasizes the comparative cutting performance evaluation of CVD- and PVD-coated carbide inserts in hard turning of AISI D2 steel. The cutting factors, namely cutting speed (100 m/min), tool feed rate (0.08 mm/rev), and depth of cut 0.2 mm, have been fixed for the entire study. The comparative study is based on the analysis of the obtained test results of flank wear, tool life, auxiliary flank wear, surface roughness, and surface texture. Both tools are catastrophically failed when tool wear reached limiting flank wear (VBc = 0. 3 mm) criteria. SEM and EDS analysis of both the tools (at their end of tool life) are carried. Diffusion followed by adhesion is found to be the prime mechanism at the end of tool life. Based on limiting flank wear criteria, the tool life of CVD and PVD tools was estimated as 65 and 57 min, respectively, i.e. the tool life of the CVD tool is 14% longer than that of the PVD tool. Considering the limiting criteria of surface roughness (Ra = 1. 6 μ m), the tool life of the CVD tool was estimated as 63 min while for the PVD tool, it was found as 54 min i.e. about 14.3% higher tool life was found for the CVD tool relative to the PVD tool. The auxiliary flank wear was observed to be lower for the CVD tool relative to the PVD tool. Surface roughness for both the tools increased with cutting time and the relatively larger rough surface was obtained with the PVD tool. The machining cost of one pass of the CVD tool is 2.5% less than that of the PVD tool. However, for mass production, the CVD tool is more efficient than the PVD tool for machining hard D2 steel (5 7 ± 1 HRC). [ABSTRACT FROM AUTHOR]