Single Cord Blood Combined with HLA-Mismatched Third Party Donor Cells: Comparable Results to Matched Unrelated Donor Transplantation in High-Risk Patients with Hematologic Disorders

AbstractMatched unrelated donor (MUD) transplantation is the first alternative in the absence of a matched sibling donor. For patients without a suitable adult donor, we have adopted the dual stem cell transplantation protocol consisting of cord blood (CB) in combination with CD34+ cells from a third party HLA-mismatched donor. We analyzed the outcomes of patients undergoing both procedures in a single center. Starting in 2004, a total of 20 patients with high-risk disease underwent 22 dual transplants and 25 patients underwent myeloablative MUD transplantation. The 30-day cumulative incidence of neutrophil engraftment was similar in both groups (91% and 95%), with a median time to engraftment of 14 and 16 days, respectively. Grade II-IV acute graft-versus-host disease was more frequent in the MUD group (40% versus 5%). Except for a tendency toward a higher incidence of viral hemorrhagic cystitis in the dual transplantation group, posttransplantation infectious events were comparable in the 2 groups. The 3-year cumulative incidence rates of relapse (41% versus 44%) and nonrelapse mortality (30% versus 25%) were similar in the MUD and dual transplantation cohorts. Estimated 3-year overall survival and disease-free survival were 47% and 41%, respectively, with no survival advantage for either group. In our experience, dual transplantation offers survival rates comparable to those from myeloablative MUD transplantation with similar nonrelapse mortality rates

Chitosan coated alginate beads containing poly(N-isopropylacrylamide) for dual-stimuli-responsive drug release

Chitosan coated alginate beads containing poly(N-isopropylacrylamide) (PNIPAAM), were prepared to be used as a controlled pH/temperature sensitive drug delivery system with improved encapsulation efficiency and delayed release rate. The studied beads were characterized by differential scanning calorimetry, scanning electron microscopy, and Fourier transform infrared spectroscopy. Water uptake and release studies using indomethacin as a model drug were also performed. The drug loading efficiency of the beads with the polyelectrolyte complex coating is significantly higher (84%) than that of the uncoated ones (74%). The equilibrium swelling of the developed materials was found to be pH- and thermoresponsive. For all the conditions it was found that the release profile was slower for the coated beads, indicating that the polyelectrolyte complex coating could slow down the release rate effectively. These results suggest that the studied smart system has potential to be used as an effective pH/temperature sustainable delivery system for biomedical applications

Evaluation of Minimal Residual Disease by Real-Time Quantitative PCR of Wilms’ Tumor 1 Expression in Patients with Acute Myelogenous Leukemia after Allogeneic Stem Cell Transplantation: Correlation with Flow Cytometry and Chimerism

Relapse remains the main cause of treatment failure in patients with acute myelogeous leukemia (AML) after allogeneic hemopoietic stem cell transplantation (SCT). The Wilms’ tumor 1 gene (WT1) is reportedly overexpressed in >90% of patients with AML and thus can be useful for minimal residual disease (MRD) monitoring. The aim of this study was to evaluate the usefulness of WT1 expression as a relapse predictor marker in patients with AML after SCT and compare it with flow cytometry (FC) and chimerism studies. WT1 expression was assessed retrospectively using quantitative RT-PCR in bone marrow and peripheral blood from 21 patients. Patients were classified according to WT1 dynamics posttransplantation. Eleven of the 21 patients had low and stable WT1 levels. All of these 11 patients showed complete chimerism and negative MRD by FC and remained in complete remission with a median follow-up of 27 months (range, 18-98 months). In contrast, 10 of 21 patients showed WT1 overexpression after SCT, and 9 of these 10 patients relapsed. The incidence of relapse differed significantly between the 2 groups of patients according to WT1 expression post-SCT (P = .00003). Relapse in the 9 patients occurred at a median of 314 days (range, 50-560 days). Interestingly, in these patients, relapse was first predicted by WT1 (with negative FC and complete chimerism) in 7 patients. WT1 overexpression was correlated with disease burden in patients with AML before and after allogeneic SCT. In patients who relapsed, both medullary and extramedullary relapse were better anticipated by WT1 overexpression compared with FC and chimerism

Performance of QuantiFERON-TB Gold Plus assays in children and adolescents at risk of tuberculosis: a cross-sectional multicentre study

Introduction: The QuantiFERON-TB Gold Plus (QFT-Plus) assay, which features two antigen-stimulated tubes (TB1 and TB2) instead of a single tube used in previous-generation interferon-gamma release assays (IGRAs), was launched in 2016. Despite this, data regarding the assay’s performance in the paediatric setting remain scarce. This study aimed to determine the performance of QFT-Plus in a large cohort of children and adolescents at risk of tuberculosis (TB) in a low-burden setting. Methods: Cross-sectional, multicentre study at healthcare institutions participating in the Spanish Paediatric TB Research Network, including patients <18 years who had a QFT-Plus performed between September 2016 and June 2020. Results: Of 1726 patients (52.8% male, median age: 8.4 years), 260 (15.1%) underwent testing during contact tracing, 288 (16.7%) on clinical/radiological suspicion of tuberculosis disease (TBD), 649 (37.6%) during new-entrant migrant screening and 529 (30.6%) prior to initiation of immunosuppressive treatment. Overall, the sensitivity of QFT-Plus for TBD (n=189) and for latent tuberculosis infection (LTBI, n=195) was 83.6% and 68.2%, respectively. The agreement between QFT-Plus TB1 and TB2 antigen tubes was excellent (98.9%, κ=0.961). Only five (2.5%) patients with TBD had discordance between TB1 and TB2 results (TB1+/TB2−, n=2; TB1−/TB2+, n=3). Indeterminate assay results (n=54, 3.1%) were associated with young age, lymphopenia and elevated C reactive protein concentrations. Conclusions: Our non-comparative study indicates that QFT-Plus does not have greater sensitivity than previous-generation IGRAs in children in both TBD and LTBI. In TBD, the addition of the second antigen tube, TB2, does not enhance the assay’s performance substantially

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence. © 2024, The Author(s)

The structure of the complex between a-tubulin, TBCE and TBCB reveals a tubulin dimer dissociation mechanism

Tubulin proteostasis is regulated by a group of molecular chaperones termed tubulin cofactors (TBC). Whereas tubulin heterodimer formation is well-characterized biochemically, its dissociation pathway is not clearly understood. Here, we carried out biochemical assays to dissect the role of the human TBCE and TBCB chaperones in a-tubulin–b-tubulin dissociation. We used electron microscopy and image processing to determine the three-dimensional structure of the human TBCE, TBCB and a-tubulin (aEB) complex, which is formed upon a-tubulin–b-tubulin heterodimer dissociation by the two chaperones. Docking the atomic structures of domains of these proteins, including the TBCE UBL domain, as we determined by X-ray crystallography, allowed description of the molecular architecture of the aEB complex. We found that heterodimer dissociation is an energy-independent process that takes place through a disruption of the a-tubulin–b-tubulin interface that is caused by a steric interaction between b-tubulin and the TBCE cytoskeleton-associated protein glycine-rich (CAP-Gly) and leucine-rich repeat (LRR) domains. The protruding arrangement of chaperone ubiquitin-like (UBL) domains in the aEB complex suggests that there is a direct interaction of this complex with the proteasome, thus mediating a-tubulin degradation

Long-term postharvest aroma evolution of tomatoes with the alcobaça (alc) mutation

The postharvest evolution of Penjar tomatoes has been studied in four accessions representative of the variability of the varietal type. The long-term shelf life of these materials, which carry the alc allele, was confirmed with 31.2-59.1% of commercial fruits after 6 months of effective conservation at room temperature and a limited loss of weight (21.1-27.9%). Aroma in Penjar tomatoes is differentiated from other tomato varieties by a characteristic 'sharp-floral' aroma descriptor. The evolution of the 'sharp-floral' aroma during postharvest showed a peak of intensity at 2 months of postharvest, though in one accession a delay of 2 months in this response was detected. Out of 25 volatiles analysed, including main and background notes, a reverse iPLS variable selection revealed that the main candidates behind this aromatic behaviour are ¿-terpineol, trans-2-hexenal, 6-methyl-5-hepten-2-one, trans-2-octenal, ¿-pinene, ß-ionone, 2 + 3-methylbutanol and phenylacetaldehyde. Between harvest and 2 months postharvest, most compounds reduced considerably their concentration, while the intensity of the 'sharp-floral' descriptor increased, which means that probably there is a rearrangement of the relative concentrations among volatiles that may lead to masking/unmasking processes. © 2011 Springer-Verlag.This work was supported by grants from the Conselleria de Agricultura, Pesca y Alimentacio de la Comunidad Valenciana, the Fundacion de la Comunidad Valenciana para la Investigacion Agroalimentaria (AGROALIMED) and from the Departament d'Agricultura, Alimentacio i Accio Rural (DAR) de la Generalitat de Catalunya.Casals Missio, J.; Cebolla Cornejo, J.; Rosello Ripolles, S.; Beltran Arandes, J.; Casanas, F.; Nuez Viñals, F. (2011). Long-term postharvest aroma evolution of tomatoes with the alcobaça (alc) mutation. 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Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

Best Treatment Option for Patients With Refractory Aggressive B-Cell Lymphoma in the CAR-T Cell Era: Real-World Evidence From GELTAMO/GETH Spanish Groups

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4-6 months, p <= 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44-0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31-0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria