Merocyanines form bacteriorhodopsins with strongly bathochromic absorption maxima.

There is a need to shift the absorbance of biomolecules to the optical transparency window of tissue for applications in optogenetics and photo-pharmacology. There are a few strategies to achieve the so-called red shift of the absorption maxima. Herein, a series of 11 merocyanine dyes were synthesized and employed as chromophores in place of retinal in bacteriorhodopsin (bR) to achieve a bathochromic shift of the absorption maxima relative to bR's [Formula: see text] of 568 nm. Assembly with the apoprotein bacterioopsin (bO) led to stable, covalently bound chromoproteins with strongly bathochromic absorbance bands, except for three compounds. Maximal red shifts were observed for molecules 9, 2, and 8 in bR where the [Formula: see text] was 766, 755, and 736 nm, respectively. While these three merocyanines have different end groups, they share a similar structural feature, namely, a methyl group which is located at the retinal equivalent position 13 of the polyene chain. The absorption and fluorescence data are also presented for the retinal derivatives in their aldehyde, Schiff base (SB), and protonated SB (PSB) forms in solution. According to their hemicyanine character, the PSBs and their analogue bRs exhibited fluorescence quantum yields (Φf) several orders of magnitude greater than native bR (Φf 0.02 to 0.18 versus 1.5 × 10-5 in bR) while also exhibiting much smaller Stokes shifts than bR (400 to 1000 cm-1 versus 4030 cm-1 in bR). The experimental results are complemented by quantum chemical calculations where excellent agreement between the experimental [Formula: see text] and the calculated [Formula: see text] was achieved with the second-order algebraic-diagrammatic construction [ADC(2)] method. In addition, quantum mechanics/molecular mechanics (QM/MM) calculations were employed to shed light on the origin of the bathochromic shift of merocyanine 2 in bR compared with native bR.

An Artificial Neural Network to Eliminate the Detrimental Spectral Shift on Mid-Infrared Gas Spectroscopy.

We demonstrate the successful implementation of an artificial neural network (ANN) to eliminate detrimental spectral shifts imposed in the measurement of laser absorption spectrometers (LASs). Since LASs rely on the analysis of the spectral characteristics of biological and chemical molecules, their accuracy and precision is especially prone to the presence of unwanted spectral shift in the measured molecular absorption spectrum over the reference spectrum. In this paper, an ANN was applied to a scanning grating-based mid-infrared trace gas sensing system, which suffers from temperature-induced spectral shifts. Using the HITRAN database, we generated synthetic gas absorbance spectra with random spectral shifts for training and validation. The ANN was trained with these synthetic spectra to identify the occurrence of spectral shifts. Our experimental verification unambiguously proves that such an ANN can be an excellent tool to accurately retrieve the gas concentration from imprecise or distorted spectra of gas absorption. Due to the global shift of the measured gas absorption spectrum, the accuracy of the retrieved gas concentration using a typical least-mean-squares fitting algorithm was considerably degraded by 40.3%. However, when the gas concentration of the same measurement dataset was predicted by the proposed multilayer perceptron network, the sensing accuracy significantly improved by reducing the error to less than ±1% while preserving the sensing sensitivity.

Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters.

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20-73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.

Measurable residual disease (MRD) status before allogeneic hematopoietic cell transplantation impact on secondary acute myeloid leukemia outcome. A Study from the Acute Leukemia Working Party (ALWP) of the European society for Blood and Marrow Transplantation (EBMT).

Measurable residual disease (MRD) assessment before allogeneic hematopoietic cell transplantation (HCT) may help physicians to identify a subgroup of patients at high risk of relapse for de novo acute myeloid leukemia (AML) but its relevance among patients affected by secondary AML (sAML) is still unknown. We assessed the impact of MRD among 318 adult patients with sAML who received an allogeneic HCT in first complete remission. At the time of HCT, a total of 208 (65%) patients achieved MRD negativity, while 110 (35%) had positive MRD. 2-year overall survival (OS) was 58.8 % (95% CI 52.2-64.9) with leukemia-free survival (LFS) of 50.0 % (95% CI 43.7-56.1), relapse incidence of 34.2% (95% CI 28.4-40.1) and non-relapse mortality (NRM) of 23.3 % (95% CI 19-27.7) for the entire cohort. In multivariate analysis, HCT recipients with KPS ≥ 90 experienced less disease recurrence (HR 0.61, 95% CI 0.4-0.94) with better LFS (HR 0.63, 95% CI 0.44-0.89) and OS (HR 0.58, 95% CI 0.39-0.86). There were no differences in major clinical endpoints between patients with MRD-positive and MRD-negative status at the time of HCT. Pre-transplantation assessment of MRD was not informative on post-HCT outcomes in this retrospective registry-based analysis among patients affected by sAML.

Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies.

PURPOSE: Total body irradiation (TBI) is a common part of the myelo- and immuno-ablative conditioning regimen prior to an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to concerns regarding acute and long-term complications, there is currently a decline in otherwise successfully established TBI-based conditioning regimens. Here we present an analysis of patient and treatment data with focus on survival and long-term toxicity. METHODS: Patients with hematologic diseases who received TBI as part of their conditioning regimen prior to allo-HSCT at Frankfurt University Hospital between 1997 and 2015 were identified and retrospectively analyzed. RESULTS: In all, 285 patients with a median age of 45 years were identified. Median radiotherapy dose applied was 10.5 Gy. Overall survival at 1, 2, 5, and 10 years was 72.6, 64.6, 54.4, and 51.6%, respectively. Median follow-up of patients alive was 102 months. The cumulative incidence of secondary malignancies was 12.3% (n = 35), with hematologic malignancies and skin cancer predominating. A TBI dose ≥ 8 Gy resulted in significantly improved event-free (p = 0.030) and overall survival (p = 0.025), whereas a total dose ≤ 8 Gy and acute myeloid leukemia (AML) diagnosis were associated with significantly increased rates of secondary malignancies (p = 0.003, p = 0.048) in univariate analysis. No significant correlation was observed between impaired renal or pulmonary function and TBI dose. CONCLUSION: TBI remains an effective and well-established treatment, associated with distinct late-toxicity. However, in the present study we cannot confirm a dose-response relationship in intermediate dose ranges. Survival, occurrence of secondary malignancies, and late toxicities appear to be subject to substantial confounding in this context.

Demographic responses of nearly extirpated endangered mountain caribou to recovery actions in Central British Columbia.

Recovering endangered species is a difficult and often controversial task that challenges status quo land uses. Southern Mountain caribou are a threatened ecotype of caribou that historically ranged in southwestern Canada and northwestern USA and epitomize the tension between resource extraction, biodiversity conservation, and Indigenous Peoples' treaty rights. Human-induced habitat alteration is considered the ultimate cause of caribou population declines, whereby an increased abundance of primary prey-such as moose and deer-elevates predator populations and creates unsustainable caribou mortality. Here we focus on the Klinse-Za and Quintette subpopulations, part of the endangered Central Group of Southern Mountain caribou in British Columbia. These subpopulations were trending toward immediate extirpation until a collaborative group initiated recovery by implementing two short-term recovery actions. We test the effectiveness of these recovery actions-maternity penning of adult females and their calves, and the reduction of a primary predator, wolves-in increasing vital rates and population growth. Klinse-Za received both recovery actions, whereas Quintette only received wolf reductions, providing an opportunity to test efficacy between recovery actions. Between 1995 and 2021, we followed 162 collared female caribou for 414 animal-years to estimate survival and used aerial counts to estimate population abundance and calf recruitment. We combined these data in an integrated population model to estimate female population growth, total population abundance, and recovery action effectiveness. Results suggest that the subpopulations were declining rapidly (λ = 0.90-0.93) before interventions and would have been functionally extirpated (<10 animals) within 10-15 years. Wolf reduction increased population growth rates by ~0.12 for each subpopulation. Wolf reduction halted the decline of Quintette caribou and allowed them to increase (λ = 1.05), but alone would have only stabilized the Klinse-Za (λ = 1.02). However, maternity penning in the Klinse-Za increased population growth by a further ~0.06, which when combined with wolf reductions, allowed populations to grow (λ = 1.08). Taken together, the recovery actions in these subpopulations increased adult female survival, calf recruitment, and overall population growth, more than doubling abundance. Our results suggest that maternity penning and wolf reductions can be effective at increasing caribou numbers in the short term, while long-term commitments to habitat protection and restoration are made.

Inhibition of human carbonyl reducing enzymes by plant anthrone and anthraquinone derivatives.

Members of the aldo-keto reductase and short-chain dehydrogenase/reductase enzyme superfamilies catalyze the conversion of a wide range of substrates, including carbohydrates, lipids, and steroids. These enzymes also participate in the transformation of xenobiotics, inactivation of the cytostatics doxo- and daunorubicin, and play a role in the development of cancer. Therefore, inhibitors of such enzymes may improve therapeutic outcomes. Plant-derived compounds such as anthraquinones have been used for medicinal purposes for several centuries. In the current study, the inhibitory potential of selected anthrone and anthraquinone derivatives (from plants) was tested on six recombinant human carbonyl reducing enzymes (AKR1B1, AKR1B10, AKR1C3, AKR7A2, AKR7A3, CBR1) isolated from an Escherichia coli expression system. Overall, the least inhibition was observed with the anthrone derivative aloin, while IC50 values obtained with the anthraquinone derivatives (frangula emodin, aloe emodin, frangulin A, and frangulin B) and the aldo-keto reductase AKR1B10 were in the low micromolar range (3.5-16.6 µM). AKR1B1 inhibition was significantly weaker in comparison with AKR1B10 inhibition (IC50 values > 50 µM). The strongest inhibition was observed with the short-chain dehydrogenase/reductase CBR1. AKR7A2, AKR7A3, and AKR1C3 were not, or less inhibited by inhibitor concentrations of up to 50 µM. Analysis of the kinetic data suggests noncompetitive or uncompetitive inhibition mechanisms. The new inhibitors described here may serve as lead structures for the development of future drugs.

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10-5 and HR 1.71, p < 10-5 , respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10-5 ), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Large herbivores in a partially migratory population search for the ideal free home.

Migration is a tactic used across taxa to access resources in temporally heterogenous landscapes. Populations that migrate can attain higher abundances because such movements allow access to higher quality resources, or reduction in predation risk resulting in increased fitness. However, most migratory species occur in partially migratory populations, a mix of migratory and non-migratory individuals. It is thought that the portion of migrants in a partial migration population is maintained either through (1) a population-level evolutionary stable state where counteracting density-dependent vital rates act on migrants and residents to balance fitness or (2) conditional migration, where the propensity to migrate is influenced by the individual's state. However, in many respects, migration is also a form of habitat selection and the proportion of migrants and residents may be the result of density-dependent habitat selection. Here, we test whether the theory of Ideal Free Distribution (IFD) can explain the coexistence of different migratory tactics in a partially migratory population. IFD predicts individuals exhibit density-dependent vital rates and select different migratory tactics to maximize individual fitness resulting in equal fitness (λ) between tactics. We tested the predictions of IFD in a partially migratory elk population that declined by 70% with 19 years of demographic data and migratory tactic switching rates from >300 individuals. We found evidence of density dependence for resident pregnancy and adult female survival providing a fitness incentive to switch tactics. Despite differences in vital rates between migratory tactics, mean λ (fitness) was equal. However, as predicted by the IFD, individuals switched tactics toward those of higher fitness. Our analysis reveals that partial migration may be driven by tactic selection that follows the ideal free distribution. These findings reinforce that migration across taxa may be a polymorphic behavior in large herbivores where migratory tactic selection is determined by differential costs and benefits, mediated by density dependence.

Carbonyl reduction of 4-oxonon-2-enal (4-ONE) by Sniffer from D. magna and D.pulex.

The α, ß-unsaturated aldehydes 4-oxonon-2-enal (4ONE) and 4-hydroxynon-2-enal (4HNE) are products of unsaturated fatty acids and ROS, and can be formed in lipid-rich tissues such as neurons. As strong electrophiles, both compounds react with DNA and proteins, and are capable of inactivating enzymes. However, both the human carbonyl reductase and the carbonyl reductase Drosophila melanogaster Sniffer are known to reduce 4ONE, a major lipid peroxidation product, to a less or non-toxic form. In this study, products formed during carbonyl reduction of 4ONE and 4HNE by recombinant Sniffer proteins from Daphnia magna and Daphnia pulex were investigated. A high-performance liquid chromatography analysis showed that Sniffer from D. magna converted 35.6% of 4ONE to 11.9% HNO and 23.7% 4HNE, while D. pulex converted 34.5% of this substrate to 14.8% HNO and 19.7% 4HNE. Thus, 4HNE is the main product formed from the sniffer-mediated reduction of 4ONE. The kinetic parameters obtained from the reduction of 4ONE were Km = 13.9 ± 2.1 µM, kcat = 1.53 s-1, kcat/km = 0.11 s-1 µM-1 for D. magna Sniffer and Km = 29.2 ± 4.3 µM, kcat = 0.64 s-1, kcat/km = 0.02 s-1 µM-1 for D. pulex Sniffer. These results demonstrate that Sniffer from D. magna and D. pulex are important enzymes involved in the carbonyl reductive biotransformation of 4ONE, a cytotoxic lipid peroxidation product. Noteworthy, the catalytic properties of both Daphnia Sniffer enzymes reflect previous findings with Sniffer from Drosophila melanogaster.

Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT.

Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n = 155); Haplo using bone marrow (Haplo-BM; n = 647) or peripheral blood (Haplo-PB; n = 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24, p < 0.01; HR 2.65, 95% CI 1.46-4.81, p < 0.01, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06-2.14, p = 0.02; Haplo-PB: 1.47, 95% CI 1.05-2.05, p = 0.02); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02-2.21, p = 0.04; Haplo-PB: HR 1.51, 95% CI 1.05-2.19, p = 0.03). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24-0.81; p < 0.01), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD. Use of PTCy in 1Ag-MMUD-HCT is a valid alternative to consider when using alternative donors. Larger analysis of 1Ag-MMUD versus Haplo-HCT are warranted.

Predictive Factors for Outcome of First Allogeneic Transplant for Elderly Patients With Acute Lymphoblastic Leukemia.

INTRODUCTION/BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) in patients older than 70 is extremely challenging with dismal outcome. Allogeneic stem cell transplantation (alloHCT) has seen many advancements in the last decades showing benefits in younger ALL patients, but this treatment modality is decreasingly used with increasing age due to high treatment-related mortality. PATIENTS AND METHODS: We identified 84 ALL patients 70 to 84 years old allografted In 2002 to 2019 from a matched related (23%), unrelated (58%), haploidentical (17%), or cord blood (2%) donor at EBMT participating centers with a median follow-up of 23 months. RESULTS: The 2-year relapse incidence (RI) and non-relapse mortality were 37% and 28%, respectively, and 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 35%, 39% and 23%, respectively. The strongest predictor of outcome was disease status at transplant whereby patients in first complete remission (CR1) had >50% 2-year OS, reflected in multivariate analysis (MVA) with significant improvement in RI, LFS, and GRFS (HR 0.23, 0.49, and 0.54, respectively). Furthermore, karnofsky score ≥90 reflective of good functional status positively influenced non-relapse mortality in both univariate and MVA (HR 0.37), and interestingly, donor CMV positivity appeared to negatively affect RI, LFS and OS in univariate analysis and RI in MVA (HR 2.87). CONCLUSION: Our data suggest that alloHCT is an option for elderly ALL patients, particularly those carefully selected and transplanted in CR1 especially if failed or without access to novel non-chemotherapy-based approaches.

Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry.

Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non-transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo-HCT in 556 MF patients aged ≥65 years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients ≥65 years managed with allo-HCT (n = 556) or conventional drug treatment (n = 176). The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow-up of 3.4 years, the estimated 5-year survival rate, non-relapse mortality (NRM), and relapse incidence after transplantation was 40%, 37%, and 25%, respectively. Busulfan-based conditioning was associated with decreased mortality (HR: 0.7, 95% CI: 0.5-0.9) whereas the recipient CMV+/donor CMV- combination (HR: 1.7, 95% CI: 1.2-2.4) and the JAK2 mutated genotype (HR: 1.9, 95% CI: 1.1-3.5) predicted higher mortality. Busulfan-based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan-based regimens. Excess mortality was higher in transplanted patients than in the non-HCT cohort in the first year of follow-up (ratio: 1.93, 95% CI: 1.13-2.80), whereas the opposite occurred between the fourth and eighth follow-up years (ratio: 0.31, 95% CI: 0.18-0.53). Comparing the excess mortality of the two treatments, male patients seemed to benefit more than females from allo-HCT, mainly due to their worse prognosis with non-transplant approaches. These findings could potentially enhance counseling and treatment decision-making in elderly transplant-eligible MF patients.

Predation landscapes influence migratory prey ecology and evolution.

Migratory prey experience spatially variable predation across their life cycle. They face unique challenges in navigating this predation landscape, which affects their perception of risk, antipredator responses, and resulting mortality. Variable and unfamiliar predator cues during migration can limit accurate perception of risk and migrants often rely on social information and learning to compensate. The energetic demands of migration constrain antipredator responses, often through context-dependent patterns. While migration can increase mortality, migrants employ diverse strategies to balance risks and rewards, including life history and antipredator responses. Humans interact frequently with migratory prey across space and alter both mortality risk and antipredator responses, which can scale up to affect migratory populations and should be considered in conservation and management.

Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma.

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with

Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia.

PURPOSE: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor. EXPERIMENTAL DESIGN: We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy. RESULTS: The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2-4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival. CONCLUSIONS: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.

Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation.

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.

Potent inhibition of human carbonyl reductase 1 (CBR1) by the prenylated chalconoid xanthohumol and its related prenylflavonoids isoxanthohumol and 8-prenylnaringenin.

In terms of drug disposal and metabolism SDR21C1 (carbonyl reductase 1; CBR1) exerts an assorted substrate spectrum among a large variety of clinically relevant substances. Additionally, this short-chain dehydrogenase/reductase is extensively expressed in most tissues of the human body, thus underpinning its role in xenobiotic metabolism. Reduction of the chemotherapeutic daunorubicin (DAUN) to daunorubicinol (DAUNol) is a prominent example of its metabolic properties in terms of chemoresistance and cardiotoxicity. The hop-derived prenylated chalcone xanthohumol (XN) and its physiological metabolites isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) have previously been reported to inhibit other DAUN reducing reductases and dehydrogenases including AKR1B1 and AKR1B10. Also with regard to their effects by means of interacting with cancer-related molecular pathways, XN and related prenylated flavonoids in particular have been in the focus of recent studies. In this study, inhibitory properties of these substances were examined with CBR1-mediated 2,3-hexanedione and DAUN reduction. All substances tested in this study turned out to efficiently inhibit recombinant human CBR1 within a low micromolar to submicromolar range. Among the substances tested, 8-PN turned out to be the most effective inhibitor when using 2,3-hexanedione as a substrate (Ki(app) = 180 ±â€¯20 nM). Inhibition rates of recombinant CBR1-mediated DAUN reduction were somewhat weaker with IC50-values ranging from 11 to 20 µM. XN, IX and 8-PN also efficiently inhibited DAUN reduction by SW480 colon adenocarcinoma cytosol (IC50 = 3.71 ±â€¯0.26 µM with 8-PN as inhibitor). This study identifies prenylated inhibitors, which might potentially interact with endogenous CBR1-driven (de-)toxication systems.