Use of half red blood cell units in oncology patients during severe shortages to extend hospital supply.

BACKGROUND: The COVID-19 pandemic exerted an unprecedented impact on the blood supply from 2020 through 2022. As a result, throughout 2021 there were months our hospital had less than one-day supply of type O RBCs. To meet transfusion needs, whole RBC units were split into half units and issued to stable, non-bleeding patients. This single-institution, retrospective study examines time intervals to subsequent transfusion and total numbers of RBC units subsequently transfused after the first half or whole RBC unit. STUDY DESIGN AND METHODS: Patients who were transfused RBC between May 21, 2021 and November 1, 2021 were divided into in- and outpatient groups, then based on whether they received at least 1 half RBC unit or only whole RBC units during the study period. The time interval between this first half unit transfusion, or first whole unit transfusion in those who did not receive half units, and the subsequent RBC transfusion within 90 days was calculated and compared, as well as the total number of RBC units transfused 30 days after the first unit. RESULTS: In general, patients transfused with half units received a subsequent transfusion significantly earlier than those transfused with whole units. Additionally, receiving an index half unit was associated with more RBC transfusions in the following 30 days (p = .001). CONCLUSION: Transfusion of half RBC units during a severe RBC blood shortage can temporarily decrease RBC usage but will result in a shorter interval to the next transfusion and greater total number of RBC units transfused in subsequent days.

Lethal Immune-Related Pneumonitis after Durvalumab Therapy for Small Cell Lung Cancer: A First Case in China.

Introduction: Although programmed death ligand 1 (PD-L1) inhibitor plus chemotherapy regimen is a promising strategy for malignant tumors, it can induce significant immune-related adverse events, such as immune-related pneumonitis. Here, we report the first case of lethal immune-related pneumonitis in an Asian patient receiving anti-PD-L1 treatment. Case Presentation: A 68-year-old man was diagnosed with small cell lung cancer and interstitial pneumonia. After his pulmonary infection was relieved by comprehensive treatment, the patient received first-line treatment with durvalumab plus etoposide and carboplatin. Two weeks after starting durvalumab treatment, the patient had chest pain and shortness of breath. He was diagnosed with immune-induced pneumonia and treated with methylprednisolone, cefoperazone, and sulbactam, followed by oxygen and pirfenidone. Oxygen partial pressure decreased to 58 mm Hg within next the 4 days and laboratory assessment suggested cytokine storm. The patient underwent 2 plasma exchanges, one double filtration plasmapheresis and oxygen saturation decreased continuously. The patient died 1 month after durvalumab treatment. Conclusion: Immune-related pneumonitis induced by PD-L1 inhibitors is rare but life-threatening. Infection should be ruled out before starting immunotherapy.

Catalytic asymmetric intramolecular propargylation of cyclopropanols to access the cuparane core.

The catalytic asymmetric propargylation of enol(ate) intermediates is a well-established method for the synthesis of α-propargyl-substituted carbonyl compounds. However, the propargylation of homo-enol(ate) or its equivalents for the synthesis of ß-propargyl-substituted carbonyl compounds remains underdeveloped. A catalytic enantioselective decarboxylative intramolecular propargylation of cyclopropanols has been developed using a PyBox-complexed copper catalyst. This reaction offers an effective approach to assemble a cyclopentanone skeleton bearing an all-carbon quaternary stereogenic center and an adjacent quaternary gem-dimethyl carbon center, which is the core scaffold of the naturally occurring cuparenoids. Key to the success of this protocol is the use of a new structurally optimized PyBox ligand. This study represents the first example of catalytic asymmetric intramolecular propargylation of cyclopropanols.

Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer Disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS: We aimed to study CSF PDGFRß protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. RESULTS: Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRß and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRß levels were not associated with either the CSF Aß42 or the amyloid-PET. CONCLUSIONS: We demonstrated a moderate positive correlation between PDGFRß and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094939.

GmTCP40 Promotes Soybean Flowering under Long-Day Conditions by Binding to the GmAP1a Promoter and Upregulating Its Expression.

Soybean [Glycine max (L.) Merr.] is a short-day (SD) plant that is sensitive to photoperiod, which influences flowering, maturity, and even adaptation. TEOSINTE-BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factors have been shown to regulate photoperiodic flowering. However, the roles of TCPs in SD plants such as soybean, rice, and maize remain largely unknown. In this study, we cloned the GmTCP40 gene from soybean and investigated its expression pattern and function. Compared with wild-type (WT) plants, GmTCP40-overexpression plants flowered earlier under long-day (LD) conditions but not under SD conditions. Consistent with this, the overexpression lines showed upregulation of the flowering-related genes GmFT2a, GmFT2b, GmFT5a, GmFT6, GmAP1a, GmAP1b, GmAP1c, GmSOC1a, GmSOC1b, GmFULa, and GmAG under LD conditions. Further investigation revealed that GmTCP40 binds to the GmAP1a promoter and promotes its expression. Analysis of the GmTCP40 haplotypes and phenotypes of soybean accessions demonstrated that one GmTCP40 haplotype (Hap6) may contribute to delayed flowering at low latitudes. Taken together, our findings provide preliminary insights into the regulation of flowering time by GmTCP40 while laying a foundation for future research on other members of the GmTCP family and for efforts to enhance soybean adaptability.

Clinical management of a patient following a granulocyte transfusion from a donor positive for COVID-19.

Granulocyte transfusions are indicated for patients with severe neutropenia and evidence of bacterial or fungal infection who are unresponsive to standard antimicrobial therapy. With a limited expiration time of 24 hours after collection, granulocytes are often transfused before results of infectious-disease screening tests are available, and before a transfusion service can perform a risk assessment if postdonation information is provided after the collection. The case we describe herein demonstrates a clinical scenario meeting indications for granulocyte transfusion, coupled with the clinical management undertaken after the granulocyte donor disclosed a positive result for a COVID-19 self-test taken 1 day after donation. In this case, the patient did not develop new COVID-19 symptoms and tested negative for COVID-19 after transfusion of the implicated unit. These findings add to the body of evidence in the literature that COVID-19 is not transmitted via blood transfusion.

Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients.

BACKGROUND: Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo-HSCT) had inferior overall survival (OS). STUDY DESIGN AND METHODS: This single-center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long-term outcomes after allo-HSCT through multivariate analyses. RESULTS: A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011-2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1-18 units) or PLT (98.2% transfused, median 6, range 1-144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8-60.3%) and 86.1% (95% CI: 83.2-88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow-up among survivors (n = 307) was 7.1 years (range: 2.7-11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5-year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49-2.25), leukemia-free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43-2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45-2.89) (p < .001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p = .34) or PLT (p = .64) transfusion independence. CONCLUSION: Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non-relapse complications.

Floral-promoting GmFT homologs trigger photoperiodic after-effects: An important mechanism for early-maturing soybean varieties to regulate reproductive development and adapt to high latitudes.

Soybean (Glycine max) is a typical short-day plant, but has been widely cultivated in high-latitude long-day (LD) regions because of the development of early-maturing genotypes which are photoperiod-insensitive. However, some early-maturing varieties exhibit significant responses to maturity under different daylengths but not for flowering, depicting an evident photoperiodic after-effect, a poorly understood mechanism. In this study, we investigated the postflowering responses of 11 early-maturing soybean varieties to various preflowering photoperiodic treatments. We confirmed that preflowering SD conditions greatly promoted maturity and other postflowering developmental stages. Soybean homologs of FLOWERING LOCUS T (FT), including GmFT2a, GmFT3a, GmFT3b and GmFT5a, were highly accumulated in leaves under preflowering SD treatment. More importantly, they maintained a high expression level after flowering even under LD conditions. E1 RNAi and GmFT2a overexpression lines showed extremely early maturity regardless of preflowering SD and LD treatments due to constitutively high levels of floral-promoting GmFT homolog expression throughout their life cycle. Collectively, our data indicate that high and stable expression of floral-promoting GmFT homologs play key roles in the maintenance of photoperiodic induction to promote postflowering reproductive development, which confers early-maturing varieties with appropriate vegetative growth and shortened reproductive growth periods for adaptation to high latitudes.

Effects of tail nerve electrical stimulation on the activation and plasticity of the lumbar locomotor circuits and the prevention of skeletal muscle atrophy after spinal cord transection in rats.

INTRODUCTION: Severe spinal cord injury results in the loss of neurons in the relatively intact spinal cord below the injury area and skeletal muscle atrophy in the paralyzed limbs. These pathological processes are significant obstacles for motor function reconstruction. OBJECTIVE: We performed tail nerve electrical stimulation (TNES) to activate the motor neural circuits below the injury site of the spinal cord to elucidate the regulatory mechanisms of the excitatory afferent neurons in promoting the reconstruction of locomotor function. METHODS: Eight days after T10 spinal cord transection in rats, TNES was performed for 7 weeks. Behavioral scores were assessed weekly. Electrophysiological tests and double retrograde tracings were performed at week 8. RESULTS: After 7 weeks of TNES treatment, there was restoration in innervation, the number of stem cells, and mitochondrial metabolism in the rats' hindlimb muscles. Double retrograde tracings of the tail nerve and sciatic nerve further confirmed the presence of synaptic connections between the tail nerve and central pattern generator (CPG) neurons in the lumbar spinal cord, as well as motor neurons innervating the hindlimb muscles. CONCLUSION: The mechanisms of TNES induced by the stimulation of primary afferent nerve fibers involves efficient activation of the motor neural circuits in the lumbosacral segment, alterations of synaptic plasticity, and the improvement of muscle and nerve regeneration, which provides the structural and functional foundation for the future use of cutting-edge biological treatment strategies to restore voluntary movement of paralyzed hindlimbs.

Human Adipose Tissue Lysate-Based Hydrogel for Lasting Immunomodulation to Effectively Improve Spinal Cord Injury Repair.

The long-term inflammatory microenvironment is one of the main obstacles to inhibit acute spinal cord injury (SCI) repair. The natural adipose tissue-derived extracellular matrix hydrogel shows effective anti-inflammatory regulation because of its unique protein components. However, the rapid degradation rate and removal of functional proteins during the decellularization process impair the lasting anti-inflammation function of the adipose tissue-derived hydrogel. To address this problem, adipose tissue lysate provides an effective way for SCI repair due to its abundance of anti-inflammatory and nerve regeneration-related proteins. Thereby, human adipose tissue lysate-based hydrogel (HATLH) with an appropriate degradation rate is developed, which aims to in situ long-term recruit and induce anti-inflammatory M2 macrophages through sustainedly released proteins. HATLH can recruit and polarize M2 macrophages while inhibiting pro-inflammatory M1 macrophages regardless of human or mouse-originated. The axonal growth of neuronal cells also can be effectively improved by HATLH and HATLH-induced M2 macrophages. In vivo experiments reveal that HATLH promotes endogenous M2 macrophages infiltration in large numbers (3.5 × 105/100 µL hydrogel) and maintains a long duration for over a month. In a mouse SCI model, HATLH significantly inhibits local inflammatory response, improves neuron and oligodendrocyte differentiation, enhances axonal growth and remyelination, as well as accelerates neurological function restoration.

From microscope to micropixels: A rapid review of artificial intelligence for the peripheral blood film.

Artificial intelligence (AI) and its application in classification of blood cells in the peripheral blood film is an evolving field in haematology. We performed a rapid review of the literature on AI and peripheral blood films, evaluating the condition studied, image datasets, machine learning models, training set size, testing set size and accuracy. A total of 283 studies were identified, encompassing 6 broad domains: malaria (n = 95), leukemia (n = 81), leukocytes (n = 72), mixed (n = 25), erythrocytes (n = 15) or Myelodysplastic syndrome (MDS) (n = 1). These publications have demonstrated high self-reported mean accuracy rates across various studies (95.5% for malaria, 96.0% for leukemia, 94.4% for leukocytes, 95.2% for mixed studies and 91.2% for erythrocytes), with an overall mean accuracy of 95.1%. Despite the high accuracy, the challenges toward real world translational usage of these AI trained models include the need for well-validated multicentre data, data standardisation, and studies on less common cell types and non-malarial blood-borne parasites.

Breeding of Saccharomyces cerevisiae with a High-Throughput Screening Strategy for Improvement of S-Adenosyl-L-Methionine Production.

S-adenosyl-l-methionine (SAM), a vital physiologically active substance in living organisms, is produced by fermentation over Saccharomyces cerevisiae. The main limitation in SAM production was the low biosynthesis ability of SAM in S. cerevisiae. The aim of this work is to breed an SAM-overproducing mutant through UV mutagenesis coupled with high-throughput selection. Firstly, a high-throughput screening method by rapid identification of positive colonies was conducted. White colonies on YND medium were selected as positive strains. Then, nystatin/sinefungin was chosen as a resistant agent in directed mutagenesis. After several cycles of mutagenesis, a stable mutant 616-19-5 was successfully obtained and exhibited higher SAM production (0.41 g/L vs 1.39 g/L). Furthermore, the transcript levels of the genes SAM2, ADO1, and CHO2 involved in SAM biosynthesis increased, while ergosterol biosynthesis genes in mutant 616-19-5 significantly decreased. Finally, building on the above work, S. cerevisiae 616-19-5 could produce 10.92 ± 0.2 g/L SAM in a 5-L fermenter after 96 h of fermentation, showing a 2.02-fold increase in the product yield compared with the parent strain. Paving the way of breeding SAM-overproducing strain has improved the good basis for SAM industrial production.

Research progress of neuronal injury mediated by microglial activation and depression / 中国药理学通报

Depression is a common neurological disorder with high incidence, high recurrence and high disability, but its pathogenesis is unclear. In recent years, the protective and attacking effects of glial cells on neurons have become the frontier of neurological disease research. Neuronal injury caused by abnormal activation of microglia (MG) plays an important role in the pathogenesis of depression. In this paper, through literature retrieval by GeenMedical and CNKI, the relevant pathways and key targets of MG activation in depression are summarized so as to provide a theoretical basis for further clinical research.

The FLOWERING LOCUS T 5b positively regulates photoperiodic flowering and improves the geographical adaptation of soybean.

Plants can sense the photoperiod to flower at the right time. As a sensitive short-day crop, soybean (Glycine max) flowering varies greatly depending on photoperiods, affecting yields. Adaptive changes in soybeans rely on variable genetic loci such as E1 and FLOWERING LOCUS T orthologs. However, the precise coordination and control of these molecular components remain largely unknown. In this study, we demonstrate that GmFT5b functions as a crucial factor for soybean flowering. Overexpressed or mutated GmFT5b resulted in significantly early or later flowering, altering expression profiles for several downstream flowering-related genes under a long-day photoperiod. GmFT5b interacts with the transcription factor GmFDL15, suggesting transcriptional tuning of flowering time regulatory genes via the GmFT5b/GmFDL15 complex. Notably, GmFT5a partially compensated for GmFT5b function, as ft5a ft5b double mutants exhibited an enhanced late-flowering phenotype. Association mapping revealed that GmFT5b was associated with flowering time, maturity, and geographical distribution of soybean accessions, all associated with the E1 locus. Therefore, GmFT5b is a valuable target for enhancing regional adaptability. Natural variants or multiple mutants in this region can be utilized to generate optimized soybean varieties with precise flowering times.

Genome-wide association study for temperature response and photo-thermal interaction of flowering time in soybean using a panel of cultivars with diverse maturity groups.

KEY MESSAGE: A total of 101 QTNs were found to be associated with soybean flowering time responses to photo-thermal conditions; three candidate genes with non-synonymous substitutions were identified: Glyma.08G302500 (GmHY5), Glyma.08G303900 (GmPIF4c), and Glyma.16G046700 (GmVRN1). The flowering transition is a crucial component of soybean (Glycine max L. Merr.) development. The transition process is regulated by photoperiod, temperature, and their interaction. To examine the genetic architecture associated with temperature- and photo-thermal-mediated regulation of soybean flowering, we here performed a genome-wide association study using a panel of 201 soybean cultivars with maturity groups ranging from MG 000 to VIII. Each cultivar was grown in artificially controlled photoperiod and different seasons in 2017 and 2018 to assess the thermal response (TR) and the interactive photo-thermal response (IPT) of soybean flowering time. The panel contained 96,299 SNPs with minor allele frequencies > 5%; 33, 19, and 49 of these SNPs were significantly associated with only TR, only IPT, and both TR and IPT, respectively. Twenty-one SNPs were located in or near previously reported quantitative trait loci for first-flowering; 16 SNPs were located within 200 kb of the main-effect flowering genes GmFT2a, GmFT2b, GmFT3a, GmFT3b, GmFT5a, GmFT5b, GmCOL2b, GmPIF4b, and GmPIF4c, or near homologs of the known Arabidopsis thaliana flowering genes BBX19, VRN1, TFL1, FUL, AGL19, SPA1, HY5, PFT1, and EDF1. Natural non-synonymous allelic variations were identified in the candidate genes Glyma.08G302500 (GmHY5), Glyma.08G303900 (GmPIF4c), and Glyma.16G046700 (GmVRN1). Cultivars with different haplotypes showed significant variations in TR, IPT, and flowering time in multiple environments. The favorable alleles, candidate genes, and diagnostic SNP markers identified here provide valuable information for future improvement of soybean photo-thermal adaptability, enabling expansion of soybean production regions and improving plant resilience to global climate change.

Missense variants in CYP4B1 associated with increased risk of lung cancer among Chinese Han population.

INTRODUCTION: Understanding the etiology and risk factors of lung cancer (LC) is the key to developing scientific and effective prevention and control strategies for LC. CYP4B1 genetic polymorphism has been reported to be associated with susceptibility to various diseases. We aimed to explore the association between CYP4B1 genetic variants and LC susceptibility. METHODS: One thousand three hundred thirty-nine participants were recruited to perform an association analysis through SNPStats online software. Statistical analysis of this study was mainly completed by SPSS 22.0 software. False-positive report probability analysis (FPRP) to detect whether the positive findings were noteworthy. Finally, the interaction of SNP-SNP in LC risk was evaluated by multi-factor dimensionality reduction. RESULTS: We found evidence that missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with LC susceptibility. In particular, genotype GA of CYP4B1-rs2297810 was significantly associated with an increased risk of LC in both overall and stratified analyses (genotype GA: OR (95% CI) = 1.35 (1.08-1.69), p = 0.010). CYP4B1-rs4646491 (overdominant: OR (95% CI) = 1.30 (1.04-1.62), p = 0.023) and CYP4B1-rs2297809 (genotype CT: OR (95% CI) = 1.26 (1.01-1.59), p = 0.046) are also associated with an increased risk of LC. FPRP analysis showed that all positive results in this study are noteworthy findings CONCLUSION: Three missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with increasing risk of LC.

Interaction mechanism of carotenoids and polyphenols in mango peels.

In this study, carotenoids and polyphenols were demonstrated to be the major active substances in the crude pigment extracts (CPE) of mango peels, accounting for 0.26 mg/g and 0.15 mg/g, respectively. The interactions between carotenoids and polyphenols in CPE was observed, as evidenced by that polyphenols significantly improved the antioxidant activity and storage stability of carotenoids in the CPE. Meanwhile, scanning electron microscopy showed that polyphenols are tightly bound to carotenoids. To further elucidate the interaction mechanism, the monomers of carotenoids and polyphenols were identified by HPLC and LC-MS analysis. Lutein (203.85 µg/g), ß-carotene (41.40 µg/g), zeaxanthin (4.20 µg/g) and α-carotene (1.50 µg/g) were authenticated as the primary monomers of carotenoids. Polyphenols were mainly consisted of gallic acid (95.10 µg/g), quercetin-3-ß-glucoside (29.10 µg/g), catechin (11.85 µg/g) and quercetin (11.55 µg/g). The interaction indexes between carotenoid and polyphenol monomer of CPE were calculated. The result indicated that lutein and gallic acid showed the greatest synergistic effect on the scavenging of DPPH and ABTS radical, suggesting the interaction between carotenoids and polyphenols in CPE was mainly caused by lutein and gallic acid. Molecular dynamics simulations and thermodynamic parameters analysis demonstrated that hydrogen bonding, electrostatic interactions, and van der Waals forces played dominant roles in the interaction between lutein and gallic acid, which was confirmed by Raman and X-ray diffraction. These results provided a new perspective on the interaction mechanism between carotenoids and polyphenols, which offered a novel strategy for the enhancement of the activities and stability of bioactive substances.

Heterologous expression of a deacetylase and its application in L-glufosinate preparation.

With potent herbicidal activity, biocatalysis synthesis of L-glufosinate has drawn attention. In present research, NAP-Das2.3, a deacetylase capable of stereoselectively resolving N-acetyl-L-glufosinate to L-glufosinate mined from Arenimonas malthae, was heterologously expressed and characterized. In Escherichia coli, NAP-Das2.3 activity only reached 0.25 U/L due to the formation of inclusive bodies. Efficient soluble expression of NAP-Das2.3 was achieved in Pichia pastoris. In shake flask and 5 L bioreactor fermentation, NAP-Das2.3 activity by recombinant P. pastoris reached 107.39 U/L and 1287.52 U/L, respectively. The optimum temperature and pH for N-acetyl-glufosinate hydrolysis by NAP-Das2.3 were 45 °C and pH 8.0, respectively. The Km and Vmax of NAP-Das2.3 towards N-acetyl-glufosinate were 25.32 mM and 19.23 µmol mg-1 min-1, respectively. Within 90 min, 92.71% of L-enantiomer in 100 mM racemic N-acetyl-glufosinate was converted by NAP-Das2.3. L-glufosinate with high optical purity (e.e.P above 99.9%) was obtained. Therefore, the recombinant NAP-Das2.3 might be an alternative for L-glufosinate biosynthesis.

Fifty years of BMT: risk stratification, donor matching, and stem cell collection for transplantation.

In this review, we discuss recipient risk assessment for allo-HCT regarding comorbidities present at baseline to predict non relapse mortality. We further reviewed the incorporation of remission status and cytogenetic risk prior to allograft transplantation to predict relapse rates for hematologic malignancies. HCT-CI and DRI are tools available to physicians to assess the risk-benefit of allo-HCT in patients referred for transplantation. Next, we discuss our algorithm for donor selection and criteria for donor selection in case matched donors are not available. Finally, we discuss our approach for stem cell mobilization, especially in donors failing G-CSF, and our approach for the use of plerixafor and data supporting its use.

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues.

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure-activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.