Hybrid Thin Film Encapsulation for Improving the Stability of PbS Quantum Dot Solar Cells.

The instability to moisture, heat, and ultraviolet (UV) light is the main problem in the application of quantum dot solar cells (QDSCs). Thin film encapsulation can effectively improve their operational stability. However, it is difficult to achieve multiple barrier effects with single layer of encapsulated film. Here, a hybrid thin-film encapsulation strategy is reported to encapsulate lead sulfide QDSCs, which can isolate moisture and partial thermal, and prevent the penetration of UV light, thus retarding the surface oxidation process of the quantum dots. After 60 h, the encapsulated device retains a normalized power conversion efficiency of 83.8% and 80.6% at 85% humidity and 75 °C, respectively, which is three and six times of the value obtained in unencapsulated devices. At continuous UV illumination, encapsulated device exhibits five times higher stability than the reference. This strategy provides the way for the overall improvement of the operating stability of lead sulfide QDSCs in harsh environments of high humidity, high temperature, and UV light.

A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells.

BACKGROUND: Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy. METHODS: Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts. RESULTS: We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs. CONCLUSIONS: Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.

Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell-tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label-retaining slow-cycling leukemia cell population from AML1-ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH-staining, a higher proportion of PKH-retaining cells are in G0 phase, and PKH-retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH-retaining cells possess high chemo-resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH-retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin-CD74- leukemia cells, Lin-CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow-cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.

Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity.

Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for cancer immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms in vivo. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.

Strong Homology Between Colonizing and Bloodstream Carbapenem-Resistant Acinetobacter Spp.: Implications for Empiric Antibiotic Therapy in Hematological Patients.

Objective: This study aimed to assess the impact of colonization status on the outcomes of Acinetobacter spp. bloodstream infection (BSI) and investigate the homology and within-host evolution between colonizing and bloodstream carbapenem-resistant Acinetobacter spp. (CRA) to inform antibiotic therapeutic decisions. Methods: We analyzed clinical outcomes of 46 hematological patients with Acinetobacter spp. BSI and performed whole-genome sequencing on the remaining CRA isolates. Results: Among the patients, 39.1% (n=18) had prior Acinetobacter spp. colonization. Colonized patients had higher rates of polymicrobial BSI (50.0% vs 21.4%, P=0.044) and CRA BSI (72.2% vs 17.9%, P<0.001), resulting in elevated inflammatory markers and increased 30-day mortality. Each of the eight pairs of the remaining respiratory colonizing and bloodstream CRA strains belonged to the same genomospecies. Each pair exhibited definitive agreement in at least 21 of the 22 most representative antibiotic susceptibility tests. The minimum spanning tree based on multilocus sequence typing (MLST) and phylogenetic trees based on MLST and single nucleotide polymorphism (SNP) all indicated that each pair shared the same minimum branch. Very few non-synonymous SNPs in genic regions were identified during the transition from respiratory colonization to bloodstream infection, with minimal changes in virulence genes. Homology analysis suggested that CRA BSI originated from colonizing isolates in the respiratory tract. Conclusion: Strict infection control measures are needed to manage Acinetobacter spp. colonisation in hematological patients. Appropriate empirical therapy can be administered for suspected CRA BSI based on the antimicrobial minimum inhibitory concentration of CRA colonising the respiratory tract.

The RTK-RAS signaling pathway is enriched in patients with rare acute myeloid leukemia harboring t(16;21)(p11;q22)/FUS::ERG.

Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUS::ERG at our center. Thirty-six AML patients harboring FUS::ERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUS::ERG AML compared to RUNX1::RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUS::ERG AML was 11.9 (95% confidence interval [CI]: 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.

Serum albumin is associated with the inherent property of acute myeloid leukemia and correlates with patient outcomes.

An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, P = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, P = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, P = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, P = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, P = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, P = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, P = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, P = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.

BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Effects of Eleutherine bulbosa extract on the myofibrillar protein oxidation and moisture migration of yak meat under oxidation stress.

The influence of Eleutherine bulbosa (EB) extract at various levels (1, 4, 7, 10 or 13 g/kg) on the myofibrillar protein oxidation and moisture migration of yak meat in Fenton oxidation system was investigated. The results showed that inclusion of EB extract in yak meat efficiently inhibited carbonyl formation triggered by hydroxyl radicals. Supplementation of EB extract at 1-10 g/kg manifested more contents of the active sulfhydryl, ε-NH2 groups and α-helix structure, and higher solubility of myofibrillar proteins (MPs), but alleviated the turbidity of MPs. However, adding high level of EB extract (13 g/kg) induced the loss of free amine and α-helix content and resulted in more aggregation of MPs. The SDS-PAGE demonstrated that adding 1-7 g/kg EB extract had an obvious protective effect for myosin heavy chain and actin, whereas 10 or 13 g/kg EB extract led to weakened intensities of protein bands. DSC and LF-NMR analysis revealed that 7 g/kg EB extract had appreciable effects on thermal stabilities of MPs, and improved the hydration of yak meat induced by oxidation, while 13 g/kg EB extract accelerated MP structure destabilization and lowered water retention. Our results suggested that incorporation of low levels of EB extract (1-7 g/kg) effectively retarded the oxidative damage to MPs and EB extract could be a promising natural antioxidant in meat processing.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Uncovering the Role of Anmeidan against Atherosclerosis from Integrated Network Pharmacology and Pharmacological Experiments.

BACKGROUND: Atherosclerosis (AS) is the leading cause of mortality in elderly individuals worldwide. Anmeidan (AMD) is a Traditional Chinese Medicine (TCM) formula composed of many herbs, many of which have been accepted for treating AS. This study aimed to explore whether AMD can inhibit the progress of AS and its possible mechanism. METHODS: ApoE-/- mice were used to establish the AS model and evaluate the therapeutic effect of AMD on AS. Based on network pharmacology technology, the potential mechanism of AMD for treating AS was explored, and lipid metabolism pathways related to AS were mainly studied. Next, the effects of AMD on liver lipid levels, antioxidant capacity, liver tissue morphology, and gene expression related to lipid metabolism in ApoE-/- mice were investigated. Cellular experiments were performed to confirm the lipid-lowering effect of AMD. Finally, the AMD composition was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In ApoE-/- mice, AMD effectively alleviated AS by reducing serum total cholesterol, triglyceride, low-density lipoprotein levels, and plaque area, and increasing high-density lipoprotein levels. Network pharmacology indicated that AMD may suppress AS by regulating lipid metabolism pathways with multiple TCM components, which is consistent with the results of in vivo experiments and LC-MS/MS component identification. AMD significantly reduced liver lipid aggregation, intensified antioxidant enzyme activity, and upregulated the mRNA levels of ABCA1, ABCG1, and LDLR with increased cholesterol efflux. In addition, AMD decreased cholesterol levels in foam cells. CONCLUSIONS: This study confirmed that AMD could treat AS by regulating lipid metabolism and preliminarily explored the related mechanism. These findings provide new ideas for the treatment of AS with TCM.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy.

BACKGROUND: Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy. METHODS: Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL. RESULTS: The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA-) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA- at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including TP53, IGLL5, PIM1, BTG1, CD79B, GNA13, and P2RY8. Notably, we observed a significant correlation between IGLL5 mutation and inferior PFS (p=0.008) and OS (p=0.014). CONCLUSIONS: Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.

Identification of red blood cell distribution width as a prognostic factor in acute myeloid leukemia.

Many prognostic factors have been identified in acute myeloid leukemia (AML). In this study, we investigated novel prognostic biomarkers using machine learning and Cox regression models in a prospective cohort of 591 patients with AML and tried to identify potential therapeutic targets based on transcriptomic data. We found that elevated red blood cell distribution width (RDW) at diagnosis was an adverse prognostic factor for AML, independent of the 2022 European LeukemiaNet (ELN2022) genetic risk. As a continuous variable, higher RDW was associated with shorter overall survival (OS) (hazard ratio [HR] 1.087, 95% confidence interval [CI] 1.036-1.139, p < 0.001) and event-free survival (EFS) (HR 1.078, 95% CI 1.033-1.124, p < 0.001). Elevated RDW returned to normal after consolidation therapy, which indicated that leukemia cells resulted in abnormal RDW. We further investigated the relationship between RDW and transcriptome in another cohort of 191 patients with AML and public datasets using gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). We found that patients in the high-RDW group were significantly enriched in the positive regulation of erythroid differentiation and inflammation-related pathways. Finally, we identified the inflammation-associated gene IL12RB2 and verified its prognostic relevance with patients with AML in public databases, suggesting it as a potential therapy target.