FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.

Development of a risk assessment model for cardiac injury in patients newly diagnosed with acute myeloid leukemia based on a multicenter, real-world analysis in China.

BACKGROUND: Studies have revealed that acute myeloid leukemia (AML) patients are prone to combined cardiac injury. We aimed to identify hematological risk factors associated with cardiac injury in newly diagnosed AML patients before chemotherapy and develop a personalized predictive model. METHODS: The population baseline, blood test, electrocardiogram, echocardiograph, and genetic and cytogenetic data were collected from newly diagnosed AML patients. The data were subdivided into training and validation cohorts. The independent risk factors were explored by univariate and multivariate logistic regression analysis respectively, and data dimension reduction and variable selection were performed using the least absolute shrinkage and selection operator (LASSO) regression models. The nomogram was generated and the reliability and generalizability were verified by receiver operating characteristic (ROC) curves, the area under the curve (AUC) and calibration curves in an external validation cohort. RESULTS: Finally, 499 AML patients were included. After univariate logistic regression, LASSO regression and multivariate logistic regression analysis, abnormal NT-proBNP, NPM1 mutation, WBC, and RBC were independent risk factors for cardiac injury in AML patients (all P < 0.05). The nomogram was constructed based on the above four variables with high accuracy. The area under the curve was 0.742, 0.750, and 0.706 in the training, internal validation, and external validation cohort, respectively. The calibration curve indicated that the model has good testing capability. The Kaplan-Meier curve showed that the higher the risk of combined cardiac injury in AML patients, the lower their probability of survival. CONCLUSIONS: This prediction nomogram identifies hematological risk factors associated with cardiac injury in newly diagnosed AML patients and can help hematologists identify the risk and provide precise treatment options.

Phased genome assemblies reveal haplotype-specific genetic load in the critically endangered Chinese Bahaba (Teleostei, Sciaenidae).

While haplotype-specific genetic load shapes the evolutionary trajectory of natural and captive populations, mixed-haplotype assembly and genotyping hindered its characterization in diploids. Herein, we produced two phased genome assemblies of the critically endangered fish Chinese Bahaba (Bahaba taipingensis, Sciaenidae, Teleostei) and resequenced 20 whole genomes to quantify population genetic load at a haplotype level. We identified frame-shifting variants as the most deleterious type, followed by mutations in the 5'-UTR, 3'-UTR and missense mutations at conserved amino acids. Phased haplotypes revealed gene deletions and high-impact deleterious variants. We estimated ~1.12% of genes missing or interrupted per haplotype, with a significant overlap of disrupted genes (30.35%) between haplotype sets. Relative proportions of deleterious variant categories differed significantly between haplotypes. Simulations suggested that purifying selection struggled to purge slightly deleterious genetic load in captive breeding compared to genotyping interventions, and that higher inter-haplotypic variance of genetic load predicted more efficient purging by artificial selection. Combining the knowledge of haplotype-resolved genetic load with predictive modelling will be immensely useful for understanding the evolution of deleterious variants and guiding conservation planning.

Global burden of hematologic malignancies and evolution patterns over the past 30 years.

Hematologic malignancies are among the most common cancers, and understanding their incidence and death is crucial for targeting prevention, clinical practice improvement, and research resources appropriately. Here, we investigated detailed information on hematological malignancies for the period 1990-2019 from the Global Burden of Disease study. The age-standardized incidence rate (ASIR), the age-standardized death rate (ASDR), and the corresponding estimated annual percentage changes (EAPC) were calculated to assess temporal trends in 204 countries and territories over the past 30 years. Globally, incident cases of hematologic malignancies have been increasing since 1990, reaching 1343.85 thousand in 2019, but the ASDR for all types of hematologic malignancies has been declining. The ASDR for leukemia, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma were 4.26, 1.42, 3.19, and 0.34 per 100,000 population in 2019, respectively, with Hodgkin lymphoma showing the most significant decline. However, the trend varies by gender, age, region, and the country's economic situation. The burden of hematologic malignancies is generally higher in men, and this gender gap decreases after peaking at a given age. The regions with the largest increasing trend in the ASIR of leukemia, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma were Central Europe, Eastern Europe, East Asia, and Caribbean, respectively. In addition, the proportion of deaths attributed to high body-mass index continued to rise across regions, especially in regions with high socio-demographic indices (SDI). Meanwhile, the burden of leukemia from occupational exposure to benzene and formaldehyde was more widespread in areas with low SDI. Thus, hematologic malignancies remain the leading cause of the global tumor burden, with growing absolute numbers but sharp among several age-standardized measures over the past three decades. The results of the study will inform analysis of trends in the global burden of disease for specific hematologic malignancies and develop appropriate policies for these modifiable risks.

Validation of a portable monitor compared with polysomnography for screening of obstructive sleep apnea in polio survivors.

Subjective: Sleep-disordered breathing (SDB) is highly prevalent in polio survivors. Obstructive sleep apnea (OSA) is the most frequent type. Full polysomnography (PSG) is recommended for OSA diagnosis in patients with comorbidities by current practice guidelines, but it is not always accessible. The purpose of this study was to evaluate whether type 3 portable monitor (PM) or type 4 PM might be a viable alternative to PSG for the diagnosis of OSA in postpolio subjects. Methods: A total of 48 community-living polio survivors (39 men and 9 women) with an average age of 54.4 ± 5.3 years referred for the evaluation of OSA and who volunteered to participate were recruited. First, they completed the Epworth Sleepiness Scale (ESS) questionnaire and underwent pulmonary function testing and blood gas tests the day before PSG night. Then, they underwent an overnight in-laboratory PSG with a type 3 PM and type 4 PM recording simultaneously. Results: The AHI from PSG, respiratory event index (REI) from type 3 PM, and ODI3 from type 4 PM was 30.27 ± 22.51/h vs. 25.18 ± 19.11/h vs. 18.28 ± 15.13/h, respectively (P < 0.001). For AHI ≥ 5/h, the sensitivity and specificity of REI were 95.45 and 50%, respectively. For AHI ≥ 15/h, the sensitivity and specificity of REI were 87.88% and 93.33%, respectively. The Bland-Altman analysis of REI on PM vs. AHI on PSG showed a mean difference of -5.09 (95% confidence interval [CI]: -7.10, -3.08; P < 0.001) with limits of agreement ranging from -18.67 to 8.49 events/h. ROC curve analysis for patients with REI ≥ 15/h showed an area under the curve (AUC) of 0.97. For AHI ≥ 5/h, the sensitivity and specificity of ODI3 from type 4 PM were 86.36 and 75%, respectively. For patients with AHI ≥ 15/h, the sensitivity was 66.67%, and the specificity was 100%. Conclusion: Type 3 PM and Type 4 PM could be alternative ways to screen OSA for polio survivors, especially for moderate to severe OSA.

Comprehensive analysis of clinical prognostic features and tumor microenvironment landscape of CD11b+CD64+ patients with acute myeloid leukemia.

BACKGROUND: Immunophenotyping surface molecules detected in the clinic are mainly applied in diagnostic confirmation and subtyping. However, the immunomodulatory molecules CD11b and CD64, are highly associated with leukemogenesis. Hence, the prognostic value of them and their potential biological functions merit further investigation. METHODS: Flow cytometry was operated to detect immunophenotypic molecules from AML bone marrow samples. Multivariate cox regression, Kaplan-Meier analyses, and nomogram were conducted to predict survival. Transcriptomic data, lymphocyte subsets, and immunohistochemical staining were incorporated to identify potential biological functions of prognostic immunophenotype in acute myeloid leukemia (AML). RESULTS: We classified 315 newly diagnosed AML patients of our center based on the expression of CD11b and CD64. The CD11b+CD64+ populations were identified as independent risk factors for overall survival and event-free survival of AML, exhibiting specific clinicopathological features. The predictive models based on CD11b+CD64+ showed high classification performance. In addition, the CD11b+CD64+ subset, characterized by high inhibitory immune checkpoints, M2-macrophage infiltration, low anti-tumor effector cells infiltration, as well as abnormal somatic mutation landscape, presented a distinctive tumor microenvironmental landscape. The CD11b+CD64+ population showd a higher expression of BCL2, and the drug sensitivity indicated that they presented a lower half-maximal inhibitory concentration value for BCL2 inhibitor, and could benefit more from the above medicine. CONCLUSIONS: This work might be of benefit to enhanced understanding of CD11b+CD64+ in the prognosis and leukemogenesis, and yielded novel biomarkers to guide immunotherapy and targeted therapy for AML.

Evaluation of an I177L gene-based five-gene-deleted African swine fever virus as a live attenuated vaccine in pigs.

African swine fever (ASF) is a highly contagious disease of domestic and wild pigs caused by the African swine fever virus (ASFV). The current research on ASF vaccines focuses on the development of naturally attenuated, isolated, or genetically engineered live viruses that have been demonstrated to produce reliable immunity. As a result, a genetically engineered virus containing five genes deletion was synthesized based on ASFV Chinese strain GZ201801, named ASFV-GZΔI177LΔCD2vΔMGF. The five-gene-deleted ASFV was safe and fully attenuated in pigs and provides reliable protection against the parental ASFV strain challenge. This indicates that the five-gene-deleted ASFV is a potential candidate for a live attenuated vaccine that could control the spread of ASFV.

A novel organic arsenic derivative MZ2 remodels metabolism and triggers mtROS-mediated apoptosis in acute myeloid leukemia.

PURPOSE: Acute myeloid leukemia (AML) is one of the most common neoplasms in adults, and it is difficult to achieve satisfactory results with conventional drugs. Here, we synthesized a novel organic arsenic derivative MZ2 and evaluated its ability to remodel energy metabolism to achieve anti-leukemia. METHODS: MZ2 was characterized by the average 1-min full mass spectra analysis. Biological methods such as Western blot, qPCR, flow cytometry and confocal microscopy were used to assess the mode and mechanism of MZ2-induced death. The in vivo efficacy of MZ2 was assessed by constructing a patient-derived xenograft (PDX) AML model. RESULTS: Unlike the precursor organic arsenical Z2, MZ2 can effectively reduce the level of aerobic glycolysis. Our in-depth found that MZ2 inhibited the expression of PDK2 in a dose-dependent manner and did not affect the expression of LDHA, another key enzyme of the glycolytic pathway. MZ2 reconstituted energy metabolism to induce the generation of mitochondrial ROS (mtROS) and then triggerd intrinsic apoptosis pathway. We also assessed whether MZ2 generates autophagy and results showed that MZ2 can induce autophagy of AML cells, which may be associated with the precursor organic arsenic drug. In vivo, MZ2 effectively attenuated leukemia progression in mice, and immunohistochemical results suggested its PDK2 inhibitory effect. CONCLUSION: In summary, the novel organic arsine derivative MZ2 exhibited excellent anti-tumor effects in acute myeloid leukemia, which may provide a potential strategy for the treatment of acute myeloid leukemia.

Serum proteomics screening intercellular adhesion molecule-2 improves intermediate-risk stratification in acute myeloid leukemia.

Background: The clinical risk classification of acute myelocytic leukemia (AML) is largely based on cytogenetic and molecular genetic detection. However, the optimal treatment for intermediate-risk AML patients remains uncertain. Further refinement and improvement of prognostic stratification are therefore necessary. Objectives: The aim of this study was to identify serum protein biomarkers to refine risk stratification in AML patients. Design: This study is a retrospective study. Methods: Label-free proteomics was used to identify the differential abundance of serum proteins in AML patients. Transcriptomic data were combined to identify key altered markers that could indicate the risk rank of AML patients. The survival status was assessed by Kaplan-Meier and multivariate Cox regression analyses. Results: We delineated serum protein expression in a population of AML patients. Many biological processes were influenced by the identified differentially expressed proteins. Association analysis of transcriptome data showed that intercellular adhesion molecule-2 (ICAM2) had a higher survival prediction value in the intermediate-risk AML group. ICAM2 was detrimental for intermediate-risk AML, regardless of whether patients received bone marrow transplantation. ICAM2 well distinguishes the intermediate group of patients, whose probability of survival is comparable to that of patients with the ELN-2017 according to the reference classification. In addition, newly established stratified clinical features were associated with leukemia stem cell scores. Conclusion: The inclusion of ICAM2 expression into the AML risk classification according to ELN-2017 was a good way to transfer patients from three to two groups. Thus, providing more information for clinical decision-making to improve intermediate-risk stratification in AML patients.

Multilocus Phylogeography and Population Genetic Analyses of Opsariichthys hainanensis Reveal Pleistocene Isolation Followed by High Gene Flow around the Gulf of Tonkin.

The ichthyofauna of continental islands is characterized by immigration through a land bridge due to fluctuating sea levels. Hainan Island is adjacent to the southern margin of mainland China and provides opportunities for understanding the origin and diversification of freshwater fishes. The aim of our study was to evaluate the level of genetic variation and phylogeographic structure of Opsariichthys hainanensis on Hainan Island and mainland China, using mtDNA cyt b gene (1140 bp) and D-loop (926 bp), nuclear RAG1 gene (1506 bp), and 12 microsatellite loci. Mitochondrial phylogenetic analysis identified five major lineages according to the geographical distribution from different populations. We suggested that two dispersal events occurred: the population in the Changhua River migrated to the Red River (Lineage B), and the populations in the South Hainan region moved northwards to the North Hainan region. However, populations in Northwest Hainan Island dispersed to the populations around the Gulf of Tonkin (Lineage A1) and populations in Northeast Hainan Island dispersed to the populations in mainland China (Lineage A2). Our results indicated that the populations of O. hainanensis suffered a bottleneck event followed by a recent population expansion supported by the ABC analysis. We suggest that O. hainanensis populations were found mostly in the lowlands and a lack of suitable freshwater habitat in southern mainland China and Hainan during the Last Interglacial period, and then expansion occurred during the Last Glacial Maximum.

Cardiac-Related Lesions in Newly Diagnosed Patients With Acute Leukemia: A Chinese Population-Based Real-World Study.

The relationship between newly diagnosed acute leukemia (AL) and heart-related lesions remains unclear. This study aimed to investigate baseline cardiac function and risk of cardiovascular diseases (CVDs) in patients with new-onset AL, and provide data on cardiac management strategies for patients with AL. We retrospectively collected data on baseline characteristics, echocardiography, and biochemical blood indicators (e.g., myocardial enzymes) from 408 patients, 200 with newly diagnosed AL, 103 with coronary artery disease (CAD), and 105 controls from January 1, 2015 to August 31, 2019. The creatine kinase isoenzyme myocardial band, lactate dehydrogenase, highly sensitive troponin-I, and B-type natriuretic peptide levels and left ventricular internal diameter (LVID) were significantly higher in patients with newly diagnosed AL than in the control group. The degree of cardiac damage was lower in newly diagnosed AL patients than in CAD patients. The best predictor of heart damage was LVID (AUC [area under the curve] = 0.709; 95% CI [confidence interval]: 0.637-0.781; p < 0.001), and independent prognostic risk factors were age and ejection fraction (HR [hazard ratio] = 1.636; 95% CI: 1.039-2.575; p = 0.033). The ratio of leukemia blasts among patients with AL was positively correlated with cardiac damage. Our data indicated that newly diagnosed AL patients had certain myocardial damage before treatment. Clinicians need to pay attention to these manifestations, which may be related to the prognosis.

Immunoadjuvant Nanoparticles as Trojan Horses for Enhanced Photo-Immunotherapy in the Treatment of Triple-Negative Breast Cancer.

Treatment of triple-negative breast cancer (TNBC) faces great challenges due to high invasiveness and poor prognosis. Therefore, effective treatment methods are urgently needed to control primary tumors and suppress distant tumors. Herein, we employed glycated chitosan (GC), a polysaccharide macromolecular immunoadjuvant, to construct a self-assembly GC@ICG nanoparticle which is accessible to tumor cells for synergistic cancer treatment based on the combination of phototherapy and immunotherapy. In this strategy, the self-associated synthesis of spherical GC@ICG significantly improved the stability of ICG and endowed GC with Trojan Horses in tumor cells to enhance tumor immunogenicity. A bilateral 4T1 tumor-bearing mouse model was established to evaluate the therapeutic outcomes and specific host antitumor immune response. Finally, GC@ICG-based phototherapy can directly eliminate primary tumors and resist the progression of untreated distant tumors. In addition, compared to the treatment of L + GC + ICG, GC@ICG-based phototherapy was evidenced to suppress lung metastasis and enhance infiltration of CD8+ T cells in untreated distant tumors. Therefore, this design shows promise in addressing the challenges of the treatment of TNBC.

Meta-analysis reveals no significant association between ERCC6 polymorphisms and bladder cancer risk.

BACKGROUND: Numerous studies have been conducted to evaluate the association between excision repair cross-complementing group 6 (ERCC6) gene polymorphisms and bladder cancer risk, but their findings have been inconsistent. Here we performed a meta-analysis to attempt to clarify this association. METHODS: Studies were retrieved from the PubMed and China National Knowledge Infrastructure databases up to October 1, 2015, with strict selection and exclusion criteria. A total of 5,032 samples, comprising samples from 2,475 bladder cancer patients and 2,557 controls from 5 studies, were included in the meta-analysis. The odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of the associations. RESULTS: Regarding the Met1097Val polymorphism, no significant association with bladder cancer risk was found in any of the genetic models evaluated (Val vs. Met: OR = 1.10, 95% CI, 0.97-1.25; Val/Val vs. Met/Met: OR = 1.23, 95% CI, 0.86-1.75; Val/Val + Val/Met vs. Met/Met: OR = 1.12, 95% CI, 0.96-1.30; Val/Val vs. Met/Met + Val/Met: OR = 0.81, 95% CI, 0.57-1.14). Similarly, as regards the Arg1230Pro polymorphism, we also found no positive results. CONCLUSIONS: According to the results of our meta-analysis, there is no evidence of a link between the ERCC6 gene polymorphisms and bladder cancer risk. Well-designed further studies, with larger sample sizes and adjustment for confounders such as smoking status, are needed to confirm these conclusions.