Basic mechanisms and novel potential therapeutic targets for ferroptosis in acute myeloid leukemia.

Ferroptosis is a form of cell death that is regulated by iron and characterized by the buildup of lipid peroxides (LPO) and subsequent rupture of the cell membrane. The molecular mechanisms of ferroptosis involve metabolic pathways related to iron, lipids, and amino acids, which contribute to the production of lipid reactive oxygen species (ROS). In recent years, there has been increasing attention on the occurrence of ferroptosis in various diseases. Ferroptosis has been found to play a crucial role in cardiovascular diseases, digestive diseases, respiratory and immunological diseases, and particularly in malignancies. However, there is still a lack of studies on ferroptosis in acute myeloid leukemia (AML). This paper provides a comprehensive review of the mechanism of ferroptosis and its regulatory molecules and therapeutic agents in AML. It also evaluates the relationship between ferroptosis-related genes (FRGs), non-coding RNAs (ncRNAs), and prognosis to develop prognostic molecular models in AML. The study also explores the association between ferroptosis and immune infiltration in AML, to identify novel potential target regimens for AML.

Potential applications of ferroptosis inducers and regulatory molecules in hematological malignancy therapy.

Ferroptosis, a novel form of iron-dependent cell death, has emerged as a potential avenue for promoting tumor cell death by causing cell membrane rupture and the accumulation of lipid peroxides (LPO) in the cell. Since its discovery in 2012, extensive research has been conducted to explore the mechanism of ferroptosis inducers, including erastin, sulfasalazine, and sorafenib. These compounds inhibit system XC-, while Ras-selective lethal small molecule 3 (RSL3) and FION2 specifically target GPX4 to promote ferroptosis. Therefore, targeting ferroptosis presents a promising therapeutic approach for malignant tumors. While the study of ferroptosis in solid tumors has made significant progress, there is limited information available on its role in hematological tumors. This review aims to summarize the molecular mechanisms of ferroptosis inducers and discuss their clinical applications in hematological malignancies. Furthermore, the identification of non-coding RNAs (ncRNAs) and genes that regulate key molecules in the ferroptosis pathway could provide new targets and establish a molecular theoretical foundation for exploring novel ferroptosis inducers in hematological malignancies.

Exploration of D-limonene as a sex pheromone for males of Bactrocera minax (Diptera: Tephritidae).

BACKGROUND: Bactrocera minax is a devastating pest of citrus fruits. However, there have been no effective control measures before. Few reports on the sex pheromones of B. minax are available. RESULTS: In this study, nine of the volatile compounds in adult females were identified using headspace solid-phase microextraction (HS-SPME) in combination with gas chromatography-mass spectrometry (GC-MS). Among them, d-limonene, caprolactam, 2-Nitro-1H-imidazole, and creatinine could evoke antennal responses in males. Field bioassays showed that only d-limonene could lure male flies, with a relative lure rate of 78.18% in all tested samples, which was significantly higher than that of paraffin oil control, while all volatile compounds did not have any lure effective to female flies. Moreover, d-limonene was diluted with paraffin oil into differential concentrations, the lure effect on males was better at 100, 500, and 800 µL d-limonene mL-1 than pure d-limonene (1000 µL mL-1 ). The relative male lure rate of d-limonene at 100 µL mL-1 was 85.88%, which was significantly higher than that of food-baits (14.12%) on day 3. However, d-limonene was unattractive to female and male Bactrocera dorsalis and Zeugodacus tau. Further kinetic analysis showed that female adults released d-limonene around 15-day post eclosion. Electroantennography 1 results showed that 500 µL mL-1 d-limonene evoked the strongest responses to antennae of 10- to 25-day-old male flies. CONCLUSION: Our results indicated that d-limonene could be a sex pheromone from female flies of B. minax, and it could be used as a male-specific sex attractant for B. minax. © 2023 Society of Chemical Industry.

Construction and validation of an NAD + metabolism-related lncRNA signature for predicting the prognosis and immune landscape of acute myeloid leukemia.

BACKGROUND: This study aimed to investigate the potential of a NAD+ metabolism-related lncRNA signature as a reliable prognostic biomarker for acute myeloid leukemia (AML). METHODS: Transcriptome profiles and clinical data of AML patients were obtained from The Cancer Genome Atlas (TCGA) database. NAD+ metabolism-related genes (NMRGs) were identified from the KEGG and Reactome databases. Coexpression analysis was used to screen NAD+ metabolism-related lncRNAs. The NAD+ metabolismrelated lncRNA signature was constructed using univariate analysis, LASSO regression, and multivariate analysis. High- and low-risk groups were compared for survival, tumor mutation burden, immune cell infiltration, and response to immunotherapy. Enrichment analysis explored the biological functions. RESULTS: LINC01679, AC079922.2, TRAF3IP2-AS1, and LINC02465 were identified to construct the risk model. The model exhibited good predictive power and outperformed age and gender as an independent prognostic marker. High-risk patients showed poorer survival, distinct TP53 mutations, and altered immune cell infiltration compared to low-risk patients. Additionally, low-risk patients exhibited greater sensitivity to immunotherapy. Enriched biological functions included leukocyte migration and positive regulation of cytokine production. CONCLUSIONS: The NAD+ metabolism-related lncRNA signature shows promise in predicting clinical outcomes for AML patients.

A nomogram based on clinical features and molecular abnormalities for predicting the prognosis of patients with acute myeloid leukemia.

Background: The high clinical and molecular heterogeneity of acute myeloid leukemia (AML) has led to an unsatisfactory clinical prognosis, thus we sought to incorporate both clinical features and molecular abnormalities to construct a new prognostic model. Methods: A database search of the Gene Expression Omnibus (GEO) revealed 238 cases of adult AML. The independent risk factors were assessed using both univariate and multivariate Cox regression, as well as least absolute shrinkage and selection operator (LASSO) regression. The predictive accuracy, discriminatory power and clinical applicability of the nomogram were determined by the consistency index (C-index), calibration curves and decision curve analysis (DCA). In addition, a single-centre cohort of 135 cases was used for external validation. Results: Multivariate Cox regression analysis showed that the independent influences on overall survival (OS) were age, type of disease, DNMT3A, IDH2 and TP53 mutations. The area under the curve (AUC) values for the training set were 0.755, 0.745 and 0.757 at 1, 2 and 3 years respectively; the AUC for the validation set were 0.648, 0.648 and 0.654 at 1, 2 and 3 years; and the AUC for the northwest China set were 0.692, 0.724 and 0.689 at 1, 2 and 3 years. The calibration and DCA indicated good consistency and clinical utility of the nomogram. Finally, younger (age <60 years) and elderly (age ≥60 years) patients were each divided into two risk groups with significantly different survival rates. Conclusions: A nomogram consisting of five risk factors was developed for forecasting the prognosis of AML with guaranteed reliability.

Bioreduction mechanisms of high-concentration hexavalent chromium using sulfur salts by photosynthetic bacteria.

Eliminating "sulfur starvation" caused by competition for sulfate transporters between chromate and sulfate is crucial to enhance the content of sulfur-containing compounds and improve the tolerance and reduction capability of Cr(VI) in bacteria. In this study, the effects of sulfur salts on the Cr(VI) bioremediation and the possible mechanism were investigated in Rhodobacter sphaeroides SC01 by cell imaging, spectroscopy, and biochemical measurements. The results showed that, when the concentration of metabisulfite was 2.0 g L-1, and the initial OD600 was 0.33, the reduction rate of R. sphaeroides SC01 reached up to 91.3% for 500 mg L-1 Cr(VI) exposure at 96 h. Moreover, thiosulfate and sulfite also markedly increased the concentration of reduced Cr(VI) in R. sphaeroides SC01. Furthermore, the characterization results revealed that -OH, -CONH, -COOH, -SO3, -PO3, and -S-S- played a major role in the adsorption of Cr, and Cr(III) reduced by bacteria was bioprecipitated in the production of Cr2P3S9 and CrPS4. In addition, R. sphaeroids SC01 combined with metabisulfite significantly increased the activity of glutathione peroxidase and the content of glutathione (GSH) and total sulfhydryl while decreasing reactive oxygen species (ROS) accumulation and cell death induced by Cr(VI) toxic. Overall, the results of this research revealed a highly efficient and reliable strategy for Cr(VI) removal by photosynthetic bacteria combined with sulfur salts in high-concentration Cr(VI)-contaminated wastewater.

Efficacy and safety of adding gemtuzumab ozogamicin to conventional chemotherapy for adult acute myeloid leukemia: a systematic review and meta-analysis.

Introduction: Compared with the 3 + 7 regimen, the addition of gemtuzumab ozogamicin (GO) has improved survival in patients with acute myeloid leukemia (AML). We conducted a systematic review and meta-analysis to examine the overall efficacy and safety of GO in combination with conventional chemotherapy regimens in patients with AML.Methods: We searched several databases (MEDLINE, Embase, Web of Science and Cochrane Library). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS); odds ratios (ORs) with 95% CIs were calculated for the other outcomes.Results: Ten records involving 11 randomized controlled trials (RCTs) met the inclusion criteria. GO plus induction chemotherapy significantly increased RFS (HR: 0.84, 95% CI: 0.73-0.98), decreased the incidence of relapse (OR: 0.78, 95% CI: 0.68-0.91) and resistant disease (OR: 0.72, 95% CI: 0.61-0.84), and had no significant effect on the rate of complete remission (CR) with or without incomplete platelet recovery (OR: 1.21, 95% CI: 0.94-1.55), 30-day mortality (OR: 1.25, 95% CI: 0.99-1.57). Subgroup analysis showed significant OS benefits for patients with favorable cytogenetic (HR: 0.50, 95% CI: 0.28-0.89) or given GO at induction stage (HR: 0.91, 95% CI: 0.84-1.00). Compared with other dosing schedule groups, 3 mg/m2 fractionated schedule had a greater RFS benefit (HR: 0.52, 95% CI: 0.36-0.76) and lower relapse risk (OR: 0.48, 95% CI: 0.28-0.84).Conclusions: Adding low-dose GO to induction or both induction and post-remission chemotherapy has considerable efficacy and unequivocal safety for newly diagnosed adult AML.

Development and validation of a novel prognosis prediction model for patients with myelodysplastic syndrome.

Background: Somatic mutations are widespread in patients with Myelodysplastic Syndrome (MDS) and are associated with prognosis. However, a practical prognostic model for MDS that incorporates somatic mutations urgently needs to be developed. Methods: A cohort of 201 MDS patients from the Gene Expression Omnibus (GEO) database was used to develop the model, and a single-center cohort of 115 MDS cohorts from Northwest China was used for external validation. Kaplan-Meier analysis was performed to compare the effects of karyotype classifications and gene mutations on the prognosis of MDS patients. Univariate and multivariate Cox regression analyses and Lasso regression were used to screen for key prognostic factors. The shinyapps website was used to create dynamic nomograms with multiple variables. The time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the model's discrimination, accuracy and clinical utility. Results: Six risk factors (age, bone morrow blast percentage, ETV6, TP53, EZH2, and ASXL1) were considered as predictor variables in the nomogram. The nomogram showed excellent discrimination, with respective the area under the ROC curve (AUC) values of 0.850, 0.839, 0.933 for the training cohort at 1 year, 3 years and 5 years; 0.715, 0.802 and 0.750 for the testing cohort at 1 year, 3 years and 5 years; and 0.668, 0.646 and 0.731 for the external validation cohort at 1 year, 3 years and 5 years. The calibration curves and decision curve showed that the nomogram had good consistency and clinical practical benefit. Finally, a stratified analysis showed that MDS patients with high risk had worse survival outcomes than patients with low risk. Conclusion: We developed a nomogram containing six risk factors, which provides reliable and objective predictions of prognosis for MDS patients.

Study on the earth pressure of a foundation pit adjacent to a composite foundation with rigid-flexible and long-short piles.

Model tests were performed to investigate the lateral earth pressure acting on the retaining structure adjacent to both natural ground (NG) and composite foundation (CFRLP), which were supported with rigid-flexible and long-short piles. Two testing procedures, namely, applying a load to the foundation and rotating the retaining structure along its toe, were considered. The results indicate that the additional lateral earth pressure acting on the retaining structure adjacent to the CFRLP is less than that of the NG in the depth of the reinforcement area strengthened by flexible piles. Compared with NG, the CFRLP yielded a smaller normalized height of application of the lateral earth pressure, suggesting that the CFRLP blocked the horizontal diffusion of the load and had a strong ability to transfer the surcharge load to the deep soil. When rotating the retaining structure, the lateral earth pressure acting on the upper part of the retaining structure experienced limited reduction once the displacement at the top of the retaining structure was greater than 8 mm, whereas the pressure acting on the lower part of the retaining structure continued to decrease with increasing displacement. In addition, a three-dimensional finite element model (FEM) was used to investigate the influence of the pile parameter and the wall-soil friction angle on the additional lateral earth pressure.

Highly efficient and sustainable removal of Cr (VI) in aqueous solutions by photosynthetic bacteria supplemented with phosphor salts.

Photosynthetic bacteria have flexible metabolisms and strong environmental adaptability, and require cheap, but plentiful, energy supplements, which all enable their use in Cr(VI)-remediation. In this study, the effects of culture conditions on the total Cr removal rate were investigated for a newly identified strain of Rhodobacter sphaeroides SC01. The subcellular distribution and Cr(VI) reduction ability of four different cellular fractions were evaluated by scanning electron microscopy and transmission electron microscopy. Experiments indicated that the optimal culture conditions for total Cr removal included a culture temperature of 35 °C, pH of 7.20, an NaCl concentration of 5 g L-1, a light intensity of 4000 lx, and an initial cell concentration (OD680) of 0.15. In addition, most Cr was found in the cell membrane in the form of Cr (III) after reduction, while cell membranes had the highest Cr(VI) reduction rate (99%) compared to other cellular components. In addition, the physical and chemical properties of SC01 cells were characterized by FTIR, XPS, and XRD analyses, confirming that Cr was successfully absorbed on bacterial cell surfaces. CrPO4‧6H2O and Cr5(P3O10)3 precipitates were particularly identified by XRD analysis. After screening supplementation with five phosphor salts, Cr(VI) reduction due to bioprecipitation was improved by the addition of Na4P2O7 and (NaPO3)6 salts, with the Cr(VI)-reduction rate combined with Na4P2O7 addition being 15% higher than that of the control. Thus, this study proposes a new Cr(VI)-removal strategy based on the combined use of photosynthetic bacteria and phosphor salts, which importantly increases its potential application in treating wastewater.

Investigation of Mechanical Properties of Large Shape Memory Alloy Bars under Different Heat Treatments.

Shape memory alloys (SMAs) are a class of functional materials that possess unique thermomechanical properties, such as shape memory effect (SME), superelasticity (SE), damping, and good fatigue and corrosion resistance, which enable them to become ideal materials for applications in earthquake engineering. Numerous studies have shown that the mechanical properties of superelastic SMAs mainly depend on the wire form, or the relationship between the microstructure and thermally induced phase transitions. However, extremely few studies have elucidated the effects of the heat-treatment strategy, size effect of large diameters, and cyclic loading. Herein, the mechanical properties of SMA bars, such as residual strain, energy dissipation, and equivalent damping ratio, were studied with different heat-treatment strategies, cyclic loadings, and strain amplitudes; this was achieved by conducting cyclic tensile tests on SMA bars with four different diameters. The results indicate that the maximum phase transformation stress was obtained with a 14 mm SMA bar subjected to heat treatment at 400 ℃ for 15 min. The mechanical properties were relatively stable after five loading-unloading cycles, which should be considered in engineering applications. The test results provide a mechanical basis for using large SMA bars in self-centering structures in seismic regions.

The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS). METHODS: Clinical studies were identified from the Cochrane Library, PubMed, Embase, Google Scholar, and ClinicalTrials.gov. Overall complete remission (CR) and overall response rate (ORR) were used to evaluate the efficacy of VEN in combination with HMAs for AML/MDS, the incidence of the 4 most common grade 3-4 adverse events was used to evaluate safety. RESULTS: We identified 13 studies that included a total of 1059 patients. 7 cohort studies and 5 non-randomized controlled trials(NRCTs) were analyzed by random-effects model, and subgroup analyses showed the pooled overall CR rate of 62% (95% CI 57-67%, I2 = 3%) for the new-diagnosed(ND) AML group, 39% (95% CI 30-48%, I2 = 28%) for relapsed/refractory(R/R)-AML, and 61% (95% CI 50-71%, I2 = 25%) for MDS, respectively. There was only one randomized controlled trial(RCT) that showed a CR rate of 66.4% in the patients who received azacitidine(AZA) plus VEN. A total of 8 studies reported adverse events, with cytopenia and infection being the most common grade 3-4 adverse events. CONCLUSIONS: The addition of VEN to HMAs may provide significant clinical benefit for AML/MDS patients, where response rates are better in MDS and ND-AML than in R/R-AML, but attention should be paid to the possible increased risk of febrile neutropenia.

Effects of arsenic disulfide on apoptosis, histone acetylation, toll like receptor 2 activation, and erythropoiesis in bone marrow mononuclear cells of myelodysplastic syndromes patients in vitro.

OBJECTIVE: As the main component of traditional Chinese medicine realgar, arsenic disulfide (As2S2) is widely used in treating myelodysplastic syndromes (MDS). The goal of the current study is to assess the effects of As2S2 on bone marrow mononuclear cells (BMMNC) of MDS. METHODS: BMMNCs were obtained from 10 lower risk MDS patients, 5 higher risk MDS patients, and 3 healthy controls. Then, the cells were treated with As2S2 for 48h, using vorinostat (also known as SAHA) as control. Cell proliferation and apoptosis were detected. mRNA and protein levels of histone deacetylase-1 (HDAC1), Toll-like receptor 2 (TLR2), and erythroid transcription factor (GATA-1) were detected by quantitative real-time PCR and western blot analysis. RESULTS: After As2S2 treatment in concentrations ranging from 3.125 to 100µmol/L, cell proliferation was inhibited in both lower risk and higher risk MDS. Fifty percent inhibitory concentrations were 24.4µmol/L and 23.6µmol/L, respectively, for lower and higher risk MDS. Apoptotic cells significantly increased in both types of MDS. mRNA and protein levels of HDAC1 and TLR2 were reduced, whereas GATA-1 was increased in both types of MDS. CONCLUSIONS: As2S2 could inhibit cell proliferation and induce apoptosis through histone acetylation modulation in MDS. Similar to SAHA, As2S2 could reduce TLR2 activation and increase GATA-1 expression. Current data suggest epigenetic and immunological alternations are involved in therapeutic mechanisms of realgar in the treatment of MDS.