In Vitro Modeling of Recurrent Dermatofibrosarcoma Protuberans: Assessment of 5-Aminolevulinic Acid Photodynamic Therapy Efficacy.

BACKGROUND: Dermatofibrosarcoma Protuberans (DFSP) is a rare, low-grade malignant tumor of the dermis with a high recurrence rate post-surgery. Current treatments, including surgery, radiotherapy, and targeted therapy, have limitations. Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) is a promising non-invasive approach, but its efficacy in DFSP treatment remains underexplored. METHODS: This study aimed to evaluate the anti-tumor efficacy of 5-ALA PDT using an in vitro model derived from a recurrent DFSP patient. The cells were treated with varying concentrations of 5-ALA and exposed to red light, followed by assessments of cell viability, proliferation, apoptosis, migration, invasion, angiogenesis, and expression of DFSP-related genes and proteins. RESULTS: 5-ALA PDT significantly reduced DFSP cell viability in a dose-dependent manner and induced apoptosis. It also effectively inhibited cell proliferation, migration, and invasion, as well as suppressed angiogenic activity in conditioned media. Furthermore, 5-ALA PDT downregulated the expression of COL1A1 and PDGFRB, key genes in DFSP pathogenesis. CONCLUSIONS: The findings provide the first evidence of 5-ALA PDT's in vitro anti-tumor efficacy against DFSP, suggesting its potential as a novel therapeutic approach for DFSP. Further studies are warranted to explore the clinical utility of 5-ALA PDT in preventing DFSP recurrence.

Genome-wide analysis of in vivo-evolved Candida auris reveals multidrug-resistance mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.

Coherent detection of the rotational Doppler effect measurement based on triple Fourier transform.

In recent years, the rotational Doppler effect (RDE) has been widely used in rotational motion measurement. However, the performance of existing detection systems based on the RDE are generally limited by the drastic reduction of signal-to-noise ratio (SNR) due to the influence of atmospheric turbulence, partial obscuration of the vortex beam (VB) during propagation, and misalignment between the optical axis of VB and the rotational axis of the object, which poses a challenge for practical applications. In this paper, we proposed a coherent detection method of the RDE measurement based on triple Fourier transform. First, the weak RDE signal in backscattered light is amplified by using the balanced homodyne detection method, and the amplified signal still retains the same characteristic of severe broadening in the frequency domain as the original signal. Furthermore, we proposed the triple Fourier transform to extract the broadened RDE frequency shift signal after the coherent amplification. The proposed method significantly improves the SNR of RDE measurement and facilitates the accurate extraction of rotational speed, which helps to further improve the RDE detection range and promote its practical application.

Predicting short-term major postoperative complications in intestinal resection for Crohn's disease: A machine learning-based study.

BACKGROUND: Due to the complexity and numerous comorbidities associated with Crohn's disease (CD), the incidence of postoperative complications is high, significantly impacting the recovery and prognosis of patients. Consequently, additional studies are required to precisely predict short-term major complications following intestinal resection (IR), aiding surgical decision-making and optimizing patient care. AIM: To construct novel models based on machine learning (ML) to predict short-term major postoperative complications in patients with CD following IR. METHODS: A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022. The study participants were randomly allocated to either a training cohort or a validation cohort. The logistic regression and random forest (RF) were applied to construct models in the training cohort, with model discrimination evaluated using the area under the curves (AUC). The validation cohort assessed the performance of the constructed models. RESULTS: Out of the 259 patients encompassed in the study, 5.0% encountered major postoperative complications (Clavien-Dindo ≥ III) within 30 d following IR for CD. The AUC for the logistic model was 0.916, significantly lower than the AUC of 0.965 for the RF model. The logistic model incorporated a preoperative CD activity index (CDAI) of ≥ 220, a diminished preoperative serum albumin level, conversion to laparotomy surgery, and an extended operation time. A nomogram for the logistic model was plotted. Except for the surgical approach, the other three variables ranked among the top four important variables in the novel ML model. CONCLUSION: Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complications in patients with CD, with the RF model showing more superiority. A preoperative CDAI of ≥ 220, a diminished preoperative serum albumin level, and an extended operation time might be the most crucial variables. The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Real-time multilingual speech recognition and speaker diarization system based on Whisper segmentation.

This research presents the development of a cutting-edge real-time multilingual speech recognition and speaker diarization system that leverages OpenAI's Whisper model. The system specifically addresses the challenges of automatic speech recognition (ASR) and speaker diarization (SD) in dynamic, multispeaker environments, with a focus on accurately processing Mandarin speech with Taiwanese accents and managing frequent speaker switches. Traditional speech recognition systems often fall short in such complex multilingual and multispeaker contexts, particularly in SD. This study, therefore, integrates advanced speech recognition with speaker diarization techniques optimized for real-time applications. These optimizations include handling model outputs efficiently and incorporating speaker embedding technology. The system was evaluated using data from Taiwanese talk shows and political commentary programs, featuring 46 diverse speakers. The results showed a promising word diarization error rate (WDER) of 2.68% in two-speaker scenarios and 11.65% in three-speaker scenarios, with an overall WDER of 6.96%. This performance is comparable to that of non-real-time baseline models, highlighting the system's ability to adapt to various complex conversational dynamics, a significant advancement in the field of real-time multilingual speech processing.

Long-term use of etomidate disrupts the intestinal homeostasis and nervous system in mice.

Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health.

Assessment of Immune Status in Patients with Mismatch Repair Deficiency Endometrial Cancer.

Objective: This study introduced a novel subtype classification method for endometrial cancer (EC) with mismatch repair deficiency (MMRd) by employing immune status and prognosis as the foundational criteria. The goal was to enhance treatment guidance through precise subtype delineation. Methods: Study Cohort: This study encompassed a cohort of 119 patients diagnosed with MMRd-EC between 2015 and 2022. Analyses using t-tests and Mann-Whitney U-tests were performed to assess prognostic markers and peripheral blood immune cell profiles in patients with MutS deficiency (MutS-d) versus those with MutL deficiency (MutL-d). Logistic regression analysis was used to identify independent risk factors. Bioinformatics Analysis: An online database was used to assess the prognostic implications, immune cell infiltration, and immune checkpoint involvement associated with the deficiency of MutS versus MutL in EC. Results: Patients with MutL-d exhibited heightened risk factors, including elevated cancer grade and increased myometrial invasion, leading to poorer prognosis and shorter overall survival and progression-free survival. Regarding systemic immune status, patients with MutL-d demonstrated decreased peripheral blood lymphocyte percentage, lymphocyte count, and CD8+ T cell percentage. For local immunity, the infiltration of natural killer cells, CD8+ T cells, and cytotoxic T lymphocytes in the tumor tissue was reduced in patients with MutL-d. Additionally, patients with MutL-d exhibited lower expression of immune checkpoint markers. The composition of immune subtypes and survival outcomes also indicate that patients with MutL-d have a poorer immune status and prognosis than the patients with MutS-d. Conclusion: Patients with MMRd-EC can be subclassified according to MutS or MutL deficiency. Patients with MutS-d exhibited better immune status, prognosis, and immunotherapy benefits than those with MutL-d. These results can help guide patients to a more precise treatment.

Selective Excitation of Exciton-Polariton Condensate Modes in an Annular Perovskite Microcavity.

Exciton-polariton systems composed of a light-matter quasi-particle with a light effective mass easily realize Bose-Einstein condensation. In this work, we constructed an annular trap in a halide perovskite semiconductor microcavity and observed the spontaneous formation of symmetrical petal-shaped exciton-polariton condensation in the annular trap at room temperature. In our study, we found that the number of petals of the petal-shaped exciton-polariton condensates, which is decided by the orbital angular momentum, is dependent on the light intensity distribution. Therefore, the selective excitation of perovskite microcavity exciton-polariton condensates under all-optical control can be realized by adjusting the light intensity distribution. This could pave the way to room-temperature topological devices, optical cryptographical devices, and new quantum gyroscopes in the exciton-polariton system.

Gut-Derived Trimethylamine N-Oxide Promotes CCR2-Mediated Macrophage Infiltration in acute kidney injury.

BACKGROUND: Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

Regulation effect of magnetic field combined with low temperature storage on postharvest quality and cell wall pectic-polysaccharide degradation of Clausena lansium (Lour.) Skeels.

This study investigated the regulation effect of magnetic field combined with low temperature storage on postharvest quality and cell wall pectic-polysaccharide degradation of wampee stored for 15 d at 4 °C and 15 °C. Results showed that magnetic field combined with low temperature storage reduced browning rate of fruit after 15 d storage, but its effect on weight loss rate and total soluble solids (TSS) did not surpass that of storage temperature. Interestingly, contents of flavonoid, total phenols and malondialdehyde (MDA) were also lowered at varying degrees by combined treatment. Furthermore, molecular weight distribution and monosaccharide compositions of cell wall pectic-polysaccharides were also affected, which resulted from the coordinated action of cell wall pectin-degrading enzymes. The activities of these enzymes during storage, including polygalacturonase (PG), pectin methylesterase (PME) and ß-galactosidase (ß-Gal) in treated wampee decreased. These findings suggested that magnetic field combined with low temperature storage was an effective technology and had great potential in preservation of postharvest wampee in future.

Enhanced Diagnostic Efficiency of Endometrial Carcinogenesis and Progression in Women with Abnormal Uterine Bleeding through Peripheral Blood Cytokine Testing: A Multicenter Retrospective Cohort Study.

Objective: This study aimed to evaluate the role of plasma cytokine detection in endometrial cancer screening and tumor progression assessment in patients with abnormal uterine bleeding. Methods: In this multicenter retrospective cohort study of 287 patients with abnormal uterine bleeding, comprehensive clinical information and laboratory assessments, including cytokines, routine blood tests, and tumor markers, were performed. Associations between the clinical indicators and endometrial carcinogenesis/progression were evaluated. The independent risk factors for endometrial cancer and endometrial cancer with deep myometrial invasion were analyzed using multivariate binary logistic regression. Additionally, a diagnostic model was used to evaluate the predictive efficacy of these identified risk factors. Results: In patients with abnormal uterine bleeding, low IL-4 and high IL-8 levels were independent risk factors for endometrial cancer (p < 0.05). Combining IL-4, IL-8, CA125, and menopausal status improved the accuracy of assessing endometrial cancer risk. The area under curve of the model is 0.816. High IL-6 and IL-8 levels were independent risk factors for deep myometrial invasion in patients with endometrial cancer (p < 0.05). Similarly, combining IL-6, IL-8, and Monocyte counts enhanced the accuracy of assessing endometrial cancer risk with deep myometrial invasion. The area under curve of the model is 0.753. Conclusions: Cytokines such as IL-4, IL-8, and IL-6 can serve as markers for monitoring endometrial cancer and its progression in women with abnormal uterine bleeding.

Enhancing Benzo[a]pyrene Degradation by Pantoea dispersa MSC14 through Biostimulation with Sodium Gluconate: Insights into Mechanisms and Molecular Regulation.

We investigated biostimulation as an effective strategy for enhancing the degradation efficiency of recalcitrant organic compounds, with MSC14 (a novel polycyclic aromatic hydrocarbon degrading bacterium Pantoea dispersa MSC14) as the study material. Here, we investigated the impact of sodium gluconate on MSC14-mediated degradation of B[a]p. This study focused on the application of sodium gluconate, a biostimulant, on MSC14, targeting Benzo[a]pyrene (B[a]p) as the model pollutant. In this study, the novel PAHs-degrading bacterium P. dispersa MSC14 demonstrated the capability to degrade 24.41% of B[a]p after 4 days. The addition of the selected sodium gluconate stimulant at a concentration of 4 g/L stimulated MSC14 to degrade 54.85% of B[a]p after 16 h. Intermediate metabolites were analyzed using gas chromatography-mass spectrometry to infer the degradation pathway. The findings indicated that sodium gluconate promoted the intracellular transport of B[a]p by MSC14, along with the secretion of biosurfactants, enhancing emulsification and solubilization capabilities for improved B[a]p dissolution and degradation. Further analysis through transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed the formation of a biofilm by MSC14 and an increase in flagella as a response to B[a]p stress. Transcriptome profiling elucidated the interplay of quorum sensing systems, chemotaxis systems, and flagellar systems in the degradation mechanism. Additionally, the study uncovered the molecular basis of B[a]p transport, degradation pathways, metabolic changes, and genetic regulation. In summary, the addition of sodium gluconate promotes the degradation of B[a]p by P. dispersa MSC14, offering the advantages of being rapid, efficient, and cost-effective. This research provides an economically viable approach for the remediation of petroleum hydrocarbon pollution, with broad potential applications.

Spatial omics techniques and data analysis for cancer immunotherapy applications.

In-depth profiling of cancer cells/tissues is expanding our understanding of the genomic, epigenomic, transcriptomic, and proteomic landscape of cancer. However, the complexity of the cancer microenvironment, particularly its immune regulation, has made it difficult to exploit the potential of cancer immunotherapy. High-throughput spatial omics technologies and analysis pipelines have emerged as powerful tools for tackling this challenge. As a result, a potential revolution in cancer diagnosis, prognosis, and treatment is on the horizon. In this review, we discuss the technological advances in spatial profiling of cancer around and beyond the central dogma to harness the full benefits of immunotherapy. We also discuss the promise and challenges of spatial data analysis and interpretation and provide an outlook for the future.

Transcriptomic and biochemical analysis of metabolic remodeling in Bacillus subtilis MSC4 under Benzo[a]pyrene stress.

Polyaromatic benzo[a]pyrene (B[a]P) is a toxic carcinogenic environmental pollutant, and the use of microorganisms to remediate B[a]P contamination is considered to be one of the most effective strategies. However, there is still a gap in studying the metabolic remodeling of microorganisms under B[a]P stress. In this study, our systematically investigated the effects of B[a]P on the metabolism of Bacillus subtilis MSC4 based on transcriptomic, molecular and biochemical analyses. The results showed that in response to B[a]P stress, MSC4 formed more biofilm matrix and endospores, the structure of the endospores also was changed, which led to a reduction in their resistance and made them more difficult to germinate. In addition to an increase in glycolysis activity, the activities of tricarboxylic acid cycle, pentose phosphate pathway and the electron transport chain were decreased. B[a]P stress forced MSC4 to strengthen arginine synthesis, urea cycle, and urea decomposition, meanwhile, synthesize more ribonucleotides. The activity of DNA replication, transcription activities and the expression of multiple ribosomal protein genes were reduced. Moreover, all of the reported enzymes involved in B[a]P degradation showed decreased transcript abundance, and the degradation of B[a]P caused significant up-regulation of the gene expression of the acid inducible enzyme OxdC and the synthesis of acetoin. In addition, the cytotoxicity of B[a]P to bacteria was directly displayed in four aspects: increased intracellular level of reactive oxygen species (ROS), elevated cell membrane permeability, up-regulation of the cell envelope stress-sensing two-component system LiaRS, and downregulation of siderophores biosynthesis. Finally, B[a]P also caused morphological changes in the cells, with some cells exhibiting significant deformation and concavity. These findings provide effective research directions for targeted improvement the cellular activity of B[a]P-degrading strains, and is beneficial for further application of microorganisms to remediate B[a]P -contaminated soils.

The A2 haplotype of Echinococcus multilocularis is the predominant variant infecting humans and dogs in Yili Prefecture, Xinjiang.

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis, is an important zoonotic disease. Yili Prefecture in Xinjiang is endemic for AE, however the molecular variability of E. multilocularis in this region is poorly understood. In this study, 127 samples were used for haplotypes analysis, including 79 tissues from humans, 43 liver tissues from small rodents, and 5 fecal samples from dogs. Genetic variability in E. multilocularis was studied using complete sequences of the mitochondrial (mt) genes of cytochrome b (cob), NADH dehydrogenase subunit 2 (nad2), and cytochrome c oxidase subunit 1 (cox1), using a total of 3558 bp per sample. The Asia haplotype 2 (A2) was the dominant haplotype, with 72.15% (57/79) prevalence in humans, 2.33% (1/43) in small rodents, and 80.00% (4/5) in dogs, followed by A5, the second most common haplotype, which infected 27.91% (12/43) small rodents. Haplotype network analysis showed that all haplotypes clustered together with the Asian group. Pairwise fixation index (FST) values showed lower level of genetic differentiation between different regions within the country. Compared with the sequences of E. multilocularis from North America and Europe, all concatenated sequences isolated from Yili Prefecture were highly differentiated and formed a single population. The A2 haplotype, analyzed using the cob, nad2, and cox1 genes of E. multilocularis, is the predominant variant in humans and dogs in Yili Prefecture.

Treatment of diabetic retinopathy with herbs for tonifying kidney and activating blood circulation: A review of pharmacological studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes. Chinese medicine believes that kidney deficiency and blood stasis are significant pathogenesis of DR. A characteristic therapeutic approach for this pathogenesis is the kidney-tonifying and blood-activating method. By literature retrieval from several databases, we methodically summarized the commonly used kidney-tonifying and blood-activating herbs for treating DR, including Lycii Fructus, Rehmanniane Radix Praeparata, and Corni Fructus with the function of nourishing kidney; Salvia Miltiorrhizae Radix et Rhizoma with the function of enhancing blood circulation; Rehmanniae Radix with the function of nourishing kidney yin; and Astragali Radix with the function of tonifying qi. It has been demonstrated that these Chinese herbs described above, by tonifying the kidney and activating blood circulation, significantly improve the course of DR. AIM OF THE STUDY: Through literature research, to gain a thorough comprehension of the pathogenesis of DR. Simultaneously, through the traditional application analysis, modern pharmacology research and network pharmacology analysis of kidney-tonifying and blood-activating herbs, to review the effectiveness and advantages of kidney-tonifying and blood-activating herbs in treating DR comprehensively. MATERIALS AND METHODS: PubMed, the China National Knowledge Infrastructure (CNKI), and Wanfang Data were used to filter the most popular herbs for tonifying kidney and activating blood in the treatment of DR. The search terms were "diabetic retinopathy" and "tonifying kidney and activating blood". Mostly from 2000 to 2023. Network pharmacology was applied to examine the key active components and forecast the mechanisms of kidney-tonifying and blood-activating herbs in the treatment of DR. RESULTS: Kidney deficiency and blood stasis are the pathogenesis of DR, and the pathogenesis is linked to oxidative stress, inflammation, hypoxia, and hyperglycemia. Scientific data and network pharmacology analysis have demonstrated the benefit of tonifying kidney and activating blood herbs in treating DR through several channels, multiple components, and multiple targets. CONCLUSIONS: This review first presents useful information for subsequent research into the material foundation and pharmacodynamics of herbs for tonifying kidney and activating blood, and offers fresh insights into the treatment of DR.

Spacecraft Attitude Measurement and Control Using VSMSCSG and Fractional-Order Zeroing Neural Network Adaptive Steering Law.

In order to improve the accuracy and convergence speed of the steering law under the conditions of high dynamics, high bandwidth, and a small deflection angle, and in an effort to improve attitude measurement and control accuracy of the spacecraft, a spacecraft attitude measurement and control method based on variable speed magnetically suspended control sensitive gyroscopes (VSMSCSGs) and the fractional-order zeroing neural network (FO-ZNN) steering law is proposed. First, a VSMSCSG configuration is designed to realize attitude measurement and control integration in which the VSMSCSGs are employed as both actuators and attitude-rate sensors. Second, a novel adaptive steering law using FO-ZNN is designed. The matrix pseudoinverses are replaced by FO-ZNN outputs, which solves the problem of accuracy degradation in the traditional pseudoinverse steering laws due to the complexity of matrix pseudoinverse operations under high dynamics conditions. In addition, the convergence and robustness of the FO-ZNN are proven. The results show that the proposed FO-ZNN converges faster than the traditional zeroing neural network under external disturbances. Finally, a new weighting function containing rotor deflection angles is added to the steering law to ensure that the saturation of the rotor deflection angles can be avoided. Semi-physical simulation results demonstrate the correctness and superiority of the proposed method.

Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA.

PURPOSE: Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. EXPERIMENTAL DESIGN: A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). CONCLUSIONS: Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.