Immunotherapy efficacy prediction through a feature re-calibrated 2.5D neural network.

BACKGROUND AND OBJECTIVE: Lung cancer continues to be a leading cause of cancer-related mortality worldwide, with immunotherapy emerging as a promising therapeutic strategy for advanced non-small cell lung cancer (NSCLC). Despite its potential, not all patients experience benefits from immunotherapy, and the current biomarkers used for treatment selection possess inherent limitations. As a result, the implementation of imaging-based biomarkers to predict the efficacy of lung cancer treatments offers a promising avenue for improving therapeutic outcomes. METHODS: This study presents an automatic system for immunotherapy efficacy prediction on the subjects with lung cancer, facilitating significant clinical implications. Our model employs an advanced 2.5D neural network that incorporates 2D intra-slice feature extraction and 3D inter-slice feature aggregation. We further present a lesion-focused prior to guide the re-calibration for intra-slice features, and a attention-based re-calibration for the inter-slice features. Finally, we design an accumulated back-propagation strategy to optimize network parameters in a memory-efficient fashion. RESULTS: We demonstrate that the proposed method achieves impressive performance on an in-house clinical dataset, surpassing existing state-of-the-art models. Furthermore, the proposed model exhibits increased efficiency in inference for each subject on average. To further validate the effectiveness of our model and its components, we conducted comprehensive and in-depth ablation experiments and discussions. CONCLUSION: The proposed model showcases the potential to enhance physicians' diagnostic performance due to its impressive performance in predicting immunotherapy efficacy, thereby offering significant clinical application value. Moreover, we conduct adequate comparison experiments of the proposed methods and existing advanced models. These findings contribute to our understanding of the proposed model's effectiveness and serve as motivation for future work in immunotherapy efficacy prediction.

DDR1-targeted therapies: current limitations and future potential.

Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.

Combined effects of azoxystrobin and oxytetracycline on rhizosphere microbiota of Arabidopsis thaliana.

The rhizosphere is one of the key determinants of plant health and productivity. Mixtures of pesticides are commonly used in intensified agriculture. However, the combined mechanisms underlying their impacts on soil microbiota remain unknown. The present study revealed that the rhizosphere microbiota was more sensitive to azoxystrobin and oxytetracycline, two commonly used pesticides, than was the microbiota present in bulk soil. Moreover, the rhizosphere microbiota enhanced network complexity and stability and increased carbohydrate metabolism and xenobiotic biodegradation as well as the expression of metabolic genes involved in defence against pesticide stress. Co-exposure to azoxystrobin and oxytetracycline had antagonistic effects on Arabidopsis thaliana growth and soil microbial variation by recruiting organic-degrading bacteria and regulating ABC transporters to reduce pesticide uptake. Our study explored the composition and function of soil microorganisms through amplicon sequencing and metagenomic approaches, providing comprehensive insights into the synergistic effect of plants and rhizosphere microbiota on pesticides and contributing to our understanding of the ecological risks associated with pesticide use.

Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment.

NIK plays a crucial role in the noncanonical NF-κB signaling pathway associated with diverse inflammatory and autoimmune diseases. Our study presents compound 54, a novel NIK inhibitor, designed through a structure-based scaffold-hopping approach from the previously identified B022. Compound 54 demonstrates remarkable selectivity and potency against NIK both in vitro and in vivo, effectively suppressing pro-inflammatory cytokines and nitric oxide production. In mouse models, compound 54 protected against LPS-induced systemic sepsis, reducing AST, ALT, and AKP liver injury markers. Additionally, it also attenuates sepsis-induced lung and kidney damage. Mechanistically, compound 54 blocks the noncanonical NF-κB signaling pathway by targeting NIK, preventing p100 to p52 processing. This work reveals a novel class of NIK inhibitors with significant potential for sepsis therapy.

Dual-signal amplified electrochemical aptasensor based on Au/MrGO and DNA nanospheres for ultra-sensitive detection of BPA without directly modified working electrode.

Rapid and sensitive analysis of bisphenol A (BPA) is essential for preventing health risks to humans and animals. Hence, a signal-amplified electrochemical aptasensor without repetitive polishing and modification of working electrode was developed for BPA using Au-decorated magnetic reduced graphene oxide (Au/MrGO)-based recognition probe (RP) and DNA nanospheres (DNS)-based signal probe (SP) cooperative signal amplification. The DNS served as a signal molecule carrier and signal amplifier, while Au/MrGO acted as a signal amplifier and excellent medium for magnetic adsorption and separation. Moreover, utilizing the excellent magnetic properties of Au/MrGO eliminates the need for repetitive polishing and multi-step direct modification of the working electrode while ensuring that all detection processes take place in solution and that used Au/MrGO can be easily recycled. The proposed aptasensor exhibited not only good stability and selectivity, but also excellent sensitivity with a limit of detection (LOD) of 8.13 fg/mL (S/N=3). The aptasensor's practicality was proven by spiking recovery tests on actual water samples and comparing the results with those detected by HPLC. The excellent sensitivity and selectivity make this aptasensor an alternative and promising avenue for rapid detection of BPA in environmental monitoring.

A Photoelectrochemical Sensor for Real-Time Monitoring of Neurochemical Signals in the Brain of Awake Animals.

Metal ion homeostasis is imperative for normal functioning of the brain. Considering the close association between brain metal ions and various pathological processes in brain diseases, it becomes essential to track their dynamics in awake animals for accurate physiological insights. Although ion-selective microelectrodes (ISMEs) have demonstrated great advantage in recording ion signals in awake animals, their intrinsic potential drift impairs their accuracy in long-term in vivo analysis. This study addresses the challenge by integrating ISMEs with photoelectrochemical (PEC) sensing, presenting an excitation-detection separated PEC platform based on potential regulation of ISMEs. A flexible indium tin oxide (Flex-ITO) electrode, modified with MoS2 nanosheets and Au NPs, serves as the photoelectrode and is integrated with a micro-LED. The integrated photoelectrode is placed on the rat skull to remain unaffected by animal activity. The potential of ISME dependent on the concentration of target K+ serves as the modulator of the photocurrent signal of the photoelectrode. The proposed design allows deep brain detection while minimizing interference with neurons, thus enabling real-time monitoring of neurochemical signals in awake animals. It successfully monitors changes in extracellular K+ levels in the rat brain after exposure to PM2.5, presenting a valuable analytical tool for understanding the impact of environmental factors on the nervous system.

A novel approach to evaluation of tumor response for advanced pulmonary adenocarcinoma using the intertumoral heterogeneity response score.

Treatment response and prognosis estimation in advanced pulmonary adenocarcinoma are challenged by the significant heterogeneity of the disease. The current Response Evaluation Criteria in Solid Tumors (RECIST) criteria, despite providing a basis for solid tumor response evaluation, do not fully encompass this heterogeneity. To better represent these nuances, we introduce the intertumoral heterogeneity response score (THRscore), a measure built upon and expanding the RECIST criteria. This retrospective study included patients with 3-10 measurable advanced lung adenocarcinoma lesions who underwent first-line chemotherapy or targeted therapy. The THRscore, derived from the coefficient of variation in size for each measurable tumor before and 4-6 weeks posttreatment, unveiled a correlation with patient outcomes. Specifically, a high THRscore was associated with shorter progression-free survival, lower tumor response rate, and a higher tumor mutation burden. These associations were further validated in an external cohort, confirming THRscore's effectiveness in stratifying patients based on progression risk and treatment response, and enhancing the utility of RECIST in capturing complex tumor behaviors in lung adenocarcinoma. These findings affirm the promise of THRscore as an enhanced tool for tumor response assessment in advanced lung adenocarcinoma, extending the RECIST criteria's utility.

PKM2 promotes lymphatic metastasis of hypopharyngeal carcinoma via regulating epithelial-mesenchymal transition: an experimental research.

BACKGROUND: Patients with hypopharyngeal carcinoma (HPC) have a poor prognosis mainly because of lymphatic metastasis. This research aimed to determine the PKM2 role in lymphatic metastasis in HPC and the underlying molecular mechanism contributing to this phenomenon. METHODS: PKM2 in HPC was studied for its expression and its likelihood of overall survival using TCGA dataset. Western blotting, qRT-PCR, and IHC were employed to confirm PKM2 expression. Methods including gain- and loss-of-function were used to examine the PKM2 role in HPC metastasis in vitro and in vivo. In vitro and in vivo studies also confirmed lymphatic metastasis's mechanism. RESULTS: Prominent PKM2 overexpression was seen in patients with lymphatic metastasis of HPC, and there was an inherent relationship between a high PKM2 level and poor prognosis. In vitro research showed that knocking down PKM2 decreased tumor cell invasion, migration, and proliferation while promoting apoptosis and inhibiting epithelial-mesenchymal transition, but overexpressing PKM2 had the reverse effect. Animal studies suggested that PKM2 may facilitate tumor development and lymphatic metastasis. CONCLUSIONS: Our findings suggest that PKM2 may be a tumor's promoter gene of lymphatic metastasis, which may promote lymphatic metastasis of HPC by regulating epithelial-mesenchymal transition. PKM2 may be a biomarker of metastatic potential, ultimately providing a basis for exploring new therapeutic targets.

Availability, price, and affordability of anti-hepatitis B virus drugs: a cross-sectional study in China.

BACKGROUND: The global prevalence of hepatitis B virus (HBV) has presented a persistent challenge for public health prevention and treatment. However, studies that assess the public's access to anti-HBV drugs are absent. AIM: To examine the availability, pricing, and affordability of anti-HBV drugs in Jiangsu province, China and provide recommendations for improvement. METHOD: An enhanced methodology developed by the World Health Organization (WHO) and Health Action International was applied in a cross-sectional study that included 1026 healthcare facilities distributed in 13 prefectural-level cities in Jiangsu province. RESULTS: Since almost all drugs had an availability of less than 30%, the accessibility of anti-HBV drugs was notably low. Primary healthcare facilities had the lowest availability, reporting 1.4% for Original Brands (OBs) and 1.7% for lowest-priced generics (LPGs). Furthermore, the northern Jiangsu region recorded the lowest availability at 0.7%. LPGs demonstrated higher availability than OBs, with median availability probabilities of 2.6% and 1.4%, respectively. The drugs listed on the WHO Essential Medicines List exhibited higher availability than those on other lists. The median price ratios for OBs, LPGs, and volume-based purchasing drugs were 0.83, 0.50, and 0.27, respectively, less than 1.5 times the international reference price. Despite favorable pricing, affordability rate was 23% for urban residents and 0% for rural residents, which was discouraging. CONCLUSION: Low availability and affordability of anti-HBV drugs were observed. Policy recommendations should emphasize the improvement of LPG availability by incentivizing priority prescribing. Healthcare subsidies should be provided more effectively and equitably.

Binary conformers of a flexible, long-chain fluoroalcohol: dispersion controlled selectivity and relative abundances in a jet.

The complex conformational panorama of binary 4,4,4-trifluoro-1-butanol (TFB) aggregates was investigated using chirped-pulse Fourier transform microwave spectroscopy, aided by conformational searches using CREST (Conformer-Rotamer Ensemble Sampling Tool) and quantum chemistry calculations. From nearly 1500 initial dimer geometries, 16 most stable binary candidates were obtained within a relative energy window of ∼4 kJ mol-1. Rotational spectra of five binary conformers were experimentally observed in supersonic expansion and assigned. Interestingly, three out of the five observed binary conformers are composed solely of monomer conformers, which were not observed in their isolated gas phase forms in jet expansion. In addition, an observed dimer that is made exclusively of the most stable TFB monomer subunits does not correspond to the global minimum. The intricate kinetically and thermodynamically controlled dimer formation mechanisms are discussed, and a modified kinetic-thermodynamic model was developed, providing conformational abundances that are in good agreement with the experiment. Subsequent non-covalent interaction analyses reveal that the observed conformers are held together by one primary O-H⋯O hydrogen bond and secondary intermolecular C-H⋯O, C-H⋯F, and/or O-H⋯F interactions, as well as C-H⋯H-C London dispersion interactions between the methylene groups. Further symmetry-adapted perturbation theory analyses of the TFB dimer conformers and related alcohol dimers reveal a considerable rise in dispersion contributions with increasing n-alkyl carbon chain length and highlight the role of dispersion interactions in preferentially stabilizing the global minimum of the TFB dimer.

Diffusion-derived vessel density (DDVD) computed from a simple diffusion MRI protocol as a biomarker of placental blood circulation in patients with placenta accreta spectrum disorders: A proof-of-concept study.

OBJECTIVES: Increasing trend of PAS (placenta accreta spectrum disorders) incidence is a major health concern as PAS is associated with high maternal morbidity and mortality during cesarean section. Prenatal identification of PAS is crucial for delivery planning and patients management. This study aims to explore whether diffusion-derived vessel density (DDVD) computed from a simple diffusion MRI protocol differs in PAS from normal placenta. METHODS: We enrolled 86 patients with PAS disorders and 40 pregnant women without PAS disorders. Each patient underwent intravoxel incoherent motion (IVIM) MRI sequence with 11 b-values. Placenta diffusion-derived vessel density (DDVD-b0b50) was the signal difference between b = 0 and b = 50 s/mm2 images. DDVD(b0b50) A/N was calculated as [accreta lesion DDVD(b0b50)]/ [normal placenta DDVD(b0b50)]. The correlation between DDVD and gestational age was explored using Spearman rank correlation. Differences of DDVD(b0b50) A/N in patients with normal placentas and with PAS, and in patients with different subtypes of PAS were explored. RESULTS: DDVD was negatively correlated with gestational age (p = 0.023, r = -0.359) in patients with normal placentas. DDVD(b0b50) A/N was significantly higher in patients with PAS (median:1.16, mean: 1.261) than normal placenta (median:1.02, mean: 1.032, p < 0.001) and especially higher in patients with placenta increta (median:1.14, mean: 1.278) and percreta (median: 1.20, mean: 1.396, p < 0.001). CONCLUSION: As a higher DDVD indicates higher physiological volume of micro-vessels in PAS, this study suggests DDVD can be a potential biomarker to evaluate the placenta perfusion.

A risk entropy approach for linking pesticides and soil bacterial communities.

Pesticides play a vital role in ensuring modern agricultural production, but also adversely affecting soil health. Microorganisms are the cornerstone of soil ecology, however, to date, there are few unified standards to measure the risk of soil pesticide residues to soil microbial community. To compensate for this gap, we collected soil samples from 55 orchards and monitored and risk-assessed 165 pesticides to microbial community in the soil. Results showed that a total of 137 pesticides were detected in all samples. Pesticide residues significantly influenced the microbial diversity and community structure in orchard soils, particularly fungicides and herbicides. The risk entropy of each pesticide was calculated in all samples and it was found that 60% of the samples had a "pesticide risk" (Risk quotient > 0.01), where the relative abundance significantly increased in 43 genera and significantly decreased in 111 genera (p < 0.05). Through multiple screens, we finally identified Bacillus and Sphingomonas as the most abundant sensitive genera under pesticide perturbation. The results showed that despite the complexity of the effects of pesticide residues on soils health, we could reveal them by identifying changes in soil bacterial, especially by the differences of microbial biomarkers abundance. The present study could provide new insights into the research strategy for pesticide pollution on soil microbial communities. ENVIRONMENTAL IMPLICATION: The risk of pesticide residues in soil needs to be quantified and standardized. We believe that microorganisms can be used as a marker to indicate soil pesticide residue risk. For this end, we investigated the residues of 165 pesticides in 55 orchard soil samples, calculated pesticide risk entropy and their effects on the soil microbial community. Through multiple analyzing and screening, we ultimately identified that, out of the 154 detected biomarkers, Bacillus and Sphingomonas were the most abundant sensitive genera under pesticide perturbation, which have the potential to be used as key biomarkers of soil microbiomes induced by pesticide perturbation.

A reversible photoelectrochemical microsensor for dynamically monitoring sulfur dioxide in the epileptic brain.

Epilepsy is considered one of the most prevalent neurological disorders, yet the precise mechanisms underlying its pathogenesis remain inadequately elucidated. Emerging evidence implicates endogenous sulfur dioxide (SO2) in the brain as playing a significant role in epilepsy and associated neuronal apoptosis. Consequently, tracking the dynamic fluctuations in the levels of SO2 and its derivatives (SO32-/HSO3-) provides valuable insights into the molecular mechanisms underlying epilepsy, with potential implications for its diagnosis and therapeutic intervention. Nonetheless, the absence of reversible in vivo detection tools constitutes a formidable obstacle in the real-time monitoring of SO2 dynamics in the brain. In response to this challenge, we propose a novel approach involving a photoelectrochemical (PEC) microsensor capable of reversibly detecting SO2. This microsensor leverages a reversibly recognizing dye for SO2 and upconversion nanoparticles as the modulator of the excitation source for the photoactive material, enabling modulation of the photocurrent by the target. The reversible output of PEC signals allows for the monitoring of SO2 levels in real time in the brains of epileptic mice. This study reveals the patterns of SO2 level changes during epilepsy and provides insights into the neuroprotective mechanism of exogenous SO2.

Differentiated adaptative genetic architecture and language-related demographical history in South China inferred from 619 genomes from 56 populations.

BACKGROUND: The underrepresentation of human genomic resources from Southern Chinese populations limited their health equality in the precision medicine era and complete understanding of their genetic formation, admixture, and adaptive features. Besides, linguistical and genetic evidence supported the controversial hypothesis of their origin processes. One hotspot case was from the Chinese Guangxi Pinghua Han people (GPH), whose language was significantly similar to Southern Chinese dialects but whose uniparental gene pool was phylogenetically associated with the indigenous Tai-Kadai (TK) people. Here, we analyzed genome-wide SNP data in 619 people from four language families and 56 geographically different populations, in which 261 people from 21 geographically distinct populations were first reported here. RESULTS: We identified significant population stratification among ethnolinguistically diverse Guangxi populations, suggesting their differentiated genetic origin and admixture processes. GPH shared more alleles related to Zhuang than Southern Han Chinese but received more northern ancestry relative to Zhuang. Admixture models and estimates of genetic distances showed that GPH had a close genetic relationship with geographically close TK compared to Northern Han Chinese, supporting their admixture origin hypothesis. Further admixture time and demographic history reconstruction supported GPH was formed via admixture between Northern Han Chinese and Southern TK people. We identified robust signatures associated with lipid metabolisms, such as fatty acid desaturases (FADS) and medically relevant loci associated with Mendelian disorder (GJB2) and complex diseases. We also explored the shared and unique selection signatures of ethnically different but linguistically related Guangxi lineages and found some shared signals related to immune and malaria resistance. CONCLUSIONS: Our genetic analysis illuminated the language-related fine-scale genetic structure and provided robust genetic evidence to support the admixture hypothesis that can explain the pattern of observed genetic diversity and formation of GPH. This work presented one comprehensive analysis focused on the population history and demographical adaptative process, which provided genetic evidence for personal health management and disease risk prediction models from Guangxi people. Further large-scale whole-genome sequencing projects would provide the entire landscape of southern Chinese genomic diversity and their contributions to human health and disease traits.

Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer.

Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H2O2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.

Deciphering Microbial Community and Nitrogen Fixation in the Legume Rhizosphere.

Nitrogen is the most limiting factor in crop production. Legumes establish a symbiotic relationship with rhizobia and enhance nitrogen fixation. We analyzed 1,624 rhizosphere 16S rRNA gene samples and 113 rhizosphere metagenomic samples from three typical legumes and three non-legumes. The rhizosphere microbial community of the legumes had low diversity and was enriched with nitrogen-cycling bacteria (Sphingomonadaceae, Xanthobacteraceae, Rhizobiaceae, and Bacillaceae). Furthermore, the rhizosphere microbiota of legumes exhibited a high abundance of nitrogen-fixing genes, reflecting a stronger nitrogen-fixing potential, and Streptomycetaceae and Nocardioidaceae were the predominant nitrogen-fixing bacteria. We also identified helper bacteria and confirmed through metadata analysis and a pot experiment that the synthesis of riboflavin by helper bacteria is the key factor in promoting nitrogen fixation. Our study emphasizes that the construction of synthetic communities of nitrogen-fixing bacteria and helper bacteria is crucial for the development of efficient nitrogen-fixing microbial fertilizers.

ADHD and family life: A cross-sectional study of ADHD prevalence among pupils in China and factors associated with parental depression.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is increasingly recognized as a major problem for children and their families in China. However, its influence on parental mental health has been seldom explored. OBJECTIVE: To examine the prevalence of attention deficit hyperactivity disorder in a community sample of children aged 6-13 years, and the extent to which it impacts parental mental health. METHOD: Cross-sectional study of primary school pupils (number = 2497) in Deyang, Sichuan Province, South-West China. We used standardized instruments to identify children with ADHD symptoms and parent depression. RESULTS: The prevalence of ADHD was 9.8%. Factors associated with the likelihood of ADHD, included family environment(P = 0.003), time spent with children(P = 0.01), parenting style(P = 0.01), and parental relationship, pupils self-harm and lower academic ability (P = 0.001). After controlling for other factors, having a child with ADHD increased the likelihood of parents' depression (OR = 4.35, CI = 2.68~7.07), additional factors included parent relationship. CONCLUSIONS: ADHD may be a common disorder among Chinese children, the symptoms of which may increase the likelihood of parent depression. There is a need for greater detection of ADHD in schools, acknowledgement of the challenges the disorder creates for academic success and family wellbeing, and psychoeducational tools for supporting parents of children with ADHD.

Potential Effects of Orally Ingesting Polyethylene Terephthalate Microplastics on the Mouse Heart.

Polyethylene terephthalate microplastics (PET MPs) are widespread in natural environment, and can enter organisms and accumulate in the body, but its toxicity has not been well studied. Therefore, in order to investigate the toxic effects of PET microplastics on mammals, this study investigated the toxic effects of PET MPs on ICR mice and H9C2 cells by different treatment groups. The results indicated the cardiac tissue of mice in the PET-H (50 µg/mL) group showed significant capillary congestion, myocardial fiber breakage, and even significant fibrosis compared to the PET-C (control) group (P < 0.01). Results of the TUNEL assay demonstrated significant apoptosis in myocardial tissue in the PET-H and PET-M (5 µg/mL) groups (P < 0.01). Meanwhile, Western blotting showed increased expression of the apoptosis-related protein Bax and decreased expression of PARP, caspase-3, and Bcl-2 proteins in both myocardial tissues and H9C2 cells. In addition, flow cytometry confirmed that PET MPs decreased the mitochondrial membrane potential and apoptosis in H9C2 cells; however, this trend was reversed by N-acetylcysteamine application. Moreover, PET MP treatment induced the accumulation of reactive oxygen species (ROS) in H9C2 cells, while the MDA level in the myocardial tissue was elevated, and the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were decreased (P < 0.01), indicating a change in the redox environment. In conclusion, PET MPs promoted cardiomyocyte apoptosis by inducing oxidative stress and activating mitochondria-mediated apoptotic processes, ultimately leading to myocardial fibrosis. This study provides ideas for the prevention of PET MP toxicity and promotes thinking about enhancing plastic pollution control.

Discovery of FLT3-targeting PROTACs with potent antiproliferative activity against acute myeloid leukemia cells harboring FLT3 mutations.

Acute myeloid leukemia (AML) patients harboring Fms-like tyrosine kinase 3 (FLT3) mutations often suffer from poor prognosis and relapse. Targeted protein degradation utilizing proteolysis targeting chimeras (PROTACs) is considered as a novel therapeutic strategy in drug discovery and may be a promising modality to target FLT3 mutations for the development of potent anti-AML drugs. Herein, a kind of FLT3-targeting PROTACs was rationally developed based on a FLT3 inhibitor previously reported by us. The representative compound 35 showed potent and selective antiproliferative activities against AML cells harboring FLT3 mutations. Western blot assay demonstrated that compound 35 effectively induced the degradation of FLT3-ITD and decreased the phosphorylation levels of FLT3-ITD, AKT, STAT5 and ERK in MV4-11 cells in a dose-dependent manner. Flow cytometry analysis illustrated that compound 35 strongly induced apoptosis and cell cycle arrest in MV4-11 cells in a dose-dependent manner. Moreover, compound 35 displayed favorable metabolic stability in in-vitro liver microsomes studies. Comparative molecular dynamic (MD) simulation studies further elucidated the underlying mechanism of compound 35 to stabilize the dynamic ensemble of the FLT3-compound 35-cereblon (CRBN) ternary complex. Taken together, compound 35 could serve as a lead molecule for developing FLT3 degraders against AML.