Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.

Validation of a pulmonary embolism risk assessment model in gynecological inpatients : Clinical trial: A single-center, retrospective study.

OBJECTIVE: To compare the predictive efficacy of the PADUA and Caprini models for pulmonary embolism (PE) in gynecological inpatients, analyze the risk factors for PE, and validate whether both models can effectively predict mortality rates. METHODS: A total of 355 gynecological inpatients who underwent computed tomography pulmonary angiography (CTPA) were included in the retrospective analysis. The comparative assessment of the predictive capabilities for PE between the PADUA and Caprini was carried out using receiver operating characteristic (ROC) curves. Logistic regression analysis was used to identify risk factors associated with PE. Additionally, Kaplan-Meier survival analysis plots were generated to validate the predictive efficacy for mortality rates. RESULTS: Among 355 patients, the PADUA and Caprini demonstrated the area under the curve (AUC) values of 0.757 and 0.756, respectively. There was no statistically significant difference in the AUC between the two models (P = 0.9542). Multivariate logistic analysis revealed immobility (P < 0.001), history of venous thromboembolism (VTE) (P = 0.002), thrombophilia (P < 0.001), hormonal treatment (P = 0.022), and obesity (P = 0.019) as independent risk factors for PE. Kaplan-Meier survival analysis demonstrated the reliable predictive efficacy of both the Caprini (P = 0.00051) and PADUA (P = 0.00031) for mortality. ROC for the three- and six-month follow-ups suggested that the Caprini model exhibited superior predictive efficacy for mortality. CONCLUSIONS: The PADUA model can serve as a simple and effective tool for stratifying high-risk gynecological inpatients before undergoing CTPA. The Caprini model demonstrated superior predictive efficacy for mortality rates.

An SEIHR model with age group and social contact for analysis of Fuzhou COVID-19 large wave.

Background: The structure of age groups and social contacts of the total population influenced infection scales and hospital-bed requirements, especially influenced severe infections and deaths during the global prevalence of COVID-19. Before the end of the year 2022, Chinese government implemented the national vaccination and had built the herd immunity cross the country, and announced Twenty Measures (November 11) and Ten New Measures (December 7) for further modifications of dynamic zero-COVID polity on the Chinese mainland. With the nation-wide vaccination and modified measures background, Fuzhou COVID-19 large wave (November 19, 2022-February 9, 2023) led by Omicron BA.5.2 variant was recorded and prevailed for three months in Fujian Province. Methods: A multi-age groups susceptible-exposed-infected-hospitalized-recovered (SEIHR) COVID-19 model with social contacts was proposed in this study. The main object was to evaluate the impacts of age groups and social contacts of the total population. The idea of Least Squares method was governed to perform the data fittings of four age groups against the surveillance data from Fujian Provincial Center for Disease Control and Prevention (Fujian CDC). The next generation matrix method was used to compute basic reproduction number for the total population and for the specific age group. The tendencies of effective reproduction number of four age groups were plotted by using the Epiestim R package and the SEIHR model for in-depth discussions. The sensitivity analysis by using sensitivity index and partial rank correlation coefficients values (PRCC values) were operated to reveal the differences of age groups against the main parameters. Results: The main epidemiological features such as basic reproduction number, effective reproduction number and sensitivity analysis were extensively discussed for multi-age groups SEIHR model in this study. Firstly, by using of the next generation matrix method, basic reproduction number R0 of the total population was estimated as 1.57 using parameter values of four age groups of Fuzhou COVID-19 large wave. Given age group k, the values of R0k (age group k to age group k), the values of R0k (an infected of age group k to the total population) and the values of R^0k (an infected of the total population to age group k) were also estimated, in which the explorations of the impacts of age groups revealed that the relationship R0k>R0k>R^0k was valid. Then, the fluctuating tendencies of effective reproduction number Rt were demonstrated by using two approaches (the surveillance data and the SEIHR model) for Fuzhou COVID-19 large wave, during which high-risk group (G4 group) mainly contributed the infection scale due to high susceptibility to infection and high risks to basic diseases. Further, the sensitivity analysis using two approaches (the sensitivity index and the PRCC values) revealed that susceptibility to infection of age groups played the vital roles, while the numerical simulation showed that infection scale varied with the changes of social contacts of age groups. The results of this study claimed that the high-risk group out of the total population was concerned by the local government with the highest susceptibility to infection against COVID-19. Conclusions: This study verified that the partition structure of age groups of the total population, the susceptibility to infection of age groups, the social contacts among age groups were the important contributors of infection scale. The less social contacts and adequate hospital beds for high-risk group were profitable to control the spread of COVID-19. To avoid the emergence of medical runs against new variant in the future, the policymakers from local government were suggested to decline social contacts when hospital beds were limited.

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole.

In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.

The effect of illness perception on psychosocial adjustment of patients with breast cancer and their spouses: actor-partner independence model.

OBJECTIVE: With the increase in the prevalence rate and improvements in the survival of breast cancer patients, there is a growing interest in understanding the level of psychosocial adjustment in these patients. The study aimed to describe the illness perception and psychosocial adjustment levels of both breast cancer patients and their spouses, to use the Actor-Partner Interdependence Model (APIM) to clarify the actor-partner relationships between spouses, and to explore the impact of illness perception on psychosocial adjustment to the disease within the joint actions of both spouses. METHODS: A total of 216 female patients with breast cancer and their spouses participated in the study. They were selected from two tertiary hospitals in Guangdong Province, China from October 2022 to May 2023 using a convenience sampling method. The participants were assessed using the Brief Illness Perception Questionnaire and the Psychosocial Adjustment to Illness Scale to examine the relationship between illness perception and psychosocial adjustment. AMOS24.0 was used to test and analyze the actor-partner interdependence model. RESULTS: The illness perception score (57.75 ± 10.91) was slightly higher than that of the spouse (57.10 ± 11.00), and the psychosocial adjustment score (64.67 ± 6.33) was slightly lower than that of the spouse (64.76 ± 7.49). The results of the actor-partner interdependence model indicated that there was a couple partner between breast cancer patients and their spouses: the spouse's illness perception significantly affected the patient's psychosocial adjustment (ß = 0.095, p = 0.015); the patient's illness perception also significantly affected the spouse's psychosocial adjustment (ß = 0.106, p = 0.033). Among them, the patient's psychosocial adjustment was found to be related to the patient's illness comprehensibility or coherence of illness (ß = 0.433, p = 0.009), the spouse's emotional illness representation (ß = 0.218, p = 0.037), and the spouse's illness comprehensibility or coherence of illness (ß = 0.416, p = 0.007), while the spouse's psychosocial adjustment was only related to the spouse's illness comprehensibility or coherence of illness (ß = 0.528, p = 0.007). CONCLUSIONS: The psychosocial adjustment of breast cancer patients is affected by both their own and spouse's illness perception. Therefore, in the future, the healthcare staff can implement early psychological interventions for patients diagnosed with breast cancer and their spouses as a unit to promote the psychosocial adjustment of them.

Design, synthesis, in vitro and in vivo evaluation and molecular docking study of novel pleuromutilin derivatives as antibacterial agents.

14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.

Mouse KL2 is a unique MTSE involved in chromosome-based spindle organization and regulated by multiple kinases during female meiosis.

Microtubule-severing enzymes (MTSEs) play important roles in mitosis and meiosis of the primitive organisms. However, no studies have assessed their roles in mammalian meiosis of females, whose abnormality accounts for over 80% of the cases of gamete-originated human reproductive disease. In the current study, we reported that katanin-like 2 (KL2) was the only MTSE concentrating at chromosomes. Furthermore, the knockdown of KL2 significantly reduced chromosome-based increase in the microtubule (MT) polymer, increased aberrant kinetochore-MT (K-MT) attachment, delayed meiosis, and severely affected normal fertility. Importantly, we demonstrated that the inhibition of aurora B, a key kinase for correcting aberrant K-MT attachment, eliminated KL2 from chromosomes completely. KL2 also interacted with phosphorylated eukaryotic elongation factor-2 kinase; they competed for chromosome binding. We also observed that the phosphorylated KL2 was localized at spindle poles, and that KL2 phosphorylation was regulated by extracellular signal-regulated kinase 1/2. In summary, our study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.

Assessing the impact of different contact patterns on disease transmission: Taking COVID-19 as a case.

Human-to-human contact plays a leading role in the transmission of infectious diseases, and the contact pattern between individuals has an important influence on the intensity and trend of disease transmission. In this paper, we define regular contacts and random contacts. Then, taking the COVID-19 outbreak in Yangzhou City, China as an example, we consider age heterogeneity, household structure and two contact patterns to establish discrete dynamic models with switching between daytime and nighttime to depict the transmission mechanism of COVID-19 in population. We studied the changes in the reproduction number with different age groups and household sizes at different stages. The effects of the proportion of two contacts patterns on reproduction number were also studied. Furthermore, taking the final size, the peak value of infected individuals in community and the peak value of quarantine infected individuals and nucleic acid test positive individuals as indicators, we evaluate the impact of the number of random contacts, the duration of the free transmission stage and summer vacation on the spread of the disease. The results show that a series of prevention and control measures taken by the Chinese government in response to the epidemic situation are reasonable and effective, and the young and middle-aged adults (aged 18-59) with household size of 6 have the strongest transmission ability. In addition, the results also indicate that increasing the proportion of random contact is beneficial to the control of the infectious disease in the phase with interventions. This work enriches the content of infectious disease modeling and provides theoretical guidance for the prevention and control of follow-up major infectious diseases.

[Mechanism and application prospects of microbial fertilizers in regulating quality formation of medicinal plants].

With the promotion of chemical fertilizer and pesticide reduction and green production of traditional Chinese medicines, microbial fertilizers have become a hot way to achieve the zero-growth of chemical fertilizers and pesticides, improve the yield and qua-lity of medicinal plants, maintain soil health, and promote the sustainable development of the planting industry of Chinese herbal medicines. Soil conditions and microenvironments are crucial to the growth, development, and quality formation of medicinal plants. Microbial fertilizers, as environmentally friendly fertilizers acting on the soil, can improve soil quality by replenishing organic matter and promoting the metabolism of beneficial microorganisms to improve the yield and quality of medicinal plants. In this regard, understanding the mechanism of microbial fertilizer in regulating the quality formation of medicinal plants is crucial for the development of herbal eco-agriculture. This study introduces the processes of microbial fertilizers in improving soil properties, participating in soil nutrient cycling, enhancing the resistance of medicinal plants, and promoting the accumulation of medicinal components to summarize the mechanisms and roles of bacterial fertilizers in regulating the quality formation of medicinal plants. Furthermore, this paper introduces the application of bacterial fertilizers in medicinal plants and makes an outlook on their development, with a view to providing a scientific basis for using microbial fertilizers to improve the quality of Chinese herbal medicines, improve the soil environment, promote the sustainable development of eco-agriculture of traditional Chinese medicine, and popularize the application of microbial fertilizers.

[A new nor-neolignan compound identified from Itea yunnanensis].

Various separation methods in combination with spectral data analysis, X-ray single crystal diffraction analysis, and litera-ture data comparison were employed to clarify the chemical constituents of Itea yunnanensis. Seven compounds were obtained from I. yunnanensis, which were identified as(S)-3-[1-(4-hydroxyphenyl)propane-2-yl]-4-methoxybenzoate methyl ester(1), iteafuranal B(2), syringaresinol(3), dihydrokaempferol(4), trimethoxybenzene(5), eicosane(6), and nonacosane(7), respectively. Among them, compound 1 was a new nor-neolignan compound named iteanorneoligan A, and the rest of the compounds were identified from I. yunnanensis for the first time. The anti-hepatocellular carcinoma effect of the compound was evaluated based on Sk-hep-1 cells model via MTT assay, and compound 2 showed a significant inhibitory effect on the proliferation of Sk-hep-1 cells with an IC_(50) of 9.4 µmol·L~(-1). The antioxidant capacity was determined via DPPH, ABTS~(·+), and O■ radical scavenging ability, and compound 1 exhibited a significant ABTS~(·+) radical scavenging effect with an IC_(50) of 0.178 mg·mL~(-1).

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Medicine is a continuously advancing science, characterized by the integration of multiple disciplines, ultimately focusing on the "human" aspect. Over the past half-century, there has been a global surge in efforts to reshape the humanistic spirit of medicine. Narrative medicine, a field that highly integrates medical professionalism with universal humanistic values, has developed rapidly in China from scratch over the past decade or so. This article introduces the development of narrative medicine both domestically and internationally, explains how to correctly understand the connotation of China's narrative medicine system and the significance of practicing narrative medicine. It analyzes current challenges in clinical practice, education and teaching, scientific research, doctor-patient consensus, and social recognition. Furthermore, it proposes directions for effort, namely, in the context of "greater health" and "new medical science", narrative medicine is empowered to help construct a harmonious medical narrative ecosystem, promote high-quality development in pediatrics, contribute to the innovation in medical education and talent training with humanistic strength and wisdom.

Tumor microenvironment-responsive size-changeable and biodegradable HA-CuS/MnO2 nanosheets for MR imaging and synergistic chemodynamic therapy/phototherapy.

Tumor microenvironment (TME)-responsive size-changeable and biodegradable nanoplatforms for multimodal therapy possess huge advantages in anti-tumor therapy. Hence, we developed a hyaluronic acid (HA) modified CuS/MnO2 nanosheets (HCMNs) as a multifunctional nanoplatform for synergistic chemodynamic therapy (CDT)/photothermal therapy (PTT)/photodynamic therapy (PDT). The prepared HCMNs exhibited significant NIR light absorption and photothermal conversion efficiency because of the densely deposited ultra-small sized CuS nanoparticles on the surface of MnO2 nanosheet. They could precisely target the tumor cells and rapidly decomposed into small sized nanostructures in the TME, and then efficiently promote intracellular ROS generation through a series of cascade reactions. Moreover, the local temperature elevation induced by photothermal effect also promote the PDT based on CuS nanoparticles and the Fenton-like reaction of Mn2+, thereby enhancing the therapeutic efficiency. Furthermore, the T1-weighted magnetic resonance (MR) imaging was significantly enhanced by the abundant Mn2+ ions from the decomposition process of HCMNs. In addition, the CDT/PTT/PDT synergistic therapy using a single NIR light source exhibited considerable anti-tumor effect via in vitro cell test. Therefore, the developed HCMNs will provide great potential for MR imaging and multimodal synergistic cancer therapy.

A rapid and sensitive one-pot platform integrating fluorogenic RNA aptamers and CRISPR-Cas13a for visual detection of monkeypox virus.

The recent global upsurge in Monkeypox virus (MPXV) outbreaks underscores the critical need for rapid and precise diagnostic solutions, particularly in resource-constrained settings. The gold standard diagnostic method, qRT-PCR, is hindered by its time-consuming nature, requirement for nucleic acid purification, expensive equipment, and the need for highly trained personnel. Traditional CRISPR/Cas fluorescence assays, relying on trans-cleavage of ssDNA/RNA reporters labeled with costly fluorophores and quenchers, pose challenges that limit their widespread application, especially for point-of-care testing (POCT). In this study, we utilized a cost-effective and stable fluorogenic RNA aptamer (Mango III), specifically binding and illuminating the fluorophore TO3-3 PEG-Biotin Fluorophore (TO3), as a reporter for Cas13a trans-cleavage activity. We propose a comprehensive strategy integrating RNA aptamer, recombinase-aided amplification (RAA), and CRISPR-Cas13a systems for the molecular detection of MPXV target. Leveraging the inherent collateral cleavage properties of the Cas13a system, we established high-sensitivity and specificity assays to distinguish MPXV from other Orthopoxviruses (OPVs). A streamlined one-pot protocol was developed to mitigate aerosol contamination risks. Our aptamer-coupled RAA-Cas13a one-pot detection method achieved a Limit of Detection (LoD) of 4 copies of target MPXV DNA in just 40 min. Validation using clinical MPX specimens confirmed the rapid and reliable application of our RAA-Cas13a-Apt assays without nucleic acid purification procedure, highlighting its potential as a point-of-care testing solution. These results underscore the user-friendliness and effectiveness of our one-pot RAA-Cas13a-Apt diagnostic platform, poised to revolutionize disease detection and management.

Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.

Clinical value of [18F]AlF-NOTA-FAPI-04 PET/CT for assessing early-stage liver fibrosis in adult liver transplantation recipients compared with chronic HBV patients.

AIMS: To investigate the clinical value and performance of [18F]AlF-NOTA-FAPI-04 PET/CT in assessing early-stage liver fibrosis in liver transplantation (LT) recipients. METHODS: A prospective study including 17 LT recipients and 12 chronic Hepatitis B (CHB) patients was conducted. All patients received liver biopsy, transient elastography (TE), and [18F]AlF-NOTA-FAPI-04 PET/CT. On [18F]AlF-NOTA-FAPI-04 PET/CT scans, the liver parenchyma's maximum standardized uptake values (SUVmax) were measured. The receiver operating characteristic (ROC) curve analysis was applied to determine the diagnostic efficacy of [18F]AlF-NOTA-FAPI-04 PET/CT in early-stage liver fibrosis (S1-S2) compared with the diagnostic performance of TE. RESULTS: Among those 29 patients enrolled in this study, 15(51.7%) had fibrosis S0, 10(34.5%) had S1, and 4(13.8%) had S2, respectively. The SUVmax of patients with early-stage liver fibrosis was significantly higher than those without liver fibrosis in LT recipients and CHB patients (P = 0.004, P = 0.02). In LT recipients, a SUVmax cut-off value of 2.0 detected early-stage liver fibrosis with an AUROC of 0.92 (P = 0.006), and a liver stiffness measurements (LSM) score cut-off value of 8.2 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.80 (P = 0.012). In CHB patients, a SUVmax cut-off value of 2.7 detected early-stage liver fibrosis with an AUROC of 0.94 (P < 0.001) and an LSM scores cut-off value of 8.4 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.91 (P < 0.001). CONCLUSION: [18F]AlF-NOTA-FAPI-04 PET/CT could be applied to evaluate early-stage liver fibrosis in LT recipients and CHB patients properly, with the potential additional advantages in monitoring and predicting complications after LT.

Valuation and comparison of the actual and optimal control strategy in an emerging infectious disease: Implication from a COVID-19 transmission model.

To effectively combat emerging infectious diseases like COVID-19, it is crucial to adopt strict prevention and control measures promptly to effectively contain the spread of the epidemic. In this paper, we propose a transmission model to investigate the influence of two control strategies: reducing contact numbers and improving medical resources. We examine these strategies in terms of constant control and time-varying control. Through sensitivity analysis on two reproduction numbers of the model with constant control, we demonstrate that reducing contact numbers is more effective than improving medical resources. Furthermore, these two constant controls significantly influence the peak values and timing of infections. Specifically, intensifying control measures can reduce peak values, albeit at the expense of delaying the peak time. In the model with time-varying control, we initially explore the corresponding optimal control problem and derive the characteristic expression of optimal control. Subsequently, we utilize real data from January 10th to April 12th, 2020, in Wuhan city as a case study to perform parameter estimation by using our proposed improved algorithm. Our findings illustrate that implementing optimal control measures can effectively reduce infections and deaths, and shorten the duration of the epidemic. Then, we numerically explore that implementing control measures promptly and increasing intensity to reduce contact numbers can make actual control be more closer to optimized control. Finally, we utilize the real data from October 31st to November 18th, 2021, in Hebei province as a second case study to validate the feasibility of our proposed suggestions.

Global stability for age-infection-structured human immunodeficiency virus model with heterogeneous transmission.

In this paper, we analyze the global asymptotic behaviors of a mathematical susceptible-infected(SI) age-infection-structured human immunodeficiency virus(HIV) model with heterogeneous transmission. Mathematical analysis shows that the local and global dynamics are completely determined by the basic reproductive number R0. If R0<1, disease-free equilibrium is globally asymptotically stable. If R0>1, it shows that disease-free equilibrium is unstable and the unique endemic equilibrium is globally asymptotically stable. The proofs of global stability utilize Lyapunov functions. Besides, the numerical simulations are illustrated to support these theoretical results and sensitivity analysis of each parameter for R0 is performed by the method of partial rank correlation coefficient(PRCC).

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

Prognosis and therapy in thyroid cancer by gene signatures related to natural killer cells.

BACKGROUND: Natural killer (NK) cells are crucial to cancer development and prognosis. However, the role of NK cell-related genes in immunotherapy and the tumor immune microenvironment (TIME) is not well understood. This study aimed to develop reliable risk signatures associated with NK cell-related genes for predicting thyroid cancer (THCA). METHODS: The single-cell RNA sequencing (scRNA-seq) data from seven THCA samples (GSE184362) and bulk-RNA-seq data of 502 THCA patients (TCGA-THCA) were included. The scRNA-seq data was analyzed using the "Seurat" R package to identify differentially expressed genes in NK cells. The clustering analysis was carried out using the R package "ConsensusClusterPlus". The gene set variation analysis (GSVA) algorithm was applied to assess the variations in biological pathways among subtypes. The ESTIMATE algorithm was utilized to calculate the scores for stromal, immune and estimate variables. In addition, we used the single sample Gene Set Enrichment Analysis and CIBERSORT algorithms to assess the degree to which immune cells and pathways related to immunity were enriched based on the meta-cohort. In the TCGA-THCA cohort, the "glmnet" R package was used for the gene selection, and LASSO Cox analysis was used to construct prognostic features. The "maftools" R package was used to examine the somatic mutation landscape of THCA in both low- and high-risk groups. RESULTS: One-hundred and eighty-five NK cell marker genes were screened, and nine genes were associated with the THCA prognosis. KLF2, OSTF1 and TAPBP were finally identified and constructed a risk signature with significant prognostic value. KLF2 and OSTF1 were protective genes, and TAPBP was a risk gene. Patients at high risk had a considerably lower overall survival compared with those at low risk. Mutations in the TCGA-THCA cohort were predominantly C > T. Increased tumor mutation burden (TMB) levels were linked to overall survival. The low-risk H-TMB+ group had a better prognosis, while the high-risk L-TMB+ group had the worst prognosis. CONCLUSION: Natural killer cell-related genes KLF2, OSTF1 and TAPBP were used to develop a novel prognostic risk signature, offering a new perspective on the prognosis and treatment of THCA.