Clinical applications of abnormal DNA methylation in chronic myeloid leukemia. / 异常DNAç”²åŸºåŒ–åœ¨æ ¢æ€§é«“ç³»ç™½è¡€ç— ä¸­çš„ä¸´åºŠåº”ç”¨.

DNA methylation, a crucial biochemical process within the human body, fundamentally alters gene expression without modifying the DNA sequence, resulting in stable changes. The changes in DNA methylation are closely related to numerous biological processes including cellular proliferation and differentiation, embryonic development, and the occurrence of immune diseases and tumor. Specifically, abnormal DNA methylation plays a crucial role in the formation, progression, and prognosis of chronic myeloid leukemia (CML). Moreover, DNA methylation offers substantial potential for diagnosing and treating CML. Accordingly, understanding the precise mechanism of DNA methylation, particularly abnormal changes in the methylation of specific genes in CML, can potentially promote the development of novel targeted therapeutic strategies. Such strategies could transform into clinical practice, effectively aiding diagnosis and treatment of CML patients.

Cost-effectiveness analysis of fruquintinib in Chinese patients with refractory metastatic colorectal cancer.

BACKGROUND: Colorectal cancer is a significant health concern worldwide, with metastatic CRC (mCRC) presenting a particularly challenging prognosis. The FRESCO-2 trial highlighted the potential of fruquintinib in heavily pretreated mCRC patients. AIM: Given the recent changes in drug pricing in China and the evolving mCRC treatments, this study aimed to evaluate the cost-effectiveness of fruquintinib in the context of current Chinese healthcare standards. METHOD: This study utilized data from the FRESCO-2 trial, incorporating a partitioned-survival model to simulate three health states: Progression-Free Survival, Progressive Disease, and death. Costs and utility values were derived from published literature and the FRESCO-2 trial. Sensitivity analyses were conducted to assess the robustness of the base-case result and to understand the impact of various parameters on the ICER. RESULTS: The base-case analysis revealed a total cost of $11,089.05 for the fruquintinib group and $5,374.48 for the placebo group. The overall QALYs were higher in the fruquintinib group (0.61 QALYs) compared to the placebo group (0.43 QALYs). The ICER was calculated to be $31,747.67 per QALY. Sensitivity analyses identified the utility of progression-free survival, the cost of fruquintinib, and the costs of best supportive care as significant determinants of ICER. CONCLUSION: Fruquintinib emerges as a promising therapeutic option for refractory mCRC. However, its cost-effectiveness depends on selected willingness-to-pay (WTP) threshold. While the drug's ICER surpasses the WTP based on China's 2022 GDP per capita, it remains below the threshold set at three times the national GDP.

[Research Progress of Pyroptosis in Leukemia: from Mechanism to Treatment --Review].

Pyroptosis is a programmed death mediated by activated caspase and Gasdermin family proteins, characterized by cell swelling, cytosolysis and release of inflammatory factors. Leukemia is a malignant disease characterized by abnormal differentiation and proliferation of hematopoietic stem cells, thus seriously threating human health. In recent years, it has been found that the transformation, proliferation, metastasis and treatment response of leukemia cells are closely related to pyrodeath. Pyroptosis provides a new perspective for the study of leukemia. This paper reviews the types and molecular mechanisms of pyroptosis, the role of pyroptosis in the occurrence and development of leukemia and the treatment of leukemia, so as to provide some references for further study of the relationship between pyroptosis and leukemia, in order to provide a new strategy for the treatment of leukemia.

N-homocysteinylation of DJ-1 promotes neurodegeneration in Parkinson's disease.

DJ-1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ-1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ-1 on the lysine 182 (K182) residue in an age-dependent manner. The N-homocysteinylation (N-hcy) of DJ-1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N-hcy of DJ-1 restores its protective effect. These results indicate that the N-hcy of DJ-1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N-hcy of DJ-1 may exert neuroprotective effect against PD.

An E3 ubiquitin ligase CSIT2 controls critical sterility-inducing temperature of thermo-sensitive genic male sterile rice.

Thermo-sensitive genic male sterile (TGMS) lines are the core of two-line hybrid rice (Oryza sativa). However, elevated or unstable critical sterility-inducing temperatures (CSITs) of TGMS lines are bottlenecks that restrict the development of two-line hybrid rice. However, the genes and molecular mechanisms controlling CSIT remain unknown. Here, we report the CRITICAL STERILITY-INDUCING TEMPERATURE 2 (CSIT2) that encodes a really interesting new gene (RING) type E3 ligase, controlling the CSIT of thermo-sensitive male sterility 5 (tms5)-based TGMS lines through ribosome-associated protein quality control (RQC). CSIT2 binds to the large and small ribosomal subunits and ubiquitinates 80S ribosomes for dissociation, and may also ubiquitinate misfolded proteins for degradation. Mutation of CSIT2 inhibits the possible damage to ubiquitin system and protein translation, which allows more proteins such as catalases to accumulate for anther development and inhibits abnormal accumulation of reactive oxygen species (ROS) and premature programmed cell death (PCD) in anthers, partly rescuing male sterility and raised the CSIT of tms5-based TGMS lines. These findings reveal a mechanism controlling CSIT and provide a strategy for solving the elevated or unstable CSITs of tms5-based TGMS lines in two-line hybrid rice.

Duchenne muscular dystrophy treatment with lentiviral vector containing mini-dystrophin gene in vivo.

Duchenne muscular dystrophy (DMD) is an incurable X-linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence-optimized dystrophin genes driven by muscle-specific promoters. The four lentiviral vectors stably expressed mini-dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn-Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3-6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini-dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin.

Homocysteine and Parkinson's disease.

Homocysteine (Hcy) is an important metabolite in methionine metabolism. When the metabolic pathway of homocysteine is abnormal, it will accumulate in the body and eventually lead to hyperhomocysteinemia. In recent years, many studies have found that hyperhomocysteinemia is related to the occurrence and development of Parkinson's disease. This study reviews the roles of homocysteine in the pathogenesis of Parkinson's disease and illustrates the harmful effects of hyperhomocysteinemia on Parkinson's disease.

L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration.

Parkinsonism is a clinical syndrome that is caused by Parkinson's disease (PD) and other neurodegenerative diseases. Here, we report a patient who exhibited progressive parkinsonism, epilepsy, and cognitive impairment and was diagnosed with adult-onset neuronal ceroid lipofuscinoses (ANCLs). The patient carries a mutation (p.Leu116 del) in the DNAJC5 gene that encodes cysteine string protein (CSPα). Since the patient shows typical parkinsonism and loss of dopamine transporter in the striatum, we investigated the effect of wild-type and L116del mutant CSPα on the aggregation of α-synuclein (α-syn) and neurotoxicity in vitro. Overexpression of wild-type CSPα attenuated the phosphorylation, ubiquitination, and aggregation of α-syn induced by α-syn fibrils. Moreover, wild-type CSPα inhibits oxidative stress and cell apoptosis and rescues inefficient SNARE complex formation induced by α-syn fibrils in SH-SY5Y cells. However, these protective effects of CSPα were abolished by the L116del mutation. Collectively, these results indicate that L116 deletion in CSPα promotes α-syn pathology and neurotoxicity. Boosting CSPα may be therapeutically useful for treating synucleinopathies.

Association of vitamin B2 intake with cognitive performance in older adults: a cross-sectional study.

BACKGROUND: To scrutinize the relationship between vitamin B2 consumption and cognitive function based on the NHANES database. METHODS: This cross-sectional study included eligible older adults from the NHANES 2011-2014. Vitamin B2 intake was determined from dietary interview data for two 24-h periods. Cognitive function was evaluated through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The regression analyses were used to evaluate the association of vitamin B2 intake with cognitive performance. Stratified analyses based on gender, race, and body mass index (BMI) were conducted. RESULTS: Higher vitamin B2 intake was correlated with higher scores on each test. As compared to the lowest quartile, the highest quartile of vitamin B2 intake was related to a 45.1-fold increase (P = 0.004) on the DSST test sores. Moreover, those who were males, non-Hispanic whites, or had a BMI of 18.5 to 30 kg/m2 had a stronger relationship between total vitamin B2 consumption and cognitive function. CONCLUSION: It's possible that older persons who consume more vitamin B2 have enhanced performance in some areas of cognitive function. To determine the causal link between vitamin B2 consumption and cognitive performance, further long-term research is required.

The Identification of the Banana Endogenous Reference Gene MaSPS1 and the Construction of Qualitative and Quantitative PCR Detection Methods.

Endogenous reference genes play a crucial role in the qualitative and quantitative PCR detection of genetically modified crops. Currently, there are no systematic studies on the banana endogenous reference gene. In this study, the MaSPS1 gene was identified as a candidate gene through bioinformatics analysis. The conservation of this gene in different genotypes of banana was tested using PCR, and its specificity in various crops and fruits was also examined. Southern blot analysis showed that there is only one copy of MaSPS1 in banana. The limit of detection (LOD) test showed that the LOD of the conventional PCR method is approximately 20 copies. The real-time fluorescence quantitative PCR (qPCR) method also exhibited high specificity, with a LOD of approximately 10 copies. The standard curve of the qPCR method met the quantitative requirements, with a limit of quantification (LOQ) of 1.14 × 10-2 ng-about 20 copies. Also, the qPCR method demonstrated good repeatability and stability. Hence, the above results indicate that the detection method established in this study has strong specificity, a low detection limit, and good stability. It provides a reliable qualitative and quantitative detection system for banana.

The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson's disease.

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating α-syn pathology induced by S. cerevisiae. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.

Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3ß pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.

Deep learning to assist composition classification and thyroid solid nodule diagnosis: a multicenter diagnostic study.

OBJECTIVES: This study aimed to propose a deep learning (DL)-based framework for identifying the composition of thyroid nodules and assessing their malignancy risk. METHODS: We conducted a retrospective multicenter study using ultrasound images from four hospitals. Convolutional neural network (CNN) models were constructed to classify ultrasound images of thyroid nodules into solid and non-solid, as well as benign and malignant. A total of 11,201 images of 6784 nodules were used for training, validation, and testing. The area under the receiver-operating characteristic curve (AUC) was employed as the primary evaluation index. RESULTS: The models had AUCs higher than 0.91 in the benign and malignant grading of solid thyroid nodules, with the Inception-ResNet AUC being the highest at 0.94. In the test set, the best algorithm for identifying benign and malignant thyroid nodules had a sensitivity of 0.88, and a specificity of 0.86. In the human vs. DL test set, the best algorithm had a sensitivity of 0.93, and a specificity of 0.86. The Inception-ResNet model performed better than the senior physicians (p < 0.001). The sensitivity and specificity of the optimal model based on the external test set were 0.90 and 0.75, respectively. CONCLUSIONS: This research demonstrates that CNNs can assist thyroid nodule diagnosis and reduce the rate of unnecessary fine-needle aspiration (FNA). CLINICAL RELEVANCE STATEMENT: High-resolution ultrasound has led to increased detection of thyroid nodules. This results in unnecessary fine-needle aspiration and anxiety for patients whose nodules are benign. Deep learning can solve these problems to some extent. KEY POINTS: • Thyroid solid nodules have a high probability of malignancy. • Our models can improve the differentiation between benign and malignant solid thyroid nodules. • The differential performance of one model was superior to that of senior radiologists. Applying this could reduce the rate of unnecessary fine-needle aspiration of solid thyroid nodules.

The E3 ubiquitin ligase CSIT1 regulates critical sterility-inducing temperature by ribosome-associated quality control to safeguard two-line hybrid breeding in rice.

Two-line hybrid breeding can fully utilize heterosis in crops. In thermo-sensitive genic male sterile (TGMS) lines, low critical sterility-inducing temperature (CSIT) is vital to safeguard the production of two-line hybrid seeds in rice (Oryza sativa), but the molecular mechanism determining CSIT is unclear. Here, we report the cloning of CSIT1, which encodes an E3 ubiquitin ligase, and show that CSIT1 modulates the CSIT of thermo-sensitive genic male sterility 5 (tms5)-based TGMS lines through ribosome-associated quality control (RQC). Biochemical assays demonstrated that CSIT1 binds to the 80S ribosomes and ubiquitinates abnormal nascent polypeptides for degradation in the RQC process. Loss of CSIT1 function inhibits the possible damage of tms5 to the ubiquitination system and protein translation, resulting in enhanced accumulation of anther-related proteins such as catalase to suppress abnormal accumulation of reactive oxygen species and premature programmed cell death in the tapetum, thereby leading to a much higher CSIT in the tms5-based TGMS lines. Taken together, our findings reveal a regulatory mechanism of CSIT, providing new insights into RQC and potential targets for future two-line hybrid breeding.

Co-application of biochar and organic amendments on soil greenhouse gas emissions: A meta-analysis.

Biochar has been shown to reduce soil greenhouse gas (GHG) and increase nutrient retention in soil; however, the interaction between biochar and organic amendments on GHG emissions remain largely unclear. In this study, we collected 162 two-factor observations to explore how biochar and organic amendments jointly affect soil GHG emissions. Our results showed that biochar addition significantly increased soil CO2 emission by 8.62 %, but reduced CH4 and N2O emissions by 27.0 % and 23.9 %, respectively. Meanwhile, organic amendments and the co-application with biochar resulted in an increase of global warming potential based on the 100-year time horizon (GWP100) by an average of 18.3 % and 26.1 %. More importantly, the interactive effect of biochar and organic amendments on CO2 emission was antagonistic (the combined effect was weaker than the sum of their individual effects), while additive on CH4 and N2O emissions. Additionally, our results suggested that when biochar is co-applied with organic amendments, soil GHG emissions were largely influenced by soil initial total carbon, soil texture, and biochar feedstocks. Our work highlights the important interactive effects of biochar and organic amendments on soil GHG emissions, and provides new insights for promoting ecosystem sustainability as well as mitigating future climate change.

27-Hydroxycholesterol Drives the Spread of α-Synuclein Pathology in Parkinson's Disease.

BACKGROUND: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. OBJECTIVE: The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. METHODS: Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. RESULTS: 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. CONCLUSIONS: 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.

Osimertinib for an Advanced NSCLC Patient with Two Common EGFR Mutations and a Concomitant MET Exon 14 Skipping Mutation: A Case Report.

Background: Lung cancer remains the leading cause of cancer-related mortality. Studies have revealed that a combination of crizotinib and EGFR tyrosine kinase inhibitors (TKIs) could be an effective treatment option for patients with sensitizing EGFR mutations and de novo or acquired MET amplification. Until now, there have been few reports of the response in patients harboring three mutations. Case Presentation: A patient was diagnosed with advanced lung adenocarcinoma harboring EGFR Del19, L858R mutation and METex14. She received osimertinib, and repeated imaging revealed further tumor progression. Sixty-six days later, combined treatment with osimertinib and crizotinib was initiated. Unfortunately, the patient succumbed to death at home after 17 days. Conclusion: This report firstly provided a lung adenocarcinoma patient with two common EGFR mutations (Del19 and L858R) and METex14. Our case raises a reminder about the tolerance and safety of combination therapy, especially in older peoples.

Evolution of biomimetic ECM scaffolds from decellularized tissue matrix for tissue engineering: A comprehensive review.

Tissue engineering is essentially a technique for imitating nature. Natural tissues are made up of three parts: extracellular matrix (ECM), signaling systems, and cells. Therefore, biomimetic ECM scaffold is one of the best candidates for tissue engineering scaffolds. Among the many scaffold materials of biomimetic ECM structure, decellularized ECM scaffolds (dECMs) obtained from natural ECM after acellular treatment stand out because of their inherent natural components and microenvironment. First, an overview of the family of dECMs is provided. The principle, mechanism, advances, and shortfalls of various decellularization technologies, including physical, chemical, and biochemical methods are then critically discussed. Subsequently, a comprehensive review is provided on recent advances in the versatile applications of dECMs including but not limited to decellularized small intestinal submucosa, dermal matrix, amniotic matrix, tendon, vessel, bladder, heart valves. And detailed examples are also drawn from scientific research and practical work. Furthermore, we outline the underlying development directions of dECMs from the perspective that tissue engineering scaffolds play an important role as an important foothold and fulcrum at the intersection of materials and medicine. As scaffolds that have already found diverse applications, dECMs will continue to present both challenges and exciting opportunities for regenerative medicine and tissue engineering.

Comparison of machine learning models based on multi-parametric magnetic resonance imaging and ultrasound videos for the prediction of prostate cancer.

Objective: To establish machine learning (ML) prediction models for prostate cancer (PCa) using transrectal ultrasound videos and multi-parametric magnetic resonance imaging (mpMRI) and compare their diagnostic performance. Materials and methods: We systematically collated the data of 383 patients, including 187 with PCa and 196 with benign lesions. Of them, 307 patients (150 with PCa and 157 with benign lesions) were randomly selected to train and validate the ML models, 76 patients were used as test set. B-Ultrasound videos (BUS), mpMRI T2 sequence (T2), and ADC sequence (ADC) were obtained from all patients. We extracted 851 features of each patient in the BUS, T2, and ADC groups and used a t-test, the Mann-Whitney U test, and LASSO regression to screen the features. Support vector machine (SVM), random forest (RF), adaptive boosting (ADB), and gradient boosting machine (GBM) models were used to establish radiomics models. In addition, we fused the features screened via LASSO regression from three groups as new features and rebuilt ML models. The performance of the ML models in diagnosing PCa in the BUS, T2, ADC, and fusion groups was compared using the area under the ROC curve (AUC), sensitivity, specificity, and accuracy. Results: In the test cohort, the AUC of each model in the ADC group was higher than that of in the.BUS and T2 groups. Among the models, the RF model had the best diagnostic performance, with an AUC of 0.85, sensitivity of 0.78 (0.61-0.89), specificity of 0.84 (0.69-0.94), and accuracy of 0.83 (0.66-0.93). The SVM model in both the BUS and T2 groups performed best. Based on the features screened in the BUS, T2, and ADC groups fused to construct the models, the SVM model was found to perform best, with an AUC of 0.87, sensitivity of 0.73 (0.56-0.86), specificity of 0.79 (0.63-0.90), and accuracy of 0.77 (0.59-0.89). The difference in the results was statistically significant (p<0.05). Conclusion: The ML prediction models had a good diagnostic ability for PCa. Among them, the SVM model in the fusion group showed the best performance in diagnosing PCa. These prediction models can help radiologists make better diagnoses.

Progress in the study of functional genes related to direct seeding of rice.

Rice is a major food crop in the world. Owing to the shortage of rural labor and the development of agricultural mechanization, direct seeding has become the main method of rice cultivation. At present, the main problems faced by direct seeding of rice are low whole seedling rate, serious weeds, and easy lodging of rice in the middle and late stages of growth. Along with the rapid development of functional genomics, the functions of a large number of genes have been confirmed, including seed vigor, low-temperature tolerance germination, low oxygen tolerance growth, early seedling vigor, early root vigor, resistance to lodging, and other functional genes related to the direct seeding of rice. A review of the related functional genes has not yet been reported. In this study, the genes related to direct seeding of rice are summarized to comprehensively understand the genetic basis and mechanism of action in direct seeding of rice and to lay the foundation for further basic theoretical research and breeding application research in direct seeding of rice.