Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.

INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019). CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Aptasensor based on gold nanostructure-decorated 2D Cu metal-organic framework nanosheets for highly sensitive and specific electrochemical lipopolysaccharide detection.

Detecting lipopolysaccharide (LPS) using electrochemical methods is significant because of their exceptional sensitivity, simplicity, and user-friendliness. Two-dimensional metal-organic framework (2D-MOF) that merges the benefits of MOF and 2D nanostructure has exhibited remarkable performance in constructing electrochemical sensors, notably surpassing traditional 3D-MOFs. In this study, Cu[tetrakis(4-carboxylphenyl)porphyrin] (Cu-TCPP) and Cu(tetrahydroxyquinone) (Cu-THQ) 2D nanosheets were synthesized and applied on a glassy carbon electrode (GCE). The 2D-MOF nanosheets, which serve as supporting layers, exhibit improved electron transfer and electronic conductivity characteristics. Subsequently, the modified electrode was subjected to electrodeposition with Au nanostructures, resulting in the formation of Au/Cu-TCPP/GCE and Au/Cu-THQ/GCE. Notably, the Au/Cu-THQ/GCE demonstrated superior electrochemical activity because of the 2D morphology, redox ligand, dense Cu sites, and improved deposition of flower-like Au nanostructure based on Cu-THQ. The electron transfer specific surface area was increased by the improved deposition of Au nanostructures, which facilitates enriched binding of LPS aptamer and significantly improved the detection performance of Apt/Au/Cu-THQ/GCE electrochemical aptasensor. The limit of detection for LPS reached 0.15 fg/mL with a linear range of 1 fg/mL - 100 pg/mL. The proposed aptasensor demonstrated the ability to detect LPS in serum samples with satisfactory accuracy, indicating significant potential for clinical diagnosis.

Association of muscle mass, grip strength and fat-to-muscle ratio and metabolic dysfunction-associated steatotic liver disease in a middle-to-elderly aged population.

OBJECTIVE: The association of appendicular skeletal muscle mass (ASM), grip strength and fat-to-muscle ratio (FMR) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) are not well known. MATERIALS AND METHODS: This study included participants older than 40 years who underwent bioelectrical impedance assessment in Prevalence of Metabolic Diseases and Risk Factors in Shunde (SPEED-Shunde). We measured grip strength with an electronic grip strength metre. ASM and grip strength were adjusted by dividing body mass index (BMI). FMR was calculated as total fat mass to total muscle mass. Liver steatosis and liver fibrosis were evaluated by vibration-controlled transient elastography. Multifactorial logistic regression was used to analyse the relationship between ASM, grip strength, FMR, and MASLD or MASLD-associated liver fibrosis. We performed subgroup analyses according to sex, age and BMI. Interaction tests and linear trend tests were also conducted. RESULTS: This study included a total of 3277 participants. FMR was positively associated with MASLD (OR: 1.89, 95% CI: 1.66-2.15) and MASLD-associated liver fibrosis (OR: 1.70, 95% CI: 1.22-2.37). While ASM/BMI (OR: 0.59, 95% CI: 0.52-0.67) or grip strength/BMI (OR: 0.72, 95% CI: 0.66-0.78) were negatively associated with MASLD. Interactions were observed between ASM/BMI and age, grip strength and sex in MASLD, as well as FMR and MASLD-associated liver fibrosis. CONCLUSION: In a middle-to-elderly aged population, FMR was positively associated with the risk of MASLD and MASLD-associated liver fibrosis, and muscle mass and grip strength were negatively associated with MASLD, rather than MASLD-associated liver fibrosis.

Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC.

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

Sex- and age-specific associations of serum essential elements with diabetes among the Chinese adults: a community-based cross-sectional study.

BACKGROUND: Although several studies have found the relationship between essential elements and diabetes, the studies about the association of essential elements with diabetes diagnosed according to an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) in a sex- and age-specific manner were limited. To investigate the linear and nonlinear relationship of five essential elements including iron (Fe), copper (Cu), Zinc (Zn), magnesium (Mg), and calcium (Ca) with diabetes, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (PPG), and HbA1c and to evaluate the sex- and age-specific heterogeneities in these relationships. METHODS: A total of 8392 community-dwelling adults were recruited to complete a questionnaire and undergo checkups of anthropometric parameters and serum levels of five metals (Fe, Cu, Zn, Mg, and Ca). The multivariable logistic and linear regression, the restricted cubic spline (RCS) analysis, and subgroup analysis were applied to find the associations between the essential elements and the prevalence of diabetes as well as FPG, PPG, and HbA1c. RESULTS: In the multivariable logistic regression and multivariable linear regression, serum Cu was positively associated with FPG, PPG, and HbA1c while serum Mg was significantly inversely correlated with FPG, PPG, HbA1c, and diabetes (all P < 0.001). In the RCS analysis, the non-linear relationship of Cu and diabetes (P < 0.001) was found. In the subgroup analysis, stronger positive associations of Cu with diabetes (P for interaction = 0.027) and PPG (P for interaction = 0.002) were found in younger women. CONCLUSIONS: These findings may lead to more appropriate approaches to essential elements supplementation in people with diabetes of different ages and sexes. However, more prospective cohort and experimental studies are needed to probe the possible mechanism of sex- and age-specific associations between serum essential elements and diabetes.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Causal relationship between blood traits and severe influenza A(H1N1)pdm09 infection in East Asian: A Mendelian randomization study.

Although a range of blood traits have been reported to be associated with influenza A(H1N1)pdm09 (H1N1pdm09) disease severity, their underlying causal relationships and biological mechanisms have remained unclear. This study aimed to investigate the causal relationship between blood traits and H1N1pdm09 using a two-sample Mendelian randomization analysis. Based on the data from our in-house genome-wide association study (GWAS) on H1N1pdm09 disease severity (Ncase [severe] = 70, Ncontrol [mild] = 95) and GWAS summaries of 44 blood traits from Biobank Japan (N = 12 303-143 658), we identified the potential causal effect of blood traits on severe H1N1pdm09. The inverse variance weighted method analysis revealed significant causal effects of lower aspartate aminotransferase (AST, ß = -3.212, p = 0.019), low-density-lipoprotein cholesterol (LDL-C, ß = -1.372, p = 0.045), and basophil counts (Baso, ß = -1.638, p = 0.047) on severe H1N1pdm09 disease. Additionally, polygenic risk score analysis further confirmed genetic overlap between these blood traits and severe H1N1pdm09 disease. This study provided evidence linking the lower level of AST, LDL-C, and lower count of Baso with severe H1N1pdm09 disease, potentially identifying new therapeutic targets for patients with severe influenza.

Novel Therapies for ANCA-associated Vasculitis: Apilimod Ameliorated Endothelial Cells Injury through TLR4/NF-κB Pathway and NLRP3 Inflammasome.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rapidly progressive form of glomerulonephritis for which effective therapeutic drugs are currently lacking, and its underlying mechanism remains unclear. AIMS: This study aimed to investigate new treatment options for AAV through a combination of bioinformatics analysis and cell molecular experiments. METHODS: The research utilized integrated bioinformatics analysis to identify genes with differential expression, conduct enrichment analysis, and pinpoint hub genes associated with AAV. Potential therapeutic compounds for AAV were identified using Connectivity Map and molecular docking techniques. In vitro experiments were then carried out to examine the impact and mechanism of apilimod on endothelial cell injury induced by MPO-ANCA-positive IgG. RESULTS: The findings revealed a set of 374 common genes from differentially expressed genes and key modules of WGCNA, which were notably enriched in immune and inflammatory response processes. A proteinprotein interaction network was established, leading to the identification of 10 hub genes, including TYROBP, PTPRC, ITGAM, KIF20A, CD86, CCL20, GAD1, LILRB2, CD8A, and COL5A2. Analysis from Connectivity Map and molecular docking suggested that apilimod could serve as a potential therapeutic cytokine inhibitor for ANCA-GN based on the hub genes. In vitro experiments demonstrated that apilimod could mitigate tight junction disruption, endothelial cell permeability, LDH release, and endothelial activation induced by MPO-ANCA-positive IgG. Additionally, apilimod treatment led to a significant reduction in the expression of proteins involved in the TLR4/NF-κB and NLRP3 inflammasome-mediated pyroptosis pathways. CONCLUSION: This study sheds light on the potential pathogenesis of AAV and highlights the protective role of apilimod in mitigating MPO-ANCA-IgG-induced vascular endothelial cell injury by modulating the TLR4/ NF-kB and NLRP3 inflammasome-mediated pyroptosis pathway. These findings suggest that apilimod may hold promise as a treatment for AAV and warrant further investigation.

Assessing usability of intelligent guidance chatbots in Chinese hospitals: Cross-sectional study.

Objective: This study aimed to assessing usability of intelligent guidance chatbots (IGCs) in Chinese hospitals. Methods: A cross-sectional study based on expert survey was conducted between August to December 2023. The survey assessed the usability of chatbots in 590 Chinese hospitals. One-way ANOVA was used to analyze the impact of the number of functions, human-like characteristics, number of outpatients, and staff size on the usability of the IGCs. Results: The results indicate that there are 273 (46.27%) hospitals scoring above 45 points. In terms of function development, 581(98.47%) hospitals have set the number of functions between 1 and 5. Besides, 350 hospitals have excellent function implementation, accounting for 59.32%. In terms of the IGC's human-like characteristic, 220 hospitals have both an avatar and a nickname. Results of One-way ANOVA show that, the number of functions(F = 202.667, P < 0.001), human-like characteristics(F = 372.29, P < 0.001), staff size(F = 9.846, P < 0.001), and the number of outpatients(F = 5.709, P = 0.004) have significant impact on the usability of hospital IGCs. Conclusions: This study found that the differences in the usability of hospital IGCs at various levels of the number of functions, human-like characteristics, number of outpatients, and staff size. These findings provide insights for deploying hospital IGCs and can inform improvements in patient's experience and adoption of chatbots.

Construction of a Prediction Model for Post-Thrombotic Syndrome After Deep Vein Thrombosis Incorporating Novel Inflammatory Response Parameter Scoring.

OBJECTIVE: To investigate the independent predictive factors for post-thrombotic syndrome (PTS) and to construct a risk prediction model for PTS by incorporating a novel inflammatory response parameter scoring. METHODS: A retrospective study analyzed patients diagnosed with lower extremity deep vein thrombosis (LEDVT) at the Affiliated Hospital of Chengde Medical College from January 2018 to January 2022. The Villalta scale was used to assess the occurrence of PTS 6-24 months after discharge. Patients were randomly divided into a training set and a validation set at a ratio of 7:3. In the training set, univariate analysis was performed on meaningful continuous variables, and those with differences were converted into dichotomous variables based on optimal cutoff values. Variable selection was performed using Log-Lambda and LASSO 10-fold cross-validation, followed by multivariable logistic regression analysis on selected variables for model construction. The model underwent internal validation in the validation set and external validation in an independent external cohort, including discriminative analysis, calibration analysis, and clinical decision curve analysis, with the model's rationale being evaluated lastly. RESULTS: A total of 356 patients with lower extremity DVT were included, with 249 in the training set for model construction and 107 in the validation set for internal validation, along with 37 external patients for external validation. A composite score of inflammatory response parameters, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to high-density lipoprotein cholesterol ratio (MHR) (NLR-PLR-MHR score, NPMscore), was developed, showing a significantly higher NPMscore in the PTS group compared to the non-PTS group (p<0.05). Predictive factors related to the risk of PTS occurrence included stage (OR=6.83, 95%CI: 2.74-18.04), varicose veins (OR=7.30, 95%CI: 2.29-25.75), homocysteine (Hcy) (OR=1.12, 95%CI: 1.04-1.22), NPMscore (OR=3.13, 95%CI: 1.94-5.36), standardized anticoagulant therapy (OR=5.77, 95%CI: 1.25-27.62), and one-stop treatment (OR=0.04, 95%CI: 0.00-0.35) were incorporated into the Nomogram model. The model showed good discrimination with a concordance index of 0.918 (95%CI: 0.876-0.959) for model construction, 0.843 (95%CI: 0.741-0.945) for internal validation, and 0.823 (95%CI: 0.667-0.903) for external validation. The Nomogram model, internal and external validation calibration curves showed good agreement between observed and predicted values. Decision curve analysis (DCA) indicated the Nomogram model predicted PTS risk probability thresholds ranging from 3%-98% for model construction, 5%-97% for internal validation, and 10%-80% for external validation, demonstrating better net benefit for predicting PTS risk in the model, internal, and external validation. Rationality analysis showed the model and internal validation had higher discrimination and clinical net benefit than other clinical indices. CONCLUSION: The novel inflammatory response parameter score (NPMscore) combined with stage, varicose veins, homocysteine (Hcy), standardized anticoagulant therapy, and one-stop treatment in the Nomogram model provides a practical tool for healthcare professionals to assess the risk of PTS in DVT patients, enabling early identification of high-risk patients for effective PTS prevention.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.

Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination.

Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.

Anlotinib synergizes with venetoclax to induce mitotic catastrophe in acute myeloid leukemia.

Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly recognized as promising treatment strategies for acute myeloid leukemia (AML). In this study, we conducted an unbiased drug screen and identified anlotinib, a promising multi-targeted receptor tyrosine kinase inhibitor with oral activity currently utilized in the treatment of solid tumor, as a potent enhancer of venetoclax's anticancer activity in AML. Our investigation encompassed AML cell lines, primary cells, and mouse models, demonstrating effective low-dose combination therapy of anlotinib and venetoclax with minimal cytopenia or organ damage. Proteomic analysis revealed abnormal mitotic signals induced by this combination in AML cells. Mechanistically, anlotinib synergized with venetoclax by suppressing ARPP19 protein, leading to sustained activation of PP2A-B55δ. This inhibited AML cells from entering the mitotic phase, culminating in mitotic catastrophe and apoptosis. Additionally, we identified a specific synthetic lethal vulnerability in AML involving an ARPP19 mutation at S62 phosphorylation. These findings underscore the therapeutic potential of anlotinib and venetoclax combination therapy in AML, warranting further clinical investigation.

Immunotherapy in resectable NSCLC: Answering the question or questioning the answer?

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern-whether it's neoadjuvant, adjuvant, or a combination of both-is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment.

Sex-specific associations between the developmental alterations in the pituitary-thyroid hormone axis and thyroid nodules in Chinese euthyroid adults: a community-based cross-sectional study.

Background: Previous studies have revealed the sex-specific features of pituitary-thyroid hormone (TH) actions and the prevalence of thyroid nodules (TNs) in children and adolescents. However, it was unclear in adults. We aimed to investigate the features of pituitary-TH actions in women and men at different ages, and the associations of thyrotropin (TSH), THs, and central sensitivity to THs indices including the thyroid feedback quantile-based index by FT4 (TFQIFT4) and the thyroid feedback quantile-based index by FT3(TFQIFT3) with of TNs in Chinese euthyroid adults. Methods: 8771 euthyroid adults from the communities in China were involved. Demographic, behavioral, and anthropometric data were gathered through the questionnaires. Ultrasound was performed to evaluate the TNs. TSH and THs levels were measured. The multivariable logistic regression and multivariable ordinal logistic regression were conducted. Results: TFQIFT3 among both genders, except women aged 43 to 59 years, where it increased slightly. Additionally, there was an age-related decline in TFQIFT4 levels in both women and men at ages < 50 and < 53, respectively, but a marked increase after that. Lower TSH levels were significantly associated with a higher prevalence and lower odds of having fewer TNs using multiple nodules as the base category in both men and women (both P for trend < 0.05). Additionally, lower TFQIFT3 and TFQIFT4 levels were significantly associated with a higher prevalence of TNs in women (both P for trend < 0.05), and lower TFQIFT3 levels were significantly associated with a higher prevalence of TNs in men. Both higher TFQIFT3 and TFQIFT4 levels were significantly associated with higher odds of having fewer TNs using multiple nodules as the base category in women. However, the relationships between TFQIFT4 and the prevalence or number of TNs in men were not found. Conclusions: The trends of THs, TSH, TFQIFT4, and TFQIFT3 at different ages were sex-dependent. Both TFQIFT4 and TFQIFT3 levels were negatively associated with the prevalence and number of TNs in women. The present results may lead to a better understanding of the sex-specific relationships between the development of the pituitary-TH axis and the formation of TNs.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

Dipeptidyl peptidase 4 inhibitors vs. metformin for new-onset dementia: a propensity score-matched cohort study.

BACKGROUND: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remains controversial, particularly about dipeptidyl peptidase 4 (DPP4) inhibitors versus metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia. METHODS: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System (CRDS) database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death. RESULTS: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin (hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89). Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98). CONCLUSION: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

Effect of Neutral Protease on Freshness Quality of Shucked Pacific Oysters at Different Storage Conditions.

The aim of this study was to investigate the effect of neutral protease treatment on the biochemical properties of various parts of Pacific oysters (Crassostrea gigas) under different storage conditions. The mechanism of quality degradation in the mantle, adductor muscle, gill, and trunk of treated oysters stored at -1.5 °C (superchilling) or 4 °C (refrigeration) for several days using different storage methods was studied. The results showed that the oyster treated with the enzyme exhibited higher glycogen content, flavor nucleotide content, and sensory scores compared to the control group. Superchilling at -1.5 °C was observed to slow the increase in total volatile basic nitrogen (TVB-N), total viable count (TVC), and pH, while maintaining sensory scores better than refrigeration at 4 °C. Both wet superchilling (WS) and dry exposed superchilling (DeS) methods effectively preserved freshness and quality at -1.5 °C. The freshness of the oysters' body trunk changed most significantly. K value, K' value, and AEC value, as the evaluation indexes of oyster freshness, were affected by the storage medium. Therefore, neutral protease enhances the flavor of oysters in a short time, and oysters stored in wet superchilling or dry exposed superchilling conditions have an extended shelf life.

Evaluation of the modified MRI vertebral bone quality score for bone quality in lumbar degenerative disorders.

OBJECTIVE: The traditional VBQ scoring method may lead to overestimation due to the concentration of intravertebral fat and vascular structures in the posterior half of vertebral bodies, potentially resulting in false-positive outcomes. This study aims to modify the measurement method of VBQ score (Modified-VBQ) and evaluate its effectiveness in evaluating bone quality of lumbar degenerative diseases. METHODS: Retrospective analysis was conducted on clinical data from patients undergoing lumbar surgery for degenerative diseases between September 2022 and September 2023. Preoperative lumbar t1-weighted Magnetic resonance imaging was used for both modified and traditional VBQ scoring. Computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA) data were collected through the picture archiving and communication system. The effectiveness of the modified VBQ score was evaluated, considering P < 0.05 as statistically significant. RESULTS: The study included 212 patients, revealing a significant difference between the modified VBQ and VBQ scores (P < 0.0001). Notably, patients with a history of hyperlipidemia exhibited a significant difference between the two scores (P = 0.0037). The area under the ROC curve (AUC) for the modified VBQ was 0.86, surpassing the VBQ score (AUC = 0.74). Linear regression analysis demonstrated a moderate to strong correlation between the modified VBQ and DEXA T-score (r = - 0.49, P < 0.0001) and a high correlation with CT Hounsfield units (HU) values (r = - 0.60, P < 0.0001). CONCLUSION: The modified VBQ score provides a simple, effective, and relatively accurate means of assessing bone quality in lumbar degenerative diseases. Preoperative implementation of the modified VBQ score facilitates rapid screening for patients with abnormal bone quality.