P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth.

Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTORP2341A is significantly reduced when compared with that of cells overexpressing mTORWT. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.

Effect of antipsychotics and mood stabilisers on metabolism in bipolar disorder: a network meta-analysis of randomised-controlled trials.

Background: Antipsychotics and mood stabilisers are gathering attention for the disturbance of metabolism. This network meta-analysis aims to evaluate and rank the metabolic effects of the commonly used antipsychotics and mood stabilisers in treating bipolar disorder (BD). Methods: Registries including PubMed, Embase, Cochrane Library, Web of Science, Ovid, and Google Scholar were searched before February 15th, 2024, for randomised controlled trials (RCTs) applying antipsychotics or mood stabilisers for BD treatment. The observed outcomes were twelve metabolic indicators. The data were extracted by two reviewers independently, and confirmed by another four reviewers and a corresponding author. The above six reviewers all participated in data analyses. Data extraction was based on PRISMA guidelines, and quality assessment was conducted according to the Cochrane Handbook. Use a random effects model for data pooling. The PROSPERO registration number is CRD42023466669. Findings: Together, 5421 records were identified, and 41 publications with 11,678 complete-trial participants were confirmed eligible. After eliminating possible sensitivity, risperidone ranked 1st in elevating fasting serum glucose (SUCRA = 90.7%) and serum insulin (SUCRA = 96.6%). Lurasidone was most likely to elevate HbA1c (SUCRA = 82.1%). Olanzapine ranked 1st in elevating serum TC (SUCRA = 93.3%), TG (SUCRA = 89.6%), and LDL (SUCRA = 94.7%). Lamotrigine ranked 1st in reducing HDL (SUCRA = 82.6%). Amisulpride ranked 1st in elevating body weight (SUCRA = 100.0%). For subgroup analyses, quetiapine is more likely to affect indicators of glucose metabolism among male adult patients with bipolar mania, while long-term lurasidone tended to affect glucose metabolism among female patients with bipolar depression. Among patients under 18, divalproex tended to affect glucose metabolism, with lithium affecting lipid metabolism. In addition, most observed antipsychotics performed higher response and remission rates than placebo, and displayed a similar dropout rate with placebo, while no between-group significance of rate was observed among mood stabilisers. Interpretation: Our findings suggest that overall, antipsychotics are effective in treating BD, while they are also more likely to disturb metabolism than mood stabilisers. Attention should be paid to individual applicability in clinical practice. The results put forward evidence-based information and clinical inspiration for drug compatibility and further research of the BD mechanism. Funding: The National Key Research and Development Program of China (2023YFC2506200), and the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (No. JNL-2023001B).

Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

Targeting TYK2 alleviates Rab27A-induced malignant progression of non-small cell lung cancer via disrupting IFNα-TYK2-STAT-HSPA5 axis.

Rab27A is a small GTPase-mediating exosome secretion, which participates in tumorigenesis of multiple cancer types. Understanding the biological role of Rab27A in non-small cell lung cancer (NSCLC) is of great importance for oncological research and clinical treatment. In this study, we investigate the function and internal mechanism of Rab27A in NSCLC. Results show that Rab27A is overexpressed in NSCLC, and regulates the tumor proliferation, migration, invasion, and cell motility in vitro and in vivo, and is negatively regulated by miR-124. Further research reveals that upregulated Rab27A can induce the production of IFNα in the medium by mediating exosome secretion. Then IFNα activates TYK2/STAT/HSPA5 signaling to promote NSCLC cell proliferation and metastasis. This process can be suppressed by TYK2 inhibitor Cerdulatinib. These results suggest that Rab27A is involved in the pathogenesis of NSCLC by regulating exosome secretion and downstream signaling, and inhibitors targeting this axis may become a promising strategy in future clinical practice.

Epigenome-augmented eQTL-hotspots reveal genome-wide transcriptional programs in 36 human tissues.

Expression quantitative trait loci (eQTLs) are used to inform the mechanisms of transcriptional regulation in eukaryotic cells. However, the specificity of genome-wide eQTL identification is limited by stringent control for false discoveries. Here, we described a method based on the non-homogeneous Poisson process to identify 125 489 regions with highly frequent, multiple eQTL associations, or 'eQTL-hotspots', from the public database of 59 human tissues or cell types. We stratified the eQTL-hotspots into two classes with their distinct sequence and epigenomic characteristics. Based on these classifications, we developed a machine-learning model, E-SpotFinder, for augmented discovery of tissue- or cell-type-specific eQTL-hotspots. We applied this model to 36 tissues or cell types. Using augmented eQTL-hotspots, we recovered 655 402 eSNPs and reconstructed a comprehensive regulatory network of 2 725 380 cis-interactions among eQTL-hotspots. We further identified 52 012 modules representing transcriptional programs with unique functional backgrounds. In summary, our study provided a framework of epigenome-augmented eQTL analysis and thereby constructed comprehensive genome-wide networks of cis-regulations across diverse human tissues or cell types.

Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses.

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Adiponectin inhibits ROS/NLRP3 inflammatory pathway through FOXO3A to ameliorate oral submucosal fibrosis.

Oral submucous fibrosis (OSF) is an oral condition characterized by chronic progression, which may lead to the development of malignancy. Currently, available treatments for OSF only provide temporary relief of symptoms, and there is a limited availability of effective interventions that can effectively cure this condition. In this study, we aimed to investigate whether adiponectin (APN) could ameliorate OSF and the mechanisms involved in it. First, human oral mucosal fibroblasts (HOMFs) were cultured, an OSF model was established using arecoline, and APN and Imiquimod treatment were administered. Then we overexpressed NLRP3 and knocked down FOXO3A. FOXO3A, fibrosis-related factors (ɑ-SMA, COL1A, CTGF), TGF-ß1/Smad3 signaling-related factors (TGF-ß1, p-Smad3, Smad3), NLRP3 inflammasome-related factors (NLRP3, Caspase-1, IL-1ß), and ROS levels were evaluated. Finally, we explored the effect of APN on OSF in mice by in vivo experiments. We found that arecoline significantly increased ɑ-SMA, COL1A, CTGF, and TGF-ß1 expressions and promoted Smad3 phosphorylation, while APN significantly inhibited the elevation of these fibrosis-related factors. ROS production was significantly elevated in HOMFs after arecoline treatment, while APN treatment inhibited ROS production. However, the addition of Imiquimod and overexpression of NLRP3 exhibited a trend of elevated ROS, resisting the inhibitory effect of APN. Furthermore, adding Imiquimod and overexpression of NLRP3 elevated ɑ-SMA, COL1A and CTGF and activated TGF-ß1/Smad3 signaling pathway. Additionally, knockdown of FOXO3A enhanced APN-inhibited ɑ-SMA and COL1A. In vivo experiments further confirmed that APN ameliorated OSF in mice by inhibiting ROS/NLRP3 inflammatory pathway. In conclusion, APN ameliorated arecoline-induced OSF by promoting FOXO3A expression and downregulating the ROS/NLRP3 pathway.

Individualized 3D-printed bolus promotes precise postmastectomy radiotherapy in patients receiving breast reconstruction.

Purpose: To evaluate the efficacy and safety of 3D-printed tissue compensations in breast cancer patients receiving breast reconstruction and postmastectomy radiotherapy (PMRT). Methods and materials: We enrolled patients with breast cancer receiving breast reconstruction and PMRT. The dose distribution of target and skin, conformability, and dose limit of organs at risk (OARs) were collected to evaluate the efficacy of the 3D-printed bolus. Radiation Therapy Oncology Group (RTOG) radiation injury classification was used to evaluated the skin toxicities. Results: A total of 30 patients diagnosed between October 2019 to July 2021 were included for analysis. Among all the patients, the 3D-printed bolus could ensure the dose coverage of planning target volume (PTV) [homogeneity index (HI) 0.12 (range: 0.08-0.18)], and the mean doses of D99%, D98%, D95%, D50%, D2% and Dmean were 4606.29cGy, 4797.04cGy, 4943.32cGy, 5216.07cGy, 5236.10cGy, 5440.28cGy and 5462.10cGy, respectively. The bolus demonstrated an excellent conformability, and the mean air gaps between the bolus and the chest wall in five quadrants were 0.04cm, 0.18cm, 0.04cm, 0.04cm and 0.07cm, respectively. In addition, the bolus had acceptable dosage limit of OARs [ipsilateral lung: Dmean 1198.68 cGy, V5 46.10%, V20 21.66%, V30 16.31%); heart: Dmean 395.40 cGy, V30 1.02%, V40 0.22%; spinal cord planning risk volume (PRV): Dmax 1634 cGy] and skin toxicity (grade 1, 76.0%; grade 2, 21.0%; grade 3, 3.3%). Conclusion: The 3D-printed bolus offers advantages in terms of dose uniformity and controllable skin toxicities in patients receiving breast reconstruction and PMRT. Further research is needed to comprehensively evaluate the effectiveness of the 3Dprinted bolus in this patient subset.

FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer.

BACKGROUND: Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. METHODS: A human m6A epitranscriptomic microarray analysis was used to identify downstream targets of FTO. Quantitative real-time PCR (qRT‒PCR) and western blotting were employed to evaluate the expression levels of FTO and FAP in NSCLC cell lines and tissues. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effects of FTO and FAP on NSCLC metastasis. M6A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assays, and RNA stability assays were used to explore the mechanism of FTO action. Co-immunoprecipitation (co-IP) assays were used to determine the mechanism of FAP in NSCLC metastasis. RESULTS: FTO was upregulated and predicted poor prognosis in patients with NSCLC. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m6A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. CONCLUSION: Our current findings provided valuable insights into the role of FTO-mediated m6A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. Video Abstract.

Emerging evidence suggests the crucial roles of N⁶-methyladenosine (m⁶A) RNA modification in tumorigenesis and progression. Nonetheless, the role of m⁶A in NSCLC remains unclear. The purpose of this study was to investigate the role of m⁶A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of non-small cell lung cancer (NSCLC). Results illustrated that FTO was upregulated and predicted poor prognosis in NSCLC patients. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m⁶A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. Our current findings provided valuable insights into the role of FTO-mediated m⁶A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC.

The disparities in prognostic prediction and annualized hazard function in different molecular subtypes between young Chinese and White American women with breast cancer.

Background and objectives: The prognostic disparities in different molecular subtypes between young Chinese and White American breast cancer patients remain unclear. The goal of this study was to explore the prognostic differences in different molecular subtypes between Chinese and White American patients aged ≤ 40 years. Methods: We included Chinese and White female breast cancer patients at or under the age of 40 from the Surveillance, Epidemiology, and End Results database (SEER) and the West China Hospital of Sichuan University. The chi-square test, log-rank test, and Cox proportional hazards model were employed to evaluate the distribution and survival disparities in the two racial/ethnic cohorts and different molecular subtypes. An annualized hazard function was used to calculate the annual failure rate among different molecular subtypes. Results: This study included 20,859 female breast cancer patients at or under the age of 40, of whom 18,400 were White women and 2,459 were Chinese women. With a median follow-up time of 47 months, the 5-year breast cancer-specific survival (BCSS) rates for young Chinese and White women were 93.9% and 90.0%, respectively (P< 0.001). Molecular subtype was found to be a significant predictor in both young Chinese and White patients (P< 0.001), but different trends were observed in the two racial/ethnic cohorts when exploring the association between BCSS and molecular subtypes. Among young White patients, the hormone receptor (HoR) (+)/epidermal growth factor receptor 2 (HER2) (+) subtype had the best 5-year BCSS rate, while in young Chinese patients, the HoR (+)/HER2 (+) and HoR (+)/HER2 (-) showed comparable survival curves and both showed superior 5-year BCSS than other subtypes. Stratification by molecular subtypes, young Chinese patients demonstrated a superior 5-year BCSS in HoR (+)/HER2 (-) (96.3% vs 92.9%, P< 0.001) and triple-negative subtypes (88% vs 81.7%, P= 0.006) compared to young White American patients, while no significant differences were found in HoR (+)/HER2 (+) and HER2 enriched tumors. The annual hazard function for BCSS showed that there were significantly different trends in the HoR (+)/HER2 (-) and HoR (+)/HER2 (+) subtypes between young Chinese and White patients. Conclusions: There are disparities in prognosis and annualized hazard function between young Chinese and White females with breast cancer in different molecular subtypes.

Survival and Trends in Annualized Hazard Function by Age at Diagnosis Among Chinese Breast Cancer Patients Aged ≤40 Years: Case Analysis Study.

BACKGROUND: Young breast cancer patients are more likely to develop aggressive tumor characteristics and a worse prognosis than older women, and different races and ethnicities have distinct epidemiologies and prognoses. However, few studies have evaluated the clinical biological features and relapse patterns in different age strata of young women in Asia. OBJECTIVE: We aimed to explore survival differences and the hazard function in young Chinese patients with breast cancer (BC) by age. METHODS: The patients were enrolled from West China Hospital, Sichuan University. The chi-squared test, a Kaplan-Meier analysis, a log-rank test, a Cox multivariate hazards regression model, and a hazard function were applied for data analysis. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), breast cancer-specific survival (BCSS), and overall survival (OS) were defined as end points. RESULTS: We included 1928 young BC patients diagnosed between 2008 and 2019. Patients aged 18 to 25, 26 to 30, 31 to 35, and 36 to 40 years accounted for 2.7% (n=53), 11.8% (n=228), 27.7% (n=535), and 57.7% (n=1112) of the patients, respectively. The diagnosis of young BC significantly increased from 2008 to 2019. Five-year LRFS, DMFS, BCSS, and OS for the entire population were 98.3%, 93.4%, 94.4%, and 94%, respectively. Patients aged 18 to 25 years had significantly poorer 5-year LRFS (P<.001), 5-year DMFS (P<.001), 5-year BCSS (P=.04), and 5-year OS (P=.04) than those aged 31 to 35, 26 to 30, and 36 to 40 years. The hazard curves for recurrence and metastasis for the whole cohort continuously increased over the years, while the BC mortality risk peaked at 2 to 3 years and then slowly decreased. When stratified by age, the annualized hazard function for recurrence, metastasis, and BC mortality in different age strata showed significantly different trends, especially for BC mortality. CONCLUSIONS: The annual diagnosis of young BC seemed to increase in Chinese patients, and the distinct age strata of young BC patients did not differ in survival outcome or failure pattern. Our results might provide strategies for personalized management of young BC.

Transcriptomic Analysis of lncRNAs and their mRNA Networks in Cerebral Ischemia in Young and Aged Mice.

BACKGROUND: Ischemic stroke comprises 75% of all strokes and it is associated with a great frailty and casualty rate. Certain data suggest multiple long non-coding Ribonucleic Acids (lncRNAs) assist the transcriptional, post-transcriptional, and epi-genetic regulation of genes expressed in the CNS (Central Nervous System). However, these studies generally focus on differences in the expression patterns of lncRNAs and Messenger Ribonucleic Acids (mRNAs) in tissue samples before and after cere-bral ischemic injury, ignoring the effects of age. METHODS: In this study, differentially expressed lncRNA analysis was performed based on RNA-seq data from the transcriptomic analysis of murine brain microglia related to cerebral ischemia injury in mice at different ages (10 weeks and 18 months). RESULTS: The results showed that the number of downregulate differentially ex-pressed genes (DEGs) in aged mice was 37 less than in young mice. Among them, lncRNA Gm-15987, RP24-80F7.5, XLOC_379730, XLOC_379726 were significant-ly down-regulated. Then, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these specific lncRNAs were mainly related to inflammation. Based on the lncRNA/mRNA co-expression network, the mRNA co-expressed with lncRNA was mainly enriched in pathways, such as im-mune system progression, immune response, cell adhesion, B cell activation, and T cell differentiation. Our results indicate that the downregulation of lncRNA, such as Gm-15987, RP24-80F7.5, XLOC_379730, and XLOC_379726 in aged mice may attenuate microglial-induced inflammation via the progress of immune system progression im-mune response, cell adhesion, B cell activation, and T cell differentiation. CONCLUSION: The reported lncRNAs and their target mRNA during this pathology have potentially key regulatory functions in the cerebral ischemia in aged mice while being important for diagnosing and treating cerebral ischemia in the elderly.

Polyamines inhibit abscisic acid-induced stomatal closure by scavenging hydrogen peroxide.

Stomatal closure is regulated by plant hormones and some small molecules to reduce water loss under stress conditions. Both abscisic acid (ABA) and polyamines alone induce stomatal closure; however, whether the physiological functions of ABA and polyamines are synergistic or antagonistic with respect to inducing stomatal closure is still unknown. Here, stomatal movement in response to ABA and/or polyamines was tested in Vicia faba and Arabidopsis thaliana, and the change in the signaling components under stomatal closure was analyzed. We found that both polyamines and ABA could induce stomatal closure through similar signaling components, including the synthesis of hydrogen peroxide (H2 O2 ) and nitric oxide (NO) and the accumulation of Ca2+ . However, polyamines partially inhibited ABA-induced stomatal closure both in epidermal peels and in planta by activating antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), to eliminate the ABA-induced increase in H2 O2 . These results strongly indicate that polyamines inhibit abscisic acid-induced stomatal closure, suggesting that polyamines could be used as potential plant growth regulators to increase photosynthesis under mild drought stress.

Development of a Nomogram That Predicts the Risk of Coronary Heart Disease in Patients With Hyperlipidemia.

BACKGROUND: Hyperlipidemia is one of the independent risk factors for the onset of coronary heart disease (CHD), and our aim is to construct a coronary risk prediction model for patients with hyperlipidemia based on carotid ultrasound in combination with other risk factors. METHODS: The nomogram risk prediction model is based on a retrospective study on 820 patients with hyperlipidemia. The predictive accuracy and discriminative ability of the nomogram were determined by receiver operating characteristic (ROC) curves and calibration curves. The results were validated using bootstrap resampling and a prospective study on 39 patients with hyperlipidemia accepted at consenting institutions from 2021 to 2022. RESULT: In the modeling cohort, 820 patients were included. A total of 33 variables were included in univariate logistic regression. On multivariate analysis of the modeling cohort, independent factors for survival were sex, age, hypertension, plaque score, LVEF, PLT, and HbAlc, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The area under the curve (AUC) of the nomogram model was 0.881 (95% CI 0.858∼0.905), with a sensitivity of 79% and a specificity of 81.7%. In the validation cohort, the AUC was 0.75, 95% CI (0.602∼0.906). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of this model were 54.16%, 80%, 81.25%, 52.17% and 64.1%. This model showed a good fitting and calibration and positive net benefits in decision curve analysis. CONCLUSION: A nomogram model for CHD risk in patients with hyperlipidemia was developed and validated using 7 predictors, which may have potential application value in clinical risk assessment, decision-making, and individualized treatment associated with CHD.

ß2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

Premorbid Use of Beta-Blockers or Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in Patients with Acute Ischemic Stroke.

This study was designed to investigate the impact of the preexisting use of beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) on the cellular immune response in peripheral blood and the clinical outcomes of patients with acute ischemic stroke. We retrospectively collected clinical data from a cohort of 69 patients with premorbid beta-blockers and 56 patients with premorbid ACEIs/ARBs. Additionally, we selected a cohort of 107 patients with acute ischemic stroke to be the control of the same age and sex. We analyzed cellular immune parameters in peripheral blood 1 day after the appearance of symptoms, including the frequencies of circulating white blood cell subpopulations, the neutrophil-to-lymphocyte ratio (NLR), and the lymphocyte-to-monocyte ratio (LMR). We found that the count of lymphocytes and the lymphocyte-to-monocyte ratio were significantly higher in the peripheral blood of patients treated with beta-blockers before stroke than in matched controls. However, the premorbid use of ACEIs/ARBs did not considerably impact the circulating immune parameters listed above in patients with acute ischemic stroke. Furthermore, we found that premorbid use of beta-blockers or ACEIs/ARBs did not significantly change functional outcomes in patients 3 months after the onset of stroke. These results suggest that premorbid use of beta-blockers, but not ACEIs/ARBs, reversed lymphopenia associated with acute ischemic stroke. As cellular immune changes in peripheral blood could be an independent predictor of stroke prognosis, more large-scale studies are warranted to further verify the impact of premorbid use of beta-blockers or ACEIs/ARBs on the prognosis of patients with ischemic stroke. Our research is beneficial to understanding the mechanism of the systemic immune response induced by stroke and has the potential for a therapeutic strategy in stroke interventions and treatment.

The prognostic differences and the effect of postmastectomy radiotherapy between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer.

BACKGROUND: The prognosis and the value of postmastectomy radiotherapy (PMRT) between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer (BC) remain controversial. We aimed to evaluate the prognostic differences and the effect of PMRT between the two patient subsets. METHODS: Patients diagnosed with pT1-2N1M0 BC were identified between 2010 and 2018. The study endpoints were overall survival (OS), breast cancer-specific survival (BCSS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). The chi-square test, Kaplan-Meier method and Cox regression analysis were used for data analysis. RESULTS: Total number of 2103 pT1-2N1M0 BC patients were included in the study, including 270 post-chemotherapy (97 without PMRT, 173 with PMRT) and 1833 de novo cases (993 without PMRT, 840 with PMRT). No significant differences were found between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients in 5-year OS (p = 0.068), BCSS (p = 0.054), LRFS (p = 0.241), DMFS (p = 0.104) or DFS (p = 0.08). PMRT did not improve any survival outcome in patients receiving neoadjuvant chemotherapy; however, the PMRT group had a better 5-year BCSS (97.0% vs. 95.8%, p = 0.033) in de novo pT1-2N1 BC. Cox multivariate analysis demonstrated that PMRT was a significant independent predictor of BCSS (HR 0.628; 95% CI, 0.403-0.978; p = 0.04) in de novo pT1-2N1 patients. CONCLUSIONS: There seemed no survival difference in post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients with contemporary systemic therapy. In addition, PMRT might be exempted in patients with post-chemotherapy ypT1-2ypN1 BC, while not in patients with de novo pT1-2N1 BC.

Different software processing affects the peak picking and metabolic pathway recognition of metabolomics data.

In untargeted liquid chromatography‒mass spectrometry (LC‒MS) metabolomics studies, data preprocessing and metabolic pathway recognition are crucial for screening important pathways that are disturbed by diseases or restored by drugs. Here, we collected high-resolution mass spectrometry data of serum samples from 221 coronary heart disease (CHD) patients under two different chromatographic columns (BEH amide and C18 column) and evaluated the three commonly used software programs (XCMS, Progenesis QI, MarkerView) from four aspects (including signal drift, peak number, metabolite annotation and metabolic pathway enrichment). The results showed that the data preprocessed by the three software programs have different degrees of signal drift, but the StatTarget could improve the data quality to meet the data analysis requirement after correction. In addition, XCMS surpassed other software in detection of real chromatographic peaks and Progenesis QI was the best performer in terms of the number of metabolite annotation. XCMS and Progenesis QI showed different performance in pathway enrichment. However, metabolic pathways based on the combination of XCMS and Progenesis QI had a high coincidence with Progenesis QI. In addition, we also reported that C18 and amide columns were highly complementary and have great potential for cooperation in the context of metabolic pathways. In this study, the effects of different chromatographic columns and software pretreatments on metabolomics data were evaluated based on clinical large cohort samples, which will provide a reference for the metabolomics of clinical samples and guide subsequent mechanistic research.

Effects of Buyang Huanwu Decoction on Intestinal Barrier, Intestinal Flora, and Trimethylamine Oxide in Rats with Heart Failure.

OBJECTIVE: To explore the mechanisms of Buyang Huanwu Decoction (BYHWD) modulating the gut microbiome and trimethylamine oxide (TAMO) to exert cardioprotective effects. METHODS: Ligation of the left anterior descending coronary artery was performed in rats to induce heart failure (HF). Except for the sham-operation group (n=10), 36 operation-induced models were randomized into 3 groups using a random number table (n=12 in each group): the model group, the BYHWD group (15.02 g/kg BYHWD), and the positive group (4.99 g/kg metoprolol succinate). After 4-week treatment (once daily by gavage), echocardiography was applied to evaluate the cardiac function and the Tei index (the ratio of ventricular isovolumic contraction time (IVCT) and isovolumic diastolic time (IVRT) to ejection time (ET)) was calculated; hematoxylin-eosin (HE) staining was observed to characterize the pathology of the myocardium and small intestinal villi. D-lactic acid was detected by an enzyme-linked immunosorbent assay (ELISA). Expressions of occludin, claudin-1, and zonula occludens (ZO-1) were detected by Western blot. 16S ribosomal ribonucleic acid (16S rRNA) sequencing was used to explore the changes in the intestinal flora. TMAO was detected via liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In the echocardiography, the Tei index was considerably lower in the positive and BYHWD groups compared with the model group (P<0.05). Besides, BYHWD improved the pathology of myocardium and small intestine of HF rats and lowered the D-lactic acid content in the serum, when compared with the model group (P<0.05). BYHWD also improved the expression of occludin and claudin-1 (P<0.05); in the gut microbiota analysis, BYHWD slowed down modifications in the structure distribution of gut microbiota and regulated the diversity of intestinal flora in HF rats. The content of TMAO in the serum was significantly lowered by BYWHT compared with the model group (P<0.05). CONCLUSION: BYHWD may delay progression of HF by enhancing the intestinal barrier structure, and regulating intestinal flora and TAMO.

Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation.

Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post-translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro-environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl-vWA domain-carrying proteins including integrin ß3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll-like receptor (TLR) family member TLR4 or TLR2 activation. TLR-activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)-mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3-K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle-like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.