Army Medical University

Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer and lacks effective targeted therapeutic drugs, resulting in a high recurrence rate and worse outcome. In this study, bioinformatic analysis and a series of experiments demonstrated that MOCR2 was highly expressed in TNBC and closely associated with poor prognosis, indicating that MOCR2 may be a potential therapeutic target for TNBC. Subsequently, Angoline was identified as an inhibitor of MORC2 protein by high-throughput screening and can significantly kill the TNBC cells by blocking cell cycle and inducing apoptosis. Furthermore, the biomimetic nanodrug delivery system (PMD) was designed by encapsulating tetrahedral DNA nanostructures with biomimetic cell membrane, and it can efficiently evade the phagocytosis of immune system and target TNBC tissue. Additionally, PMD can markedly enhance the killing effect of Angoline on TNBC tumors. Therefore, PMD-enveloped Angoline provide a highly effective targeted therapeutic regimen for TNBC and may improve the outcome for patients with TNBC.

BACKGROUND Percutaneous adrenal ablation (PAA) is an effective and safe therapy for treating patients with primary aldosteronism (PA). However, its effectiveness in comparison to that of adrenalectomy (ADX) and mineralocorticoid receptor antagonists (MRAs) remains unclear. METHODS Databases were searched including: Pubmed, Embase, and The Cochrane Library. Studies were included if patients with PA who received two of three different treatments (ADX, MRAs, or PAA) and reported our interested outcomes, including blood pressure, serum potassium and the aldosterone-to-renin ratio (ARR). RESULTS In total of 10,681 patients from forty-seven studies were identified. Both ADX and PAA showed superior clinical success (systolic BP: ADX: -4.69 [-6.4, -2.95], PAA: -3.96 [-9.05, 0.99]; diastolic BP: ADX: -3.14 [-4.55, -1.85], PAA: -2.99 [-6.96, 0.98]) compared with MRAs. According to the Bayesian ranking curves (SUCRA values), ADX ranked first for all outcomes of interest (systolic BP: 81.02%, diastolic BP: 76.95%, serum potassium: 96.55%, and ARR: 88.03%), while PAA ranked second for all outcomes (systolic BP: 65.94%, diastolic BP: 69.66%, serum potassium: 50%, and ARR: 45.14%). CONCLUSIONS The findings of this network meta-analysis suggest that PAA could be an alternative treatment for patients with PA who are unable to opt for surgery or MRA therapy, and its clinical and biochemical success fall between those of ADX and MRAs.

Background This study aimed to investigate the relationship between the dietary intake of total flavonoids and their six subclasses and the risk of atherosclerotic cardiovascular disease (ASCVD) in adults, and to evaluate the potential mediating effect of inflammation in this association. Methods Cross-sectional data from 3841 individuals participating in the National Health and Nutrition Examination Survey 2017–2018 were included in the analysis. Flavonoid intake was assessed using a 2-day dietary recall method, and ASCVD status was determined by extracting relevant information from the medical condition questionnaire. To determine the relationship between flavonoid intake and ASCVD risk, we employed logistic regression, subgroup, mediation, and restricted cubic spline analyses. Results Intake of flavan-3-ols, flavones, flavonols, and total flavonoids was negatively correlated with ASCVD risk. Subgroup analysis revealed that the association between flavonoid intake and ASCVD risk exhibits sex-specific differences, with the relationship being more pronounced among women. The significant associations between increased flavonoid intake and reduced ASCVD risk were observed in smokers, non-alcohol consumers, physically inactive individuals, those with hypertension. A nonlinear relationship was observed between the intake of total flavonoids, flavan-3-ols and flavonols and ASCVD risk. Additionally, high-sensitivity C-reactive protein (hs-CRP) and the neutrophil-to-lymphocyte ratio (NLR), inflammatory markers relevant to ASCVD, were found to mediate the association between flavonoid intake and ASCVD risk. Flavonoids demonstrated a dose‒response relationship with reductions in the levels of hs-CRP and the NLR. Conclusions This study indicates the inverse association between flavonoid intake, particularly flavan-3-ols, flavones, and flavonols, and the risk of ASCVD. It highlights the mediating role of CRP and NLR in this relationship. Furthermore, the study emphasizes the importance of considering lifestyle factors and sex when evaluating the cardiovascular benefits of flavonoids.

The transdifferentiation from adenocarcinoma to neuroendocrine prostate cancer (NEPC) in men confers antiandrogen therapy resistance. Here our analysis combining CRISPR‒Cas9 screening with single-cell RNA sequencing tracking of tumor transition demonstrated that antiandrogen-induced zinc finger MYND-type containing 8 (ZMYND8)-dependent epigenetic programming orchestrates NEPC transdifferentiation. Ablation of Zmynd8 prevents NEPC development, while ZMYND8 upregulation mediated by achaete-scute homolog 1 promotes NEPC differentiation. We show that forkhead box protein M1 (FOXM1) stabilizes ZMYND8 binding to chromatin regions characterized by H3K4me1–H3K14ac modification and FOXM1 targeting. Antiandrogen therapy releases the SWI/SNF chromatin remodeling complex from the androgen receptor, facilitating its interaction with ZMYND8–FOXM1 to upregulate critical neuroendocrine lineage regulators. We develop iZMYND8-34, a small molecule designed to inhibit ZMYND8’s histone recognition, which effectively blocks NEPC development. These findings reveal the critical role of ZMYND8-dependent epigenetic programming induced by androgen deprivation therapy in orchestrating lineage fate. Targeting ZMYND8 emerges as a promising strategy for impeding NEPC development.

ESIPT‐based fluorochromes are promising materials for the detection of various chemical/biological species, especially the metal cations. Herein, we elaborately designed a prototypical ESIPT‐active ɑ‐naphtholphthalein‐ derived “turn‐on” fluorogenic tweezer NPDM for selectively detecting and visualizing Al3+ in biological and environmental samples. NPDM was found to specifically interact with Al3+ with dual emissions, good sensitivity (50 s), large Stokes shifts (140 nm/176 nm) and low detection limit (16.3 nM). Noteworthily, the sensing mechanism of NPDM towards Al3+ has been supported by Job’s plot, HRMS, 1H NMR titrations, as well as detailed DFT calculations. Interestingly, the NPDM‐Al3+ ensemble can act as a secondary chromo‐fluorogenic tweezers for monitoring F‐ with a low detection limit down to 34.8 nM level. Thus, an advanced molecular memory device was constructed based on the fluorescence ‘‘off‐on‐off” strategy and its excellent sensing properties. Moreover, a portable smartphone‐aided intelligent platform was fabricated to realize the portable detection of Al3+ in real samples. Significantly, NPDM was successfully employed for imaging the intracellular Al3+ and F‐ ions in Hela cells without interference from the oxidative stress and it is the first reported smart molecular tweezers capable of determining the Al3+ ions formed during electroporation inside living cells.

Recent advancements in multi-agent reinforcement learning (MARL) have shown significant progress in the field of autonomous driving. However, the key issue of guaranteeing safe decision-making and control of autonomous vehicles in complex and dynamic traffic environments, while avoiding collisions, remains a critical challenge. To further enhance the safety and reliability of autonomous driving systems, this paper presents a novel MARL approach called Priority Sequential Inference Proximal Policy Optimization (PSIPPO) to enhance the decision-making capabilities and safety of autonomous vehicles in mixed traffic highway environments. The proposed method introduces a sequential decision-making framework that enables autonomous vehicles to make informed decisions based on the actions and states of preceding agents, effectively managing the order of decisions and prioritizing critical ones. Moreover, PSIPPO incorporates a future reasoning mechanism, allowing autonomous vehicles to predict and respond to potential collision risks by simulating road scenarios several time steps ahead. An adaptive risk avoidance strategy is also introduced to assess the appropriateness and safety of lane changes, considering factors such as inter-vehicle distance, relative velocity, and acceleration. Extensive experiments conducted in various highway driving scenarios demonstrate the superior performance of PSIPPO compared to several mainstream baseline MARL methods, achieving higher rewards, maintaining higher average speeds, and significantly reducing collision rates, especially in complex traffic conditions.

Although endovascular treatment (EVT) was the first-line therapeutic strategy for acute ischemic stroke (AIS), half of the patients could not achieve functional independence. Previous studies suggested arterial collateral was an important predictor of this phenomenon. However, cerebral collateral circulation was regulated by arteries, venous, and microcirculation, and its role remained unclear. Therefore, based on the integrated cerebral collateral cascade (CCC) system, this study aimed to explore the relationship and potential mechanisms between CCC and futile recanalization. This was a multicenter retrospective study for AIS patients receiving EVT. The CCC model was used to comprehensively assess the collateral circulation, which consisted of arterial collaterals, venous outflow, and tissue-level collaterals. Imaging outcomes included ischemic core, hypoperfusion volume, and penumbra volume. The clinical outcome was futile recanalization, defined as a 90-day modified Rankin Scale (mRS) 3–6 after successful recanalization. Multivariate regression and mediation analyses were used to assess the relationship between CCC, futile recanalization, and potential mediators. Among 513 patients with successful recanalization, 50.6% (260) experienced futile recanalization. In the multivariable regression analysis, favorable CCC (aOR 0.48, 95% CI 0.31–0.75; P = 0.001) was independently associated with unfavorable outcome despite successful recanalization. Furthermore, mediation analysis revealed that favorable CCC significantly reduced the ischemic core accounting for 27.62% (95% CI 9.69–66.00%) of its beneficial effect on futile recanalization. The benefit of favorable CCC on futile recanalization may be mediated by a reduction in ischemic core volume in AIS patients undergoing EVT. Our findings deepen the understanding of futile recanalization and microcirculation.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by a high rate of postoperative recurrence and poor long-term survival outcomes. Structural maintenance of chromosome 4 (SMC4) is frequently overexpressed in various types of cancer and plays a pivotal role in tumor cell growth, migration, and invasion. Bioinformatics analysis has revealed a significant correlation between the tumor-node metastasis (TNM) stage (P < 0.01) and SMC4 expression (P < 0.05), and SMC4 was associated with poor prognosis in HCC. Furthermore, SMC4 was identified as an independent prognostic factor for HCC. Ubiquitin-specific peptidase 39 (USP39) was found whether the regulation was observed to affect protein synthesis or stability through bioinformatics analysis and immunoprecipitation. The expression levels and cellular localization of SMC4 and USP39 in hepatoma cells were evaluated using quantitative real-time PCR (qPCR), western blotting, and immunohistochemistry (IHC), all of which indicated significantly elevated expression of USP39 and SMC4 in HCC. The roles of the SMC4/USP39 were further investigated through several assays, including the 3-(4,5-Dimethylthiazol-2-yl) -2,5- diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, and wound healing assay. The results demonstrated that USP39/SMC4 plays a crucial role in enhancing the viability and proliferation of HepG2 cells. Additionally, bioinformatics analysis identified ZNF207 and TIAL1 as potential target proteins of SMC4. Drug-resistant hepatoma cell lines were established, and both MTT and EdU assays were performed to assess cell viability and proliferation. The results demonstrated that HepG2/5-FU cells regained their sensitivity to 5-FU following the knockdown of SMC4. Additionally, the knockdown of either TIAL1 or ZNF207 also restored 5-FU sensitivity in HepG2/5-FU cells, effectively inhibiting cell viability and proliferation. Our study underscores the significant role of the USP39/SMC4 in HCC development and suggests that SMC4 may contribute to the regulation of drug resistance in hepatoma cell lines, potentially through interactions with TIAL1 and ZNF207.

Hematologic malignancy stands as a grave form of cancer characterized by its arduous treatment and heightened likelihood of recurrence. Over the recent years, immunotherapy has progressively evolved into a pivotal approach for addressing hematologic malignancies. As a novel inhibitory receptor of NK and T cells, TIGIT is similar to PD-1, and blocking TIGIT can play a huge anti-tumor effect. At present, target TIGIT is still in clinical trials. Within this context, the TIGIT/PVR axis, serving as a pivotal element within the immunomodulatory framework, assumes a critical role in tumor immunity orchestration. This composition delves into the advancement of research concerning the TIGIT/PVR axis within hematologic malignancies, elucidating its mechanism for impeding anti-tumor immune responses. Furthermore, potential therapeutic avenues are explored, encompassing immunotherapeutic strategies aimed at targeting the TIGIT/PVR axis, alongside the conceivable integration with alternative immune checkpoint inhibitors. Ultimately, the paper encapsulates forthcoming research trajectories, aspiring to provide a compass for deeper comprehension of the TIGIT/PVR axis’s role within hematologic malignancies, consequently fostering the creation of more potent immunotherapeutic tactics. This review details the therapeutic prospects of TIGIT in hematological malignancies, which is expected to advance research targeting TIGIT in hematological malignancies and bring hope for survival to these patients.

The precise molecular mechanisms through which neutrophils regulate macrophages in the progression and resolution of acute inflammation remain poorly understood. Here, we present new findings on the role of Dicer in regulating macrophage phenotypic transitions essential for proper inflammatory progression and resolution, influenced by neutrophils. Using a zymosan A (Zym A)-induced self-limited mouse peritonitis model, we observed that Dicer expression in macrophages was significantly reduced by neutrophil-derived IFN-γ during the progression phase, but gradually returned to normal levels during the resolution phase following the engulfment of apoptotic neutrophils. Our study on macrophage-specific Dicer1-depletion (Dicer1-CKO) mice demonstrated that inflammation in these mice was more severe during the progression phase, characterized by increased pro-inflammatory cytokines and enhanced neutrophil trafficking. Additionally, resolution was impaired in Dicer1-CKO mice, leading to the accumulation of uncleared apoptotic neutrophils. Specifically, the absence of Dicer in macrophages resulted in M1 polarization and heightened bactericidal activity, facilitating the progression of acute inflammation. Conversely, inducing Dicer expression promoted macrophage transition to M2 polarization, enhancing apoptotic cell clearance and expediting the resolution of inflammation. Our findings suggest that Dicer plays a central role in regulating the progression and resolution of acute inflammation, with implications for the treatment of inflammatory diseases.

Insulin resistance is a common metabolic disease, and its pathogenesis is still unclear. The decrease of glucagon‐like peptide‐1 (GLP‐1) level mediated by the alteration of gut microbiota may be the pathogenesis. The study was to investigate the regulatory effect of dihydromyricetin (DHM) on GLP‐1 level and insulin resistance induced by high‐fat diet (HFD), and to further explore its possible molecular mechanism. Mice were fed an HFD to establish the model of insulin resistance to determine whether DHM had a protective effect. DHM could improve insulin resistance. DHM increased serum GLP‐1 by improving intestinal GLP‐1 secretion and inhibiting GLP‐1 decomposition, associated with the alteration of intestinal intraepithelial lymphocytes (IELs) proportions and decreased expression of CD26 in IELs and TCRαβ ⁺ CD8αβ ⁺ IELs in HFD‐induced mice. DHM could ameliorate GLP‐1 level and insulin resistance by modulation of gut microbiota and the metabolites, particularly the regulation of chenodeoxycholic acid (CDCA) content, followed by the inhibition of farnesoid X receptor (FXR) expression in intestinal L cells and increased glucagon gene (Gcg) mRNA expression and GLP‐1 secretion. This research demonstrates the role of “gut microbiota‐CDCA” pathway in the improvement of intestinal GLP‐1 levels in HFD‐induced mice by DHM administration, providing a new target for the prevention of insulin resistance.

Objectives This study aimed to explore the mechanisms through which trait mindfulness affects the sleep quality of Chinese People's Armed Police (PAP) in plateau regions, as well as the temporal trends involved, to provide theoretical support for subsequent psychological interventions. Method A questionnaire survey was conducted on male PAP personnel stationed in a certain plateau region of China, using the Mindful Attention Awareness Scale (MAAS), Rumination Response Scale (RRS), Attention to Negative Information Scale (ANI), and Pittsburgh Sleep Quality Index (PSQI). In both a cross-sectional study (Study 1) and a longitudinal study (Study 2), chain mediation models and cross-lagged models were respectively constructed to investigate the impact mechanisms of trait mindfulness on the sleep quality of plateau-based armed police officers and soldiers. Results The results of the cross-sectional study (Study 1) showed significant correlations between mindfulness and rumination, negative attentional bias and sleep quality. Mindfulness had a direct impact on the sleep quality of PAP personnel. rumination and negative attentional bias partially mediated and sequentially mediated the relationship between mindfulness and sleep quality. The results of the longitudinal study (Study 2) indicated that mindfulness at Time 1 (T1) significantly predicted sleep quality at Time 2 (T2), and sleep quality at T2 significantly predicted T3 mindfulness at Time 3 (T3). Mindfulness at T1 could predict sleep quality at T3 through the longitudinal mediation of rumination and negative attentional bias at T2. However, sleep quality at T1 could not predict mindfulness at T3 through the longitudinal mediation of rumination and negative attentional bias at T2. Conclusions Among the population of PAP personnel, there was a bidirectional predictive relationship between trait mindfulness and sleep quality, and trait mindfulness influenced sleep quality through the mediation of rumination and negative attentional bias over time. Negative cognitive patterns had proven to be key factors affecting sleep quality, and implementing mindfulness interventions focused on improving individual negative cognitive patterns, can effectively enhance their sleep quality. Preregistration This study is not preregistered.

Mantle cell lymphoma (MCL) exhibits significant biological and clinical heterogeneity, necessitating a refined prognostic model. According to the drawbacks of existing models which do not truly define the complexity of the disease, we used the clinical and molecular data from nine medical centers of China to validate the predictive utility of progression of disease within 24 months (POD24), and also established a novel prognostic risk model to predict the survival outcome of MCL patients. POD24 occurred in 37.7% of evaluable patients, with the median over survival being 21 months (vs. 122 months for those without POD24, P < 0.0001). The POD24-based risk model had the highest sensitivity to predict survival with the most satisfying AUC value for risk score (AUC = 0.869). In conclusion, we confirm the obviously predictive performance of POD24 and established a novel risk model combined POD24 and clinical factors. Our new prognostic model might be helpful in effectively classify MCL patients with high-risk groups in terms of survival rate, which may help in selecting high-risk MCL patients for more intensive treatment at time of relapse.