Immunotherapy has become a pivotal modality in clinical cancer treatment. However, its effectiveness is limited to a small subset of patients due to the low antigenicity, impaired innate response, and various adaptive immune resistance mechanisms of the tumor microenvironment (TME). Accumulating evidence reveals the critical roles of metal elements in shaping immunity against tumor progression and metastasis. The marriage of metalloimmunotherapy and nanotechnology further presents new opportunities to optimize the physicochemical and pharmacokinetic properties of metal ions in a precise spatiotemporal control manner. Several metallodrugs have demonstrated encouraging immunotherapeutic potential in preliminary studies and are currently undergoing clinical trials at different stages, yet challenges persist in scaling up production and addressing long-term biosafety concerns. This review delineates how metal materials modulate biological activities across diverse cell types to orchestrate antitumor immunity. Moreover, it summarizes recent progress in smart drug delivery-release systems integrating metal elements, either as cargo or vehicles, to enhance antitumor immune responses. Finally, the review introduces current clinical applications of nanomedicines in metalloimmunotherapy and discusses potential challenges that impede its widespread translation into clinical practice.

Mice ; Animals ; Spiral Ganglion/physiology* ; Cochlea/physiology* ; Neurons

The cochlear auditory epithelium contains two types of sound receptors, inner hair cells (IHCs) and outer hair cells (OHCs). Mouse models for labelling juvenile and adult IHCs or OHCs exist; however, labelling for embryonic and perinatal IHCs or OHCs are lacking. Here, we generated a new knock-in Fgf8^P2A-3×GFP/+ (Fgf8^GFP/+) strain, in which the expression of a series of three GFP fragments is controlled by endogenous Fgf8 cis-regulatory elements. After confirming that GFP expression accurately reflects the expression of Fgf8, we successfully obtained both embryonic and neonatal IHCs with high purity, highlighting the power of Fgf8^GFP/+. Furthermore, our fate-mapping analysis revealed, unexpectedly, that IHCs are also derived from inner ear progenitors expressing Insm1, which is currently regarded as an OHC marker. Thus, besides serving as a highly favorable tool for sorting early IHCs, Fgf8^GFP/+ will facilitate the isolation of pure early OHCs by excluding IHCs from the entire hair cell pool.
Animals ; Mice ; Hair Cells, Auditory, Inner ; Cochlea/metabolism* ; Hair Cells, Auditory, Outer/metabolism* ; Disease Models, Animal ; Fibroblast Growth Factor 8/metabolism*

Circadian Clocks ; ARNTL Transcription Factors

Objective:To analyze the correlation and diagnostic value of serum homocysteine (Hcy), methionine (Met) and cysteine (Cys) in patients with chronic heart failure (CHF).Methods:One hundred and seventy-eight patients with acute decompensation CHF (CHF group) and 70 healthy persons (healthy control group) from October 2018 to September 2019 in Affiliated Zhongshan Hospital of Dalian University were continuously enrolled. In CHF group, heart failure with reduced ejection fraction (HFrEF) was in 53 cases, heart failure with mid-range ejection fraction (HFmrEF) was in 50 cases, and heart failure with preserved ejection fraction (HFpEF) was in 75 cases. Serum levels of Hcy, Met and Cys were detected by tandem mass spectrometry. Serum level of N-terminal brain natriuretic peptide precursor (NT-proBNP) was detected by electrochemical luminescence immunity. The left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVESd) and early diastolic peak blood flow velocity of mitral valve annulus/early diastolic peak velocity of mitral annulus (E/e′) were detected by echocardiography, then left ventricular eject fraction (LVEF) was calculated. Correlation was analyzed by Pearson correlation analysis. The receiver operator characteristic (ROC) curve was drawn, and the area under curve (AUC) was used to evaluate the efficacy of serum Hcy, Met, Cys, NT-proBNP and LVEF in the diagnosis of CHF.Results:The Hcy, Met, Cys, NT-proBNP, LVEDd and E/e′ in CHF group were significantly higher than those in healthy control group: (12.64 ± 5.02) μmol/L vs. (8.71 ± 3.47) μmol/L, (23.38 ± 5.75) μmol/L vs. (20.52 ± 4.18) μmol/L, (343.45 ± 44.49) μmol/L vs. (290.53 ± 48.38) μmol/L, (5 759.43 ± 3 806.22) pg/L vs. (40.24 ± 31.91) pg/L, (52.67 ± 12.27) mm vs. (46.41 ± 12.27) mm and (17.32 ± 5.61)% vs. (9.54 ± 2.64)%, the LVEF was significantly lower than that in healthy control group: (45.27 ± 4.93)% vs. (62.37 ± 5.41)%, and there were statistical differences ( P<0.01 or <0.05). The Hcy and Cys in patients with HFmrEF and HFrEF were significantly higher than those in patients with HFpEF: (16.29 ± 8.18) and (18.68 ± 8.99) μmol/L vs. (13.75 ± 6.48) μmol/L, (346.64 ± 51.85) and (361.40 ± 52.34) μmol/L vs. (329.35 ± 55.16) μmol/L, and there were statistical differences ( P<0.05); there were no statistical differences between patients with HFmrEF and patients with HFrEF ( P>0.05). The serum Met in patients with HFrEF was significantly higher than that in patients with HFpEF and HFmrEF: (28.74 ± 8.22) μmol/L vs. (24.76 ± 7.60) and (25.15 ± 6.96) μmol/L, and there was statistical difference ( P<0.05); there was no statistical difference between patients with HFpEF and patients with HFmrEF ( P>0.05). Pearson correlation analysis result showed that serum Hcy, Met and Cys were positively correlated with NT-proBNP ( r = 0.632, 0.206 and 0.455; P<0.01), positively correlated with E/e′( r = 0.463, 0.198 and 0.346; P<0.01), and negatively correlated with LVEF ( r = -0.491, -0.152 and -0.330; P<0.05 or <0.01). ROC curve analysis result showed that ROC the cut-off value for the diagnosis of CHF with serum NT-proBNP based on the maximum Youden index (0.994) was 120 pg/L, and AUC was 0.994 (95% CI was 0.997 to 1.000); the cut-off value for the diagnosis of CHF with serum Hcy based on the maximum Youden index (0.646) was 10.56 μmol/L, and AUC was 0.899 (95% CI 0.859 to 0.939); the cut-off value for the diagnosis of CHF with serum Met based on the maximum Youden index (0.218) was 25.58 μmol/L, and AUC was 0.637 (95% CI 0.563 to 0.711); the cut-off value for the diagnosis of CHF with serum Cys based on the maximum Youden index (0.391) was 298.05 μmol/L, and AUC was 0.765 (95% CI 0.700 to 0.830); the AUC of LVEF less than 0.5. Conclusions:Serum Hcy, Met and Cys levels in patient with CHF are significantly increased, which are positively correlated with NT-proBNP and E/e′, negatively correlated with LVEF. Moreover, serum Hcy has certain application value in the diagnosis of CHF.

Objective:A comparative study of non-invasive hemodynamics and echocardiography in 139 cases of heart failure patients with preserved ejection fraction (HFpEF) at baseline and one year follow-up to explore its value on diagnosis, monitoring and prognosis in patients with HFpEF.Methods:The baseline and one year follow-up data of 139 patients with HFpEF in Affiliated Zhongshan Hospital of Dalian University patients who had been enrolled in the China PEACE 5P-HF from June 2016 to May 2018 were analyzed retrospectively. The general data were collected which contented age of the study subjects is (30 - 80) y, average age (64.0 ± 12.3) y, and 63.31% male, (88/139) and 36.69% female (51/139), 56.8% smokers (79/139). t-test way was used to analyze the baseline and one year follw-up data, The indexs included blood pressure (BP), estimated glomerular filtration rate (eGFR) and 6-munites walk test (6MWT). Non-invasive hemodynamic indicators included stroke volume (SV), ejection fractions (EF), cardiac index (CI), index of contratility (IC), pulmonary artery wedge pressure (PCWP), maximum angiectatic velocity(AMPC), left ventricular ejection time (LVET), left ventricular isovolumetric relaxation time (LVLVIVRT), pre-ejection period/left ventricular ejection fractions (PEP/LVET), left ventricular end diastolic pressure (LVEDP) and left cardiac work index (LCWI). Hemodynamic indicators included left ventricular end diastolic dimension(LVEDd), left ventricular end systolic dimension (LVEDs), interventricular septal thickness at diastole (IVSD), left ventricular ejection fractions (LVEF) and E/e′.Results:There was no significant difference between the baseline and one year follow-up data in SBP, DBP, NT-proBNP, eGFR, 6MWT ( P>0.05). There were significant increase in SV, EF, CI, IC in one year′ follow-up compared with that in baselinee [(73.39 ± 29.47) ml vs. (63.39 ± 30.08) ml, (64.87 ± 9.16)% vs. (61.81 ± 9.02)%, (3.06 ± 1.10) ml/(min·m 2) vs. (2.62 ± 1.06) ml/(min·m 2), (0.039 ± 0.037) L/s vs. (0.028 ± 0.015) L/s] ( P<0.05). PCWP in one year′ follow-up was significantly decreased compared with that in baselin [(9.21 ± 3.34) mmHg (1 mmHg = 0.133 kPa) vs. (9.87 ± 3.13) mmHg]( P<0.05), However, AMPC, LVE, LVLVIVRT, PEP/LVET, LVEDP, LCWI in baseline and one year′ follow-up showed no significant difference ( P>0.05). The Hemodynamic indicators in baseline and one year′s follow-up were as followed: LVEF in one year′ follow-up was significantly elevated compared with that in the baseline [(63.53 ± 8.39)% vs. (61.02 ± 7.16)%]; E/e′ in one year′s follow-up was significantly decresed compared with that in the baseline [12.89 ± 5.86 vs. 14.32 ± 6.61]( P<0.05); there were no significant differences in LVEDd, LVEDs and IVSD in baseline compared with those in one year′s followed-up ( P>0.05). Conclusions:Hemodynamic indicators including SV, EF, CI, IC and PCWP could be new reflections of early diagnosis, monitoring and prognosis on HFpEF. The combination of non-invasive hemodynamics and echocardiography on HFpEF can be more significant in reflecting the changes of myocardial remodeling and cardiac function.

The mechanism of biological actions of quercetin was studied by using metabolomic method and biomolecular network. HPLC-MS was used to analyze the serum metabolome in rats of blank group and quercetin administration group rats, and MS data were processed by MATLAB software. With multivariate statistical analysis of serum metabolite profiles, a clear separation among blank group and quercetin administration group was achieved, potential biomarkers were selected according to the parameters of variable importance in the projection (VIP) and identified according to MS information and database retrieval. Four compounds, related enzymes, action targets and metabolic pathways had been confirmed, namely retinoic acid and RARbeta, arachidonate and COX-2, 3, 5-diodotyrosine and TPO, uridine diphosphate glucose and PDEs. The mechanism of quercetin enhancing ability of retinoic acid on the induction of RARbeta, activating TPO, using as COX-2 and PDEs inhibitor was approved by biomolecular network and related literatures. In this study, a mechanism of multiple biological actions of quercetin was evaluated at the level of the biomolecular network, metabolomics and biomolecular network can be used to investigate the biological effects mechanism of quercetin, which provided a new method to further revealing mechanism of drug action.