Hyperthermia combined with immune checkpoint inhibitor therapy in the treatment of primary and metastatic tumors.

According to the difference in temperature, thermotherapy can be divided into thermal ablation and mild hyperthermia. The main advantage of thermal ablation is that it can efficiently target tumors in situ, while mild hyperthermia has a good inhibitory effect on distant metastasis. There are some similarities and differences between the two therapies with respect to inducing anti-tumor immune responses, but neither of them results in sustained systemic immunity. Malignant tumors (such as breast cancer, pancreatic cancer, nasopharyngeal carcinoma, and brain cancer) are recurrent, highly metastatic, and highly invasive even after treatment, hence a single therapy rarely resolves the clinical issues. A more effective and comprehensive treatment strategy using a combination of hyperthermia and immune checkpoint inhibitor (ICI) therapies has gained attention. This paper summarizes the relevant preclinical and clinical studies on hyperthermia combined with ICI therapies and compares the efficacy of two types of hyperthermia combined with ICIs, in order to provide a better treatment for the recurrence and metastasis of clinically malignant tumors.

Luteolin Isolated from Polygonum cuspidatum Is a Potential Compound against Nasopharyngeal Carcinoma.

Introduction: To reveal the mechanisms by which luteolin, the major bioactive component of the Traditional Chinese Medicine (TCM) Polygonum cuspidatum, inhibits proliferation and promotes apoptosis in nasopharyngeal carcinoma (NPC) CNE2 cells. Methods: Based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), bioactive compounds of P. cuspidatum, potential target genes and NPC disease targets of TCMSP were screened, relationship networks were constructed using these potential targets of NPC, and Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The predicted compounds, targets and pathways were corroborated using in vitro experiments, such as MTT, Cytation™ 5 real-time cell monitoring, cell cycle detection, Annexin V-FITC/PI double staining, Hoechst 33342 staining, and mitochondrial membrane potential (ΔΨm) detection. Results: The results showed that 10 bioactive compounds (OB ≥30% and DL ≥0.18), 157 potential target genes from P. cuspidatum, and 56 common targets related to NPC were found. These included important bioactive compounds such as luteolin, quercetin, and beta-sitosterol. Key common targets included EGFR, MYC, AKT1, CASP3, CCND1, ERBB2, and common targets were enriched for the PI3K-AKT, JAK/STAT, MAPK, and C-type lectin receptor signaling pathways. The binding energy of luteolin for six common targets was less than -5.0 kcal·mol-1. After luteolin (20 µM, and 40 µM) treatment to CNE2 cells for 36 h, cell survival rates decreased, accompanied by cell morphology changes, inhibition of the cell cycle at G2/M phase, and an induction of apoptosis. The expression of the cell proliferation related protein PCNA, the antiapoptosis protein XIAP, and the PI3K-AKT pathway diagram related proteins p-ERK1/2, ERK1/2, AKT, and PI3K, all decreased. Conclusion: Luteolin derived from P. cuspidatum inhibited the proliferation of NPC CNE2 cells and promoted cell apoptosis through the PI3K-AKT signal pathway.

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway / Pioglitazona Induz Apoptose e Inibe Hipertrofia de Cardiomiócitos pela Via de Sinalização do VEGFR-2

Abstract Background: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. Objectives: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. Methods: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. Results: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. Conclusions: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

Resumo Fundamento: A pioglitazona tem sido amplamente utilizada como droga sensibilizadora da insulina para melhorar o controle glicêmico em pacientes com diabetes mellitus tipo 2. No entanto, o risco cardiovascular bem como os efeitos protetores da pioglitazona ainda são controversos. Objetivos: Neste estudo, investigamos se os efeitos da pioglitazona sobre a apoptose e a hipertrofia de cardiomiócitos ocorrem via regulação da via de sinalização do VEGFR-2. Métodos: os cardiomiócitos foram isolados enzimaticamente dos ventrículos de ratos Sprague-Dawley de 1-3 anos de vida. Os efeitos da pioglitazona e do inibidor seletivo de VEGFR-2 apatinib sobre a taxa de apoptose dos cardiomiócitos foram avaliados por citometria de fluxo, e a hipertrofia avaliada por incorporação de leucina-[3H]. As expressões de VEGFR-2, Akt, P53, e mTOR fosforiladas e não fosforiladas foram determinadas por Western Blotting. Análise de variância (ANOVA) foi usada para avaliar diferenças entre os grupos. Resultados: a pioglitazona e o apatinib reduziram a viabilidade e a hipertrofia de cardiomiócitos induzida por angiotensina II in vitro. Além disso, no mesmo modelo in vitro, a pioglitazona e o apatinib aumentaram significativamente a expressão de Bax e P53 fosforilada, e diminuiu a expressão de VEGFR-2, Akt, e mTOR, que promove hipertrofia de cardiomiócitos. Conclusões: Esses resultados indicam que a pioglitazona induz a apoptose e inibe a hipertrofia de cardiomiócitos pela modulação da via de sinalização de VEGFR-2.

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway.

BACKGROUND: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. OBJECTIVES: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. METHODS: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. RESULTS: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. CONCLUSIONS: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

Effects of losartan on vasomotor function and canonical transient receptor potential channels in the aortas of sinoaortic denervation rats.

Increased short-term blood pressure variability (BPV) is strongly correlated with target organ damage. However, the molecular mechanisms underlying abnormal BPV-induced organ damage and effective therapeutic targets are poorly understood. The purpose of this study was to investigate the effects of losartan on vasomotor function and canonical transient receptor potential (TRPC) channels in the aortas of rats with arterial pressure lability induced by sinoaortic denervation (SAD). SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. The experiment included sham-operated (Sham), SAD, and losartan-treated SAD (SAD+Los) groups. After 8 weeks of treatment, hemodynamic parameters were measured via catheterization, thoracic aortic vasomotor functions were evaluated using a physiological vascular ring tension recording system, and TRPC1 and 6 mRNA and protein expression levels in the endothelial cells (ECs) and smooth muscle cells (SMCs) of the thoracic aorta were determined via reverse transcription polymerase chain reaction (RT-PCR) and Western-blotting, respectively. Compared with Sham rats, SAD rats exhibited significantly increased BPV, enhanced norepinephrine-induced aortic contraction, and attenuated acetylcholine-induced aortic relaxation. Both the mRNA and the protein expression levels of TRPC1 and 6 were significantly downregulated in the ECs and upregulated in the SMCs of the thoracic aortas of SAD rats. Losartan treatment prevented these SAD-induced changes. In conclusion, losartan efficiently prevented vasomotor function impairment in SAD rats by reducing BPV and regulating TRPC1 and 6 expression levels.

Correlation between ambulatory blood pressure variability and vasodilator function in middle-aged normotensive individuals.

OBJECTIVE: The aim of this study was to investigate the association between ambulatory blood pressure variability and vasodilator function in a cohort of normotensive middle-aged individuals. PARTICIPANTS AND METHODS: This was a cross-sectional study of 285 randomly selected 40-59-year-old normotensive participants who underwent 24-h ambulatory blood pressure monitoring and brachial artery ultrasound assessment. Systolic and diastolic blood pressure variability (BPV) of 24-h, daytime, and night-time were calculated using the coefficients of variation (CV) and the average real variability (ARV) index. Brachial arterial endothelium-dependent vasodilation (EDD) was assessed in response to increased flow and endothelium-independent vasodilation (EID) was assessed in response to nitroglycerin. Relationships were explored using univariate and multivariate linear regression. RESULTS: The EDD were negatively associated with the CV of 24-h systolic blood pressure (SBP), the ARV of 24-h SBP, and diastolic blood pressure (DBP) in univariate analysis. However, the CV and ARV of 24-h SBP remained associated independently with % EDD in multivariate analysis. In addition, the mean levels of 24-h SBP and DBP, the CV of 24-h SBP and DBP, the ARV of 24-h SBP and DBP, the CV of daytime SBP, and the ARV of daytime DBP were all associated with % EID. However, in a multiple linear regression model, adjusting for covariates, only the CV and ARV of 24-h SBP, and the ARV of 24-h DBP were correlated negatively but weakly with % EID. CONCLUSION: Our results indicated that a higher 24-h BPV was associated independently with decreased endothelial-dependent and endothelial-independent vasodilator functions in a middle-aged normotensive population. Although 24-h BPV was associated with vasodilator function, relationships were attenuated after adjusting for covariates.

Ex vivo mono-ring technique simplifies culotte stenting for treatment of true bifurcation lesions: Insights from bench testing and clinical application.

BACKGROUND: Despite various culotte-based stenting techniques available clinically, the optimal one remains undetermined. The study aimed to test whether ex vivo mono-ring culotte stenting (MRC) was technically feasible and superior to mini culotte stenting (MCS) in treatment of coronary bifurcation lesions. METHODS: Mono-ring culotte stenting was characterized by ex vivo wiring of the most proximal cell of the side branch (SB) stent to ensure a mono-ring result of the culotte stenting. Comparison of MRC vs. MCS in treatment of true bifurcation lesions was performed in vitro (n = 15 for each group) and in clinical case-controlled study with propensity matching at a ratio of 1:2 (n = 21 for MRC group; n = 42 for MCS group). RESULTS: Compared to MCS, MRC had lower incidence of stent under-expansion band (0% vs. 53.3%, p = 0.002) and less residual ostial area stenosis of SB (9.2 ± 9.0% vs. 20.0 ± 14.8%, p = 0.023), as assessed in vitro by micro-computed tomography. In a case-controlled study, no adverse cardiac events were observed in the MRC group. The procedural success was similar between MRC and MCS (100% vs. 95.2%, p = 0.548), but MRC had less residual ostial stenosis of the SB (8.7% ± 11.0% vs. 16.8% ± 11.2%, p = 0.008), lower procedural (33.3 ± 9.5 min vs. 46.7 ± 15.6 min, p = 0.001) and fluoroscopic (19.7 ± 4.9 min vs. 26.2 ± 7.1 min, p < 0.001) time, and less contrast use (114.3 ± 28.9 mL vs. 156.5 ± 56.4 mL, p = 0.002). CONCLUSIONS: Mono-ring culotte stenting as compared to MCS is associated with better bifurcation stent morphology, less procedural complexity and residual ostial SB stenosis.

A Pilot Study on Culottes versus Crossover Single Stenting for True Coronary Bifurcation Lesions.

BACKGROUND: The purpose of our study was to compare clinical and angiographic outcomes of planned culottes technique with that of provisional crossover single stenting in the treatment of true coronary bifurcation lesions (CBL) with drug-eluting stent (DES). METHODS: True CBL patients (n = 104) were randomly assigned to either the provisional stenting of the side branch (crossover group) or the culottes group. Additional side branch (SB) stenting in the crossover group was required if there was thrombolysis in myocardial infarction flow ≤ 1 flow). The primary end point was the occurrence of major adverse cardiac events (MACE) at nine months, including cardiac death, myocardial infarction, target lesion/vessel revascularization and in-stent thrombosis. The secondary end point was angiographic in-segment restenosis at nine months. RESULTS: The rate of MACE at nine months was similar between the crossover and culottes groups (7.7% vs. 7.7%, p = 1.000). Additional SB stenting in the crossover group was required in 3.8% of patients. There was one procedural occlusion of SB in the crossover group. At nine months, the rate of in-segment restenosis was similar in the parent main vessel (0% vs. 1.9%, p = 1.000), main branch (1.9% vs. 7.7%, p = 0.363) and SB (17.3% vs. 9.6%, p = 0.250) between the crossover and culottes groups, respectively. CONCLUSIONS: This study demonstrated that there is no significant difference in cumulative MACE or in-segment restenosis between crossover and culottes groups. Larger randomized clinical trials are warranted to re-evaluate the outcomes of the provisional crossover stenting versus the culottes stenting techniques utilizing DES for true CBL.

DK mini-culotte stenting in the treatment of true coronary bifurcation lesions: a propensity score matching comparison with T-provisional stenting.

The conventional culotte technique remains not to be widely used for the treatment of coronary bifurcation lesions due to its inherent drawbacks. Here, we developed a double kissing mini-culotte stenting (DK mini-culotte) and assessed its efficacy and safety by a propensity score matching comparison (PSM) with T-provisional stenting. From June 2010 to June 2012, a total of 223 consecutive patients with true coronary bifurcation lesions (TCBLs) were treated with DK mini-culotte (91 patients with 92 lesions) or T-provisional stenting (132 patients with 135 lesions). We performed a PSM to correct the confounders from clinical and lesion's characteristics. The primary endpoint was cumulative major adverse cardiac event (MACE) at 1 year including cardiac death, myocardial infarction, and target vessel revascularization or target lesion revascularization (TVR/TLR). The secondary endpoint was the rate of side branch (SB) restenosis at 12 months. After a PSM, there were 66 patients in each group. Additional SB stenting in the T-provisional group was performed in 10 (15.2 %) lesions. The incidence of 1-year cumulative MACE was 4.55 % for the DK mini-culotte versus 13.6 % for T-provisional stenting (P = 0.127), the rate of TVR/TLR was 1.52 % for DK mini-culotte versus 12.12 % for T-provisional stenting (P = 0.033). The SB binary restenosis rate was 5.6 % in the DK mini-culotte group and 22.4 % in the T-provisional group (P = 0.014). In summary, despite that there is no difference in MACE between groups, DK mini-culotte significantly reduce TVR/TLR and SB restenosis in the treatment of true coronary bifurcation lesions.

Delayed versus immediate stenting for the treatment of ST-elevation acute myocardial infarction with a high thrombus burden.

OBJECTIVES: High thrombus burden (HTB) is an independent predictor of no flow or low reflow during a primary percutaneous coronary intervention. This study aimed to compare immediate versus delayed stenting in ST-elevation myocardial infarction (STEMI) patients with HTB. METHODS: In this retrospective, nonrandomized study, a total of 103 consecutive STEMI patients with HTB (thrombus burden score, TBS≥3) were assigned to immediate stenting (IS group, n=50) or delayed stenting (DS group, n=53), a decision that was made at the discretion of the operators. The IS group received stent placement immediately, whereas the DS group was given enhanced antithrombotic therapies and deferred for stenting at least 7 days later. Thrombolysis in myocardial infarction (TIMI) flow score (TIMIs) and myocardial blush grade (MBG) were assessed angiographically and the left ventricular ejection fraction (LVEF) was measured echocardiographically. The major adverse cardiac event (MACE) was the composite of cardiac death, reinfarction, target vessel revascularization, heart failure, and major bleeding. RESULTS: The DS group had better immediate MBG (P<0.001), higher LVEF at 6 months (P=0.044), and lower MACE rate at 1 year (log-rank P=0.008). Multiple logistic regression identified immediate stenting (odds ratio 7.4, 95% confidence interval 2.1-26.6; P=0.002) and high TBS (odds ratio 2.6, 95% confidence interval 1.1-6.5, P=0.034) as the independent predictors of poor myocardial perfusion. Delayed stenting benefited the male patients, those who were of a younger age, and those who had a larger infarction-related artery, higher TBS, or lower TIMIs in terms of MBG or MACE. Delayed stenting avoided stent implantation of the infarct-related artery in 12/53 (22.6%) patients particularly in the younger patients. CONCLUSION: For STEMI patients with HTB who have undergone initial thrombectomy, delayed stenting is safe and feasible, and may be associated with better immediate myocardial perfusion, more LV function recovery, and less occurrence of MACE at the 1-year follow-up.

[Peripheral dendritic cell subsets and changes in plasma monocyte chemoattractant protein 1 in patients with coronary heart disease].

OBJECTIVE: To assess the association between peripheral blood dendritic cells subtype distribution and plasma monocyte chemoattractant protein 1 (MCP-1) concentration in patients with coronary heart disease (CHD). METHODS: Sixty consecutive CHD patients admitted in our department during the period from November, 2010 to December, 2011 were enrolled, including 10 with stable angina pectoris (SAP), 25 with unstable angina pectoris (UAP), and 25 with acute myocardial infarction (AMI), with 28 healthy volunteers as normal controls. All the subjects underwent routine tests and coronary angiography. The percentages of peripheral blood myeloid dendritic cells (mDCs) and plasma cell-like dendritic cells (pDCs) in peripheral blood mononuclear cells were detected by flow cytometry, and plasma MCP-1 levels were detected using enzyme-linked immunosorbent assay. RESULTS: The percentage and absolute quantity of mDCs and pDCs were significantly lower in AMI and UAP groups than in the normal control and SAP groups (P<0.001). In the CHD patients, the plasma MCP-1 level was significantly higher than that in the normal control group (P<0.001) with an inverse correlation with the percentage of peripheral mDCs. CONCLUSION: MCP-1 may promote the migration of mDCs into atherosclerotic plaques and mediate the local immune and inflammatory responses to aggravate plaque instability in CHD patients.

Incorporating the loss function into discriminative clustering of structured outputs.

Clustering using the Hilbert Schmidt independence criterion (CLUHSIC) is a recent clustering algorithm that maximizes the dependence between cluster labels and data observations according to the Hilbert Schmidt independence criterion (HSIC). It is unique in that structure information on the cluster outputs can be easily utilized in the clustering process. However, while the choice of the loss function is known to be very important in supervised learning with structured outputs, we will show in this paper that CLUHSIC is implicitly using the often inappropriate zero-one loss. We propose an extension called CLUHSICAL (which stands for "Clustering using HSIC and loss") which explicitly considers both the output dependency and loss function. Its optimization problem has the same form as CLUHSIC, except that its partition matrix is constructed in a different manner. Experimental results on a number of datasets with structured outputs show that CLUHSICAL often outperforms CLUHSIC in terms of both structured loss and clustering accuracy.