The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in ...cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.
The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry.
antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.
TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells.
, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.
These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.
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Background
Studies examining the efficiency of drug-coated balloon (DCB) compared to drug-eluting stents (DES) for de novo lesions in large vessels have reported inconsistent results.
Objective
This ...comprehensive meta-analysis of clinical trials compared the efficacy and safety of DCB and DES for the treatment of de novo coronary lesions.
Methods
The authors formally searched electronic databases before October 2019 to identify randomized and non-randomized clinical trials (RCTs and non-RCTs, respectively). Clinical trials were eligible for inclusion if they compared DCB with DES in patients with coronary lumen diameters >2.5 mm.
Results
Three RCTs and one non-RCT with a total of 321 patients were included in our meta-analysis (DCB group = 152, DES group = 169). The primary endpoint was in-segment late lumen loss (LLL) with a standardized mean difference (SMD) of −0.07 (95% confidence interval CI: −0.31, 0.316;
P
= 0.548) and the secondary endpoint was target lesion revascularization (TLR) with a risk ratio (RR) of 1.17 (95% CI: 0.46, 2.95;
P
= 0.746).
Conclusion
This meta-analysis indicated that DCB might be non-inferior to DES as evidenced by quantitative coronary angiography (QCA) assessed at 6–9 months after percutaneous coronary intervention in patients presenting with coronary artery disease.
Background. This prospective study compared the success rate and safety of a distal transradial artery (dTRA) approach to that of the conventional transradial artery (TRA) for coronary angiography or ...percutaneous coronary intervention. Methods. From January 2019 to April 2020, nine hundred consecutive patients (height < 190 cm) scheduled for coronary angiography or percutaneous coronary interventions were randomly and equally assigned to receive either dTRA or conventional TRA catheterization. Results. Successful access was achieved in 96.00% and 96.67% of the dTRA and conventional TRA groups, respectively (P=0.814). Compared with the TRA group, patients in the dTRA experienced significantly less hemostatic band removal time (150.5 ± 50.5 cf. 210.6 ± 60.5 min, P=0.032); minor bleeding of the access site (2.44% cf. 6.44%, P=0.038); hemostatic band cost (USD; 0.1 cf. 59.4, P=0); and postprocedural radial artery occlusion (1.56% cf. 3.78%, P=0.035). A lower body mass index was a higher risk factor for dTRA access failure (odds ratio = 0.79, P=0.024), with a cutoff of 22.04 kg/m2. Conclusion. Compared to conventional TRA, dTRA had a comparable high success rate, with fewer associated complications. Clinicians should use the dTRA with caution in patients with low body mass index.
Beneficial effects of therapeutic drugs are controversial for heart failure with preserved ejection fraction (HFpEF). This meta-analysis aimed to evaluate and compare the interactive effects of ...different therapeutic drugs and placebo in patients with HFpEF. A comprehensive search was conducted using PubMed, Google Scholar, and Cochrane Central Register to identify related articles published before March 2021. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality, heart failure (HF) hospitalization, and worsening HF events. A total of 14 randomized controlled trials, comprising 19,573 patients (intervention group,
= 9,954; control group,
= 9,619) were included in this network meta-analysis. All-cause mortality, cardiovascular mortality, and worsening HF events among therapeutic drugs and placebo with follow-up of 0.5-4 years were not found to be significantly correlated. The angiotensin receptor neprilysin inhibitor (ARNI) and angiotensin-converting enzyme inhibitor (ACEI) significantly reduced the HF hospitalizations compared with placebo (hazard ratio HR 0.73, 95% confidence interval CI 0.60-0.87 and HR 0.64, 95% CI 0.43-0.96, respectively), without heterogeneity among studies. The ARNI was superior to angiotensin receptor blocker (ARB) in reducing HF hospitalizations (HR 0.80, 95% CI 0.71-0.91), and vericiguat 10 mg ranked worse than beta-blockers for reducing all-cause mortality in patients with HFpEF (HR 3.76, 95% CI 1.06-13.32). No therapeutic drugs can significantly reduce mortality, but the ARNI or ACEI is associated with the low risk of HF hospitalizations for patients with HFpEF.
https://www.crd.york.ac.uk/prospero/, identifier CRD42021247034.
Abstract
Background
Optimal treatment strategies for patients with heart failure with preserved ejection fraction (HFpEF) remain uncertain. The goal of this study was to compare the treatment effects ...of different therapeutic agents for patients with HFpEF.
Methods
Randomized controlled trials (RCTs) published before June 2022 were searched from PubMed, Clinical Trials gov, and the Cochrane Central Register databases. Combined odds ratios (ORs) with 95% confidence intervals (CI) were calculated for the primary and secondary outcomes. All-cause death was the primary endpoint and cardiac death, hospitalization for HF, and worsening HF (WHF) events were secondary endpoints in this meta-analysis.
Results
Fifteen RCTs including 31,608 patients were included in this meta-analysis. All-cause and cardiac death were not significantly correlated between drug treatments and placebo. Compared with placebo, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly reduced HF hospitalizations odds ratio (OR) = 0.64, (95% confidence interval (95%CI 0.43 − 0.96), OR = 0.73, (95%CI 0.61 − 0.86), and OR = 0.74, (95%CI 0.66 − 0.83), respectively without heterogeneity among studies. Only SGLT2 inhibitors significantly reduced WHF events OR = 0.75, (95%CI 0.67 − 0.83).
Conclusions
No treatments were effective in reducing mortality, but ARNIs, ACEIs or SGLT2 inhibitors reduced HF hospitalizations and only SGLT2 inhibitors reduced WHF events for patients with HFpEF.
Tumor-associated macrophages (TAMs) are heterogeneous and can adopt a spectrum of activation states between pro-inflammatory and pro-tumorigenic in response to the microenvironment. We have ...previously shown that TTI-621, a soluble SIRPαFc fusion protein that blocks the CD47 "do-not-eat" signal, promotes tumor cell phagocytosis by IFN-γ-primed macrophages. To assess the impact of CD47 blockade on diverse types of macrophages that are found within the tumor microenvironment, six different polarized human macrophage subsets (M(-), M(IFN-γ), M(IFN-γ+LPS), M(IL-4), M(HAGG+IL-1β), M(IL-10 + TGFβ)) with distinct cell surface markers and cytokine profiles were generated. Blockade of CD47 using TTI-621 significantly increased phagocytosis of lymphoma cells by all macrophage subsets, with M(IFN-γ), M(IFN-γ+LPS) and M(IL-10 + TGFβ) macrophages having the highest phagocytic response. TTI-621-mediated phagocytosis involves macrophage expression of both the low- and high-affinity Fcγ receptors II (CD32) and I (CD64), respectively. Moreover, macrophages with lower phagocytic capabilities (M(-), M(IL-4), M(HAGG+IL-1β)) could readily be re-polarized into highly phagocytic macrophages using various cytokines or TLR agonists. In line with the in vitro study, we further demonstrate that TTI-621 can trigger phagocytosis of tumor cells by diverse subsets of isolated mouse TAMs ex vivo. These data suggest that TTI-621 may be efficacious in triggering the destruction of cancer cells by a diverse population of TAMs found in vivo and support possible combination approaches to augment the activity of CD47 blockade.
Iron deficiency has detrimental effects in patients with acute coronary syndrome (ACS), which is a common nutritional disorder and inflammation-related disease affects up to one-third people ...worldwide. However, the specific role of iron metabolism in ACS progression is opaque. In this study, we construct an iron metabolism-related genes (IMRGs) based molecular signature of ACS and to identify novel iron metabolism gene markers for early stage of ACS. The IMRGs were mainly collected from Molecular Signatures Database (mSigDB) and two relevant studies. Two blood transcriptome datasets GSE61144 and GSE60993 were used for constructing the prediction model of ACS. After differential analysis, 22 IMRGs were differentially expressed and defined as DEIGs in the training set. Then, the 22 DEIGs were trained by the Elastic Net to build the prediction model. Five genes, PADI4, HLA-DQA1, LCN2, CD7, and VNN1, were determined using multiple Elastic Net calculations and retained to obtain the optimal performance. Finally, the generated model iron metabolism-related gene signature (imSig) was assessed by the validation set GSE60993 using a series of evaluation measurements. Compared with other machine learning methods, the performance of imSig using Elastic Net was superior in the validation set. Elastic Net consistently scores the higher than Lasso and Logistic regression in the validation set in terms of ROC, PRC, Sensitivity, and Specificity. The prediction model based on iron metabolism-related genes may assist in ACS early diagnosis.
Aimed to evaluate and compare the interactive effects of different antiplatelet or anticoagulation strategies in patients with chronic coronary syndromes (CCS) after percutaneous coronary ...intervention (PCI). Randomized controlled trials comparing different antiplatelet or anticoagulant strategies in patients with CCS after PCI were included. The primary outcomes were major adverse cardiovascular event (MACE), mortality, ischemic and bleeding events. Compared to aspirin alone, addition of prasugrel or ticagrelor to aspirin resulted in lower risk of myocardial infarction (MI) odds ratio (OR): 0.38 (95% confidence interval 0.38–0.62); 0.810–0.84 (0.69–0.98) and any stroke 0.56 (0.42–0.75) at the expense of increased risk of major bleeding 1.79 (1.34–2.39); 2.08–2.38 (1.56–3.28), whereas, clopidogrel monotherapy reduced the risk of any stroke, major bleeding, and intracranial bleeding. On subgroup analysis, compared with aspirin alone, addition of prasugrel resulted in lower MACE 0.72 (0.60–0.86), MI 0.48 (0.38–0.62), and stent thrombosis 0.29 (0.09–0.91), whereas, addition of rivaroxaban 2.5 mg resulted in lower risk of MACE 0.72 (0.60–0.87), cardiac death 0.71 (0.52–0.98) and any stroke 0.65 (0.45–0.95), but not reduced MI. Both prasugrel and rivaroxaban 2.5 mg increased major bleeding 1.79 (1.34–2.39); 1.72 (1.33–2.22). Clopidogrel monotherapy was associated with lower MACE 0.72 (0.58–0.90), any stroke 0.42 (0.24–0.73), and major bleeding 0.62 (0.40–0.96). Adding prasugrel or ticagrelor led to a reduced incidence of MI and prasugrel was also found to reduce the risk of MACE and stent thrombosis in CCS patients with low risk of bleeding after PCI. Clopidogrel monotherapy has advantage in reducing MACE, stroke, and major bleeding events in CCS patients at high risk of bleeding after PCI.
Systematic Review Registration:
https://clinicaltrials.gov/
, PROSPERO Identifier: CRD 42021291050.
Background and aims
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has long been considered a key regulator in lipid metabolism. Its role as a potential player in immune response has recently ...earned much attention. However, the effects of evolocumab, an approved PCSK9 monoclonal antibody, on lipid reduction and inflammation regulation in Chinese patients with acute coronary syndrome (ACS) during their in-hospital stage after an index event are not well known.
Methods
We conducted a case-crossover pilot study (
http://www.clinicaltrials.gov/
, NCT04730648) involving 31 patients hospitalized for ACS with elevated low-density lipoprotein cholesterol (LDL-C) level (≥70 mg/dL despite high-intensity statin) and 8 age- and gender-matched patients without coronary heart disease (CHD) as the baseline control. The patients with ACS received one dose of subcutaneous evolocumab (140 mg) on top of 10 mg/day rosuvastatin during hospitalization. Blood samples at baseline and 72 h post-evolocumab administration were collected for lipid and cytokine assessments.
Results
The patients without CHD shared similar risk factors and LDL-C levels with the patients with ACS but exhibited a more activated inflammatory status. After single-dose in-hospital evolocumab, the median LDL-C level of patients with ACS decreased from 109.0 to 41.4 mg/dL as early as 72 h, accompanied with reductions in other atherogenic lipids. Systemic inflammatory pattern was also altered, rendering a decrease in pro-inflammatory and anti-inflammatory cytokines.
Conclusion
In this case-crossover study of the effect of PCSK9 antibody among Chinese patients, evolocumab on top of high-intensity statin during hospitalization led to a remarkable and rapid reduction in atherogenic lipids and an alteration in inflammatory status at early-stage post-ACS.
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