Injectable Nanocomposite Hydrogels Improve Intraperitoneal Co-delivery of Chemotherapeutics and Immune Checkpoint Inhibitors for Enhanced Peritoneal Metastasis Therapy.

Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.

A nanocomposite hydrogel for co-delivery of multiple anti-biofilm therapeutics to enhance the treatment of bacterial biofilm-related infections.

The characteristics of biofilms have exacerbated the issue of clinical antibiotic resistance, rendering it a pressing challenge in need of resolution. The combination of biofilm-dispersing agents and antibiotics can eliminate biofilms and promote healing synergistically in infected wounds. In this study, we developed a novel nanocomposite hydrogel (NC gel) comprised of the poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) based bioadhesive nanoparticles (BNPs) and a hydrophilic carboxymethyl chitosan (CS) network. The NC gel was designed to co-deliver two biofilm-dispersing agents (an NO-donor SNO, and an α-amylase Am) and an antibiotic, cefepime (Cef), utilizing a synergistic anti-biofilm mechanism in which Am loosens the matrix structure and NO promotes the release of biofilm bacteria via quorum sensing, and Cef kills bacteria. The drug-loaded NC gel (SNO/BNP/CS@Am-Cef) demonstrated sustained drug release, minimal cytotoxicity, and increased drug-bacterial interactions at the site of infection. When applied to mice infected with methicillin-resistant Staphylococcus aureus (MRSA) biofilms in vivo, SNO/BNP/CS@Am-Cef enhanced biofilm elimination and promoted wound healing compared to traditional antibiotic treatments. Our work demonstrates the feasibility of the co-delivery of biofilm-dispersing agents and antibiotics using the NC gel and presents a promising approach for the polytherapy of bacterial biofilm-related infections.

Critical values of monitoring indexes for perioperative major adverse cardiac events in elderly patients with biliary diseases.

BACKGROUND: Major adverse cardiac events (MACE) in elderly patients with biliary diseases are the main cause of perioperative accidental death, but no widely recognized quantitative monitoring index of perioperative cardiac function so far. AIM: To investigate the critical values of monitoring indexes for perioperative MACE in elderly patients with biliary diseases. METHODS: The clinical data of 208 elderly patients with biliary diseases in our hospital from May 2016 to April 2021 were retrospectively analysed. According to whether MACE occurred during the perioperative period, they were divided into the MACE group and the non-MACE group. RESULTS: In the MACE compared with the non-MACE group, postoperative complications, mortality, hospital stay, high sensitivity troponin-I (Hs-TnI), creatine kinase isoenzyme (CK-MB), myoglobin (MYO), B-type natriuretic peptide (BNP), and D-dimer (D-D) levels were significantly increased (P < 0.05). Multivariate logistic regression showed that postoperative BNP and D-D were independent risk factors for perioperative MACE, and their cut-off values in the receiver operating characteristic (ROC) curve were 382.65 pg/mL and 0.965 mg/L, respectively. CONCLUSION: The postoperative BNP and D-D were independent risk factors for perioperative MACE, with the critical values of 382.65 pg/mL and 0.965 mg/L respectively. Consequently, timely monitoring and effective maintenance of perioperative cardiac function stability are of great clinical significance to further improve the perioperative safety of elderly patients with biliary diseases.

Methylation of CpG sites in C1QTNF1 (C1q and tumor necrosis factor related protein 1) differs by gender in acute coronary syndrome in Han population: a case-control study.

BACKGROUND: ACS (acute coronary syndrome), a subgroup of coronary artery disease (CHD), is a leading cause of death worldwide. Reports shown the association between methylation and CHD, while the abnormal expression of C1QTNF1 (C1q and tumor necrosis factor related protein 1) in CHD patients, but the underlying mechanisms are still unclear. OBJECTIVE: To analyze the methylation of CpG sites of C1QTNF1 in ACS patients. METHODS: Peripheral blood samples were collected from healthy controls and ACS patients. The methylation of total C1QTNF1, promoter sequence and CpG sites of C1QTNF1 were measured using methylation detection kits. The outcomes were compared between patients and controls based on gender, clinical classification and clinical stages. RESULTS: The promoter sequences from 37 ACS patients and 20 controls indicate that the methylation rate of C1QTNF1 was significantly lower in male patients compared to healthy controls at + 63 CpG sites (p = 0.03). Whereas, the methylation rate of C1QTNF1 in female patients was significantly lower than female health controls at - 89, + 39 and + 167 CpG sites (p = 0.021, 0.042, 0.021). In addition, the methylation rate of C1QTNF1 was significantly higher in male patients than female patients at - 89, - 41 and + 39 CpG sites (p = 0.011, 0.043, 0.006). Moreover, the methylation rate significantly decreased at - 24 sites (p = 0.021), but it significantly increased at - 14 site (p = 0.048) in patients with UA, compared to patients with STEMI (ST-segment elevation myocardial infarction). CONCLUSIONS: There were significant differences in the methylation rate + 63 CpG sites between controls and male ACS patients. The - 14 site methylation increased in patients with UA, compared to patients with STEMI.

[Characterization of atherosclerotic plaque in patients with unstable angina pectoris and stable angina pectoris by optical coherence tomography].

OBJECTIVE: To compare the characterization of coronary atherosclerotic plaques in patients with unstable angina pectoris (UAP) and stable angina pectoris (SAP) by optical coherence tomography (OCT). METHODS: OCT was performed in 47 patients (23 UAP and 24 SAP) undergoing coronary angiography. Lipid-rich plaque (defined by > or = 2 quadrants of the cross-section area), thin cap fibroatheroma (TCFA), thickness of fibrous cap, plaque rupture, calcification and thrombus visualized by OCT were compared between UAP and SAP patients. RESULTS: OCT imaging was successfully in 44 out of 47 patients (22 UAP, 22 SAP). Proportion of lipid-rich plaques was similar between UAP and SAP groups [91% (20/22) vs. 73% (16/22), P = 0.741]. The minimum thickness of fibrous cap in the UAP group was significantly thinner than that in SAP group [(69.5 +/- 34.7) microm vs. (141.1 +/- 68.5) microm, P = 0.000] and the rate of fibrous cap erosion in the UAP group was significantly higher than that in the SAP group [59% (13/22) vs. 9% (2/22), P = 0.000]. Percents of TCFA [73% (16/22) vs. 14% (3/22), P = 0.000] and plaque rupture [50% (11/22) vs. 9% (2/22), P = 0.003] were significantly higher in UAP group compared those in SAP group. Incidence of thrombus and calcification were similar between two groups. CONCLUSIONS: OCT imaging can clearly define plaque characterization of coronary atherosclerosis. UAP patients have thinner fibrous cap, higher incidences of fibrous cap erosion, plaque rupture and TCFA compared patients with SAP.

[Diagnostic value of 128-slice CT coronary angiography in comparison with invasive coronary angiography].

OBJECTIVE: To observe the diagnostic value of non-invasive 128-slice computed tomography coronary angiography (CTA) in comparison with invasive coronary angiography. METHODS: 128-slice CTA and invasive coronary angiography were performed in 78 unselected consecutive patients (63 patients with suspected coronary artery disease and 15 patients with previous coronary stenting, 56 males, mean age 61 +/- 10 years) and > 50% reduction of minimal lumen diameter was defined as significant coronary stenosis. RESULTS: Fifty-eight out of 879 segments (7%) from CTA were not assessable because of irregular rhythm, vessel calcification or tachycardia. Compared with invasive coronary angiography, segment-based analysis from the 821 segments showed the sensitivity by CTA was 87%, specificity 97%, PPV 83% and NPV 97%. Four out of 22 stents implanted in 15 patients were not assessable by CTA because of poor image quality. Compared with invasive coronary angiography, the sensitivity of diagnosing in-stent restenosis by CTA was 100%, specificity 77%, PPV 63% and NPV 100% for the remaining 18 stents. CONCLUSIONS: One hundred and twenty-eight-slice CTA has a high accuracy for detecting coronary artery disease and in-stent restenosis after coronary stenting and could be considered as a valuable noninvasive technique for screening coronary artery disease in suspected patients.

[Risk factors related to mortality in old patients with coronary heart disease after revascularization].

OBJECTIVE: To evaluate the risk factors related to mortality in old patients with coronary heart disease after revascularization. METHODS: A total of 675 patients (498 males) with age >or= 70 years old who received revascularization during July 2003 to June 2004 and followed up > 30 days after discharge were included in this study. Clinical characteristics, death and major adverse cardiac and cerebral events (MACCE) during follow up were recorded. RESULTS: The patients were followed up for a mean period of (754 +/- 355) days. 27 patients (4.0%) died and MACCE developed in 50 patients (7.4%) during follow up. Female and patients with anemia took a significantly higher risk of mortality (RR = 2.750, 95% CI 1.116 - 6.779, P = 0.028, RR = 0.385 95% CI 0.164 - 0.904, P = 0.028, respectively); Creatinine level is positively related to mortality rate. When comparing patients with Cr > 115 micromol/L and Cr > 177 micromol/L with patients with Cr < 115 micromol/L, the hazard rate was 2.963 and 10.785, respectively (95% CI 1.114 - 9.952, P = 0.035 and 95% CI 2.659 - 78.097, P = 0.000) after adjustment for other risk factors. CONCLUSION: Preexisting anaemia (male Hb < 120 g/L, female Hb < 110 g/L), renal insufficiency (Cr > 115 micromol/L) and female gender were found to be independent risk factors for mortality in old patients with coronary heart disease post revascularization.

[Visualization of intimal proliferation of drug-eluting stent and bare mental stent by use of optical coherence tomography].

OBJECTIVE: To compare neointimal proliferation of drug-eluting stent (DES) with bare mental stent (BMS) by optical coherence tomography (OCT). METHODS: OCT images were obtained in 21 diseased coronary vessels with 23 stents in 19 patients with coronary artery disease at 5 - 93 months post DES or BMS stents. Twenty-two stents of all 23 stents were divided into three groups. Nine DES stents at 6 - 10 months post stenting were considered as group A, 8 BMS stents at 5 - 10 months post stenting as group B, and 5 BMS stents at 23 - 93 months post stenting as group C. OCT images were quantitatively analyzed to compare neointimal proliferation of three groups after stenting. RESULTS: All 21 vessels and 23 stents OCT images were successfully acquired. The maximal neointima, luminal loss in diameter and cross sectional area (CSA), and restenosis in diameter and CSA were significantly statistically different within three groups. The maximal intimal proliferations post stenting in group A were significantly lower than group B (0.20 mm +/- 0.13 mm vs 0.81 mm +/- 0.46 mm, P = 0.019) or group C (0.91 mm +/- 0.27 mm, P = 0.007), luminal loss of diameter in group A were significantly lower than group B (0.27 mm +/- 0.17 mm vs 1.12 mm +/- 0.79 mm, P = 0.009) or group C (1.20 mm +/- 0.31 mm, P = 0.013), restenosis rates in diameter in group A were significantly less than group B (8.90% +/- 4.47% vs 36.36% +/- 24.34%, P = 0.009) or group C (35.48 +/- 6.09, P = 0.017), luminal loss in CSA in group A were lower than group B (1.14 mm(2) +/- 0.9 mm(2) vs 3.96 mm(2) +/- 2.62 mm(2), P = 0.009) or group C (4.66 mm(2) +/- 1.66 mm(2), P = 0.006), and restenosis rates in CSA in group A were less than group B (15.43% +/- 7.89% vs 48.14% +/- 30.43%, P = 0.017) or group C (55.20% +/- 11.24%, P = 0.009). Almost all surfaces of 13 BMS stent struts were covered by significant neointimal coverage, surfaces of 10 DES struts were less significantly neointimal coverage, and some surfaces of DES struts were uncovered with neointima even at 29 months post stenting. CONCLUSION: OCT imaging can clearly visualize stent struts and neointimal formation of strut surfaces post DES or BMS stenting, and this new imaging modality will play important role in evaluating the efficacy of drug-eluting stent.

[Coronary artery atherosclerotic plaque and stent visualizations by optical coherence tomography].

OBJECTIVE: To evaluate coronary artery atherosclerotic plaque characteristics and changes post coronary stenting by optical coherence tomography (OCT). METHODS: OCT images were obtained in 22 diseased coronary vessels after coronary angiography or percutaneous coronary interventions (PCI) in 20 patients and in 23 stents [7 sirolimus-eluting stents (SES) follow up at 4-29 months post stenting and 8 bare mental stents (BMS) at 4-35 months post stenting, 8 stents immediately after PCI]. RESULTS: All 22 vessels and 23 stents OCT images were successfully acquired. Two thromboses, 8 fibrous, 9 lipid-rich and 3 calcium plaques as well as 3 plaque ruptures were visualized by OCT. No significant neointimal proliferation and restenosis were found in SES stents and some struts were not covered with neointima even at 29 months post stenting. Significant neointimal proliferation on surfaces of stent struts were visualized in all 8 BMS stents and restenosis was detected in 3 BMS stents. OCT images obtained immediately after PCI showed that 3 stents were well positioned, tissue prolapse between coronary stent struts occurred in 4 stents and stent dissociation with vessel wall could be seen in 1 stent. CONCLUSIONS: OCT imaging can clearly visualize different types of atherosclerotic plaques. By providing detailed information on plaque characteristics, this technique might help cardiologists in choosing suitable stents and guiding preventive therapy for patients with coronary heart disease.