Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence.

Objective: This study aimed to explore the association of single nucleotide polymorphisms (SNP) in the matrix metalloproteinase 2 (MMP-2) signaling pathway and the risk of vascular senescence (VS). Methods: In this cross-sectional study, between May and November 2022, peripheral venous blood of 151 VS patients (case group) and 233 volunteers (control group) were collected. Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway, assessed through carotid-femoral pulse wave velocity (cfPWV), and analyzed using multivariate logistic regression. The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality regression (GMDR) modeling. Results: Within the multivariate logistic regression models, four SNPs were screened to have significant associations with VS: chemokine (C-C motif) ligand 2 (CCL2) rs4586, MMP2 rs14070, MMP2 rs7201, and MMP2 rs1053605. Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype, and those of the T/T genotype had a 19.375-fold increased risk. CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. Conclusion: CCL2 rs4586, MMP-2 rs14070, MMP-2 rs7201, and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

Enhancement of bicycle exercise capacity in patients with chronotropic incompetence through closed-loop stimulation: a randomized crossover trial.

AIMS: This study aimed to investigate the effectiveness of closed-loop stimulation (CLS) pacing compared with the traditional DDD mode in patients with chronotropic incompetence (CI) using bicycle-based cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: This single-centre, randomized crossover trial involved 40 patients with CI. Patients were randomized to receive either DDD-CLS or DDD mode pacing for 2 months, followed by a crossover to the alternative mode for an additional 2 months. Bicycling-based CPET was conducted at the 3- and 5-month follow-up visits to assess exercise capacity. Other cardiopulmonary exercise outcome measures and health-related quality of life (QoL) were also assessed. DDD-CLS mode pacing significantly improved exercise capacity, resulting in a peak oxygen uptake (14.8 ± 4.0 vs. 12.0 ± 3.6 mL/kg/min, P < 0.001) and oxygen uptake at the ventilatory threshold (10.0 ± 2.2 vs. 8.7 ± 1.8 mL/kg/min, P < 0.001) higher than those of the DDD mode. However, there were no significant differences in other cardiopulmonary exercise outcome measures such as ventilatory efficiency of carbon dioxide production slope, oxygen uptake efficiency slope, and end-tidal carbon dioxide between the two modes. Patients in the DDD-CLS group reported a better QoL, and 97.5% expressed a preference for the DDD-CLS mode. CONCLUSION: DDD-CLS mode pacing demonstrated improved exercise capacity and QoL in patients with CI, highlighting its potential as an effective pacing strategy for this patient population.

Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.

Inhibition of epithelial-to-mesenchymal transition augments antitumor efficacy of nanotherapeutics in pancreatic ductal adenocarcinoma.

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-ß1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-ß-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC.

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system.

Carbonyl reductase (CR)-catalyzed bioreduction in the organic phase and the neat substrate reaction system is a lasting challenge, placing higher requirements on the performance of enzymes. Protein engineering is an effective method to enhance the properties of enzymes for industrial applications. In the present work, a single point mutation E145A on our previously constructed CR mutant LsCRM3 , coevolved thermostability, and activity. Compared with LsCRM3 , the catalytic efficiency kcat /KM of LsCRM3 -E145A (LsCRM4 ) was increased from 6.6 to 21.9 s-1 mM-1 . Moreover, E145A prolonged the half-life t1/2 at 40°C from 4.1 to 117 h, T m ${T}_{m}$ was increased by 5°C, T 50 30 ${T}_{50}^{30}$ was increased by 14.6°C, and Topt was increased by 15°C. Only 1 g/L of lyophilized Escherichia coli cells expressing LsCRM4 completely reduced up to 600 g/L 2-chloro-1-(3,4-difluorophenyl)ethanone (CFPO) within 13 h at 45°C, yielding the corresponding (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol ((S)-CFPL) in 99.5% eeP , with a space-time yield of 1.0 kg/L d, the substrate to catalyst ratios (S/C) of 600 g/g. Compared with LsCRM3 , the substrate loading was increased by 50%, with the S/C increased by 14 times. Compared with LsCRWT , the substrate loading was increased by 6.5 times. In contrast, LsCRM4 completely converted 600 g/L CFPO within 12 h in the neat substrate bioreaction system.

Comparison of Application of MD-VF-Auto SEM Method and Plankton Gene Multiplex PCR System in the Diagnosis of Drowning.

OBJECTIVES: To compare the application effect of microwave digestion - vacuum filtration - automated scanning electron microscopy (MD-VF-Auto SEM) method and plankton gene multiplex PCR system in the diagnosis of drowning. METHODS: Lung, liver and kidney tissue of 10 non-drowning cases and 50 drowning cases were prepared for further MD-VF-Auto SEM method analysis and plankton gene multiplex PCR system analysis. The positive detection rate of the two methods in each tissue was calculated. RESULTS: The positive rate of the MD-VF-Auto SEM method detecting diatoms in drowning cases was 100%, and few diatoms were detected in the liver and kidney tissues of 6 non-drowning cases. By using the plankton gene multiplex PCR system, the diatom positive rate of drowning cases was 84%, and all the non-drowning cases were negative. There were significant differences in the positive rate of the liver, kidney tissues between MD-VF-Auto SEM method and plankton gene multiplex PCR system (P<0.05), as well as the total positive rate of cases. However, no significant differences were found in the positive rates of lung tissues (P>0.05). CONCLUSIONS: MD-VF-Auto SEM method is more sensitive than plankton gene multiplex PCR system in diatom test. But the plankton gene multiplex PCR system can also detect plankton other than diatoms. Combination of the two methods can provide a more reliable basis for the diagnosis of drowning.

SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15+ TAM, rather than SIGLEC15+ PDAC cells or SIGLEC15- TAM, correlated with poor prognosis and immunosuppressive microenvironment in the PDAC microarray cohort. Compared with SIGLEC15- TAM, SIGLEC15+ TAM presented an M2-like phenotype that could be modulated by SIGLEC15 in a tumor cell-dependent manner. In mechanism, SIGLEC15 interacted with PDAC-expressed sialic acid, preferentially α-2, 3 sialic acids, to stimulate SYK phosphorylation in TAM, which further promoted its immunoregulatory cytokines and chemokines production. In vivo, SIGLEC15+ TAM also presented an M2-like phenotype, accelerated tumor growth, and facilitated immunosuppressive microenvironment, which was greatly abolished by SYK inhibitor. Our study highlighted a novel M2-promoting function of SIGLEC15 and strongly suggested SIGLEC15 as a potential immunotherapeutic target for PDAC.

Successful bailout stenting strategy against rare spontaneous retrograde dissection of partially absorbed magnesium-based resorbable scaffold: A case report.

BACKGROUND: In the development of coronary stent technology, bioresorbable scaffolds are promising milestones in improving the clinical treatment of coronary artery disease. The "leave nothing behind" motto is the premise of the fourth revolution in percutaneous coronary intervention (PCI). Studies proving the safety and efficacy of the magnesium-based resorbable scaffolds (MgBRSs) include the BIOSOLVE-I and BIOSOLVE-II trials and the latest BIOSOLVE-IV registry. However, spontaneous retrograde dissection of a partially absorbed MgBRS may still occur, albeit rarely. CASE SUMMARY: We describe an unusual case of coronary artery disease in a patient who had undergone a successful PCI 8 mo earlier, where an MgBRS was implanted into the left anterior descending artery (LAD) and left circumflex artery with drug-coated balloons for a ramus intermedius branch stenosis to achieve the "leave nothing behind" therapeutic intention and was currently presenting with a gradual worsening of chest tightness. The distal edge vascular response, during subsequent attempts with balloon angioplasty was performed smoothly. However, spontaneous retrograde dissection of a partially absorbed MgBRS in the LAD ensued. Successful bailout stenting was performed with revascularization of the entry and exit sites created by spontaneous dissection and complete sealing of the intramural hematoma. The patient recovered well and was discharged after 2 d of intervention. When followed up in August 2020 (7 mo later), the patient showed uneventful recovery. CONCLUSION: Spontaneous retrograde dissection of a partially absorbed MgBRS was successfully treated using bailout sirolimus-eluting coronary stent strategy.

Chrysin Inhibits High Glucose-Induced Migration on Chorioretinal Endothelial Cells via VEGF and VEGFR Down-Regulation.

BACKGROUND: Diabetes mellitus (DM) is a chronic inflammatory disease, which causes multiple complications. Diabetic retinopathy (DR) is among these complications and is a dominant cause of vision loss for diabetic patients. Numerous studies have shown that chrysin, a flavonoid, has many biological activities such as anti-oxidation and anti-inflammation. However, it is rarely used in ocular diseases. In this study, we examined the inhibitory effects of flavonoid on high glucose induced migration of chorioretinal endothelial cells (RF/6A cells) and its mechanism. MATERIALS AND METHODS: The viability of RF/6A cells treated with chrysin was examined with a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The migration of RF/6A cells was assessed by the transwell migration and scratch wound assays. The expression of AKT, ERK, vascular endothelial growth factor (VEGF), HIF-1α and MMP-2 were determined by western blotting. To observe the mRNA expression of VEGF receptor (VEGFR), qRT-PCR, was utilized. RESULTS: The results showed that chrysin can dose-dependently inhibit the RF/6A cell migration in vitro transwell and the scratch wound assays which are induced by high glucose. After pretreatment of RF/6A cells with different concentrations of chrysin, they did not produce any cytotoxicity in MTT assay. Moreover, chrysin down-regulated both phosphorylated AKT and ERK, as well as attenuated the expression levels of MMP-2. It also decreased the expression of the VEGF transcription factor and VEGF. Furthermore, it was shown that chrysin could suppress the protein and mRNA expression levels of VEGFR. CONCLUSION: The results indicate that chrysin could down-regulate the phosphorylation of AKT, ERK and MMP-2 and reduce the effects of VEGF and VEGFR in a high glucose environment. It further inhibits the high glucose-induced migration of RE/6A cells. Therefore, chrysin may have the potential for visual protection.

Comparison of Arrhythmia Detection by 24-Hour Holter and 14-Day Continuous Electrocardiography Patch Monitoring.

BACKGROUND: Although 24-hour Holter monitoring is routinely used for patients with suspected paroxysmal arrhythmia, its sensitivity in detecting such arrhythmias is insufficient. METHODS: We compared a 14-day electrocardiography (ECG) monitor patch - a single-use, noninvasive, waterproof, continuous monitoring patch - with a 24-hour Holter monitor in 32 consecutive patients with suspected arrhythmia. RESULTS: The 14-day ECG patch was well tolerated, and its rates of detection of relevant arrhythmias on days 1, 3, 7, and 14 were 13%, 28%, 47%, and 66%, respectively. The detection rate of paroxysmal arrhythmias was significantly higher for the 14-day ECG patch than for the 24-hour Holter monitor (66% vs. 9%, p < 0.001). Among the 32 patients, 202 atrial fibrillation or atrial flutter episodes were detected in 6 patients (22%) with the 14-day ECG patch; however, only 1 atrial fibrillation episode was detected in a patient (3%, p < 0.05) with the 24-hour Holter monitor. Other clinically relevant arrhythmias recorded on the 14-day ECG patch included 21 (65.5%) episodes of supraventricular tachycardia, 2 (6.3%) long pause, and 2 (6.3%) ventricular arrhythmias. The mean dermal response score immediately after removal of the 14-day ECG patch from the patients was 0.64, which indicated minimal erythema. CONCLUSIONS: The 14-day ECG patch was well tolerated and allowed for longer continuous monitoring than the 24-hour Holter monitor, thus resulting in improved clinical accuracy in the detection of paroxysmal arrhythmias. Future studies should examine the long-term effectiveness of 14-day ECG patches for managing selected patients.

Effectiveness of intracavitary electrocardiogram-guided peripherally inserted central catheter tip placement in premature infants: a multicentre pre-post intervention study.

This pre-post intervention study was conducted in Neonatal Intensive Care Units in two Chinese hospitals. The objective was to evaluate the effectiveness and safety of intracavitary electrocardiogram (IC-ECG)-guided peripherally inserted central catheter (PICC) placement and tip positioning in premature infants. A total of 161 premature infants who required a PICC were enrolled and divided into two groups: pre-intervention group (n = 83) from October 2017 to July 2018 and post-intervention IC-ECG group (n = 78) from August 2018 to March 2019. Nurses were trained from May 2018 to July 2018. The reposition rate in the IC-ECG group and pre-interventions group was 3.85% and 19.28%, respectively (OR 5.970; 95% CI 1.666-21.395; p = 0.002). More infants achieved optimal tip position at the first attempt in the IC-ECG group than the pre-intervention group (93.59% vs 73.49%; OR 0.190; 95%CI 0.068-0.531; p = 0.001). The overall catheter-related complications in the pre-intervention group were 14.46% compared to 3.84% in the IC-ECG group (OR 2.962; 95%CI 1.013-8.661; p = 0.040). However, no significant differences were observed between the individual complication leakage, phlebitis and catheter-related blood stream infection.Conclusions: IC-ECG-guided peripherally inserted central catheter placement and tip positioning technology might decrease reposition rates, achieve more accurate tip positioning at the first attempt and might reduce catheter-related complications in premature infants. Further robust RCTs are needed to confirm the effectiveness of IC-ECG-guided PICC placement and tip positioning in neonates.What is Known:• Chest radiography is the gold standard for tip position confirmation of peripherally inserted central catheter placement.• Studies in adult patients have shown that electrocardiogram guidance in the placement of central venous catheters can be beneficial, while evidence in neonates is limited.What is New:• Intracavitary electrocardiogram-guided peripherally inserted central catheter placement might be superior to chest radiography in preterm infants.• Decreasing the repositioning rates and correct tip position of peripherally inserted central catheters might reduce catheter-related complications.

A Novel Strategy for Chronic Total Occlusion of the Stumpless Ostial Left Anterior Descending Artery.

BACKGROUND Despite improvements in percutaneous coronary intervention (PCI) devices and operator expertise, coronary chronic total occlusion (CTO) poses a management dilemma for interventional cardiologists. Occasionally, in CTO lesions and in bifurcation lesions with severe curvature and stenosis, wires cannot be introduced into the main artery, although wiring into the side branch is possible. We herein report a case of stumpless ostial left anterior descending artery (LAD) CTO that was successfully treated with a novel strategy. CASE REPORT A 64-year-old female with symptoms of heart failure was admitted to our hospital. Coronary angiography showed CTO of the stumpless ostial LAD. The patient had invisible and continuous collaterals; therefore, we used the antegrade approach for CTO access. However, the wire could be guided only in the direction of the diagonal branch due to a severe angulation at the CTO exit site, despite successful wire crossing into the CTO lesion. We attempted intravascular ultrasound-guided direct wire entry technique to obtain additional information about the occlusion cap location and to assist in negotiating the wire into the true lumen. The guidewire (Conquest pro) could cross the lesion after several approaches and successfully advance the device over the wire through the occluded segment after the modified See-saw wiring technique was employed. CONCLUSIONS This method appears to be a promising novel strategy for difficult and complex lesions when performing CTO revascularization.

Relation of carotid artery diameter with cardiac geometry and mechanics in heart failure with preserved ejection fraction.

BACKGROUND: Central artery dilation and remodeling are associated with higher heart failure and cardiovascular risks. However, data regarding carotid artery diameter from hypertension to heart failure have remained elusive. We sought to investigate this issue by examining the association between carotid artery diameter and surrogates of ventricular dysfunction. METHODS AND RESULTS: Two hundred thirteen consecutive patients including 49 with heart failure and preserved ejection fraction (HFpEF), 116 with hypertension, and an additional 48 healthy participants underwent comprehensive echocardiography and tissue Doppler imaging. Ultrasonography of the common carotid arteries was performed for measurement of intima-media thickness and diameter (CCAD). Cardiac mechanics, including LV twist, were assessed by novel speckle-tracking software. A substantial graded enlargement of CCAD was observed across all 3 groups (6.8 ± 0.6, 7.7 ± 0.73, and 8.7 ± 0.95 mm for normal, hypertension, and HFpEF groups, respectively; ANOVA P<0.001) and correlated with serum brain natriuretic peptide level (R(2)=0.31, P<0.001). Multivariable models showed that CCAD was associated with increased LV mass, LV mass-to-volume ratio (ß-coefficient=10.9 and 0.11, both P<0.001), reduced LV longitudinal and radial strain (ß-coeffficient=0.81 and -3.1, both P<0.05), and twist (ß-coefficient=-0.84, P<0.05). CCAD set at 8.07 mm as a cut-off had a 77.6% sensitivity, 82.3% specificity, and area under the receiver operating characteristic curves (AUROC) of 0.86 (95% CI 0.80 to 0.92) in discriminating HFpEF. In addition, CCAD superimposed on myocardial deformation significantly expanded AUROC (for longitudinal strain, from 0.84 to 0.90, P of ΔAUROC=0.02) in heart failure discrimination models. CONCLUSIONS: Increased carotid artery diameter is associated with worse LV geometry, higher brain natriuretic peptide level, and reduced contractile mechanics in individuals with HFpEF.

Large aortic aneurysm mimicking a cardiac tumor.

INTRODUCTION: Extrinsic left atrial compression caused by a displaced, crooked descending thoracic aorta is rare. This anomaly may mimic primary cardiac tumors or metastatic neoplasms from the first look. CASE PRESENTATION: We reported a 78-year-old woman presented to our emergency room with back pain, increased exercise intolerance and intermittent angina. She also had one syncopal event 1 month ago and gastric cancer post gastrectomy history. Subsequent chest plain film showed no mediastinum widening.Two-dimensional echocardiography was performed and revealed a heterogeneous mass as large as 2.3 x 2.4 cm occupying the left atrium (LA). Three-dimensional echocardiography vividly demonstrated that LA was constrained between the aortic valve (AV) and a luminal structure with pulsatile character suggestive of the aorta. CONCLUSIONS: We successfully demonstrated the detailed structure and location of an anomalous descending aorta on the oblique imaging plane of RT-3DE, which may not be readily available by traditional 2D method.

Evaluation of a lipopeptide biosurfactant from Bacillus natto TK-1 as a potential source of anti-adhesive, antimicrobial and antitumor activities / Avaliação de um lipopeptídio biosurfactante de Bacillus natto TK-1 com fonte potencial de atividade antiadesiva, antimicrobiana e antitumoral

A lipopeptide biosurfactant produced by Bacillus natto TK-1 has a strong surface activity. The biosurfactant was found to be an anti-adhesive agent against several bacterial strains, and also showed a broad spectrum of antimicrobial activity. The biosurfactant induced a significant reduction in tumor cells viability in a dose- dependent manner.

Um lipopeptídio biosurfactante produzido por Bacillus natto TK-1 apresenta intensa atividade de superfície. Verificou-se que o biosurfactante apresentou atividade antiadesiva contra várias cepas bacterianas, e também atividade antimicrobiana de amplo espectro. O biosurfactante causou uma redução significativa na viabilidade de células tumorais, de forma dose-dependente.

Purification and antitumour activity of a lipopeptide biosurfactant produced by Bacillus natto TK-1.

An antitumour lipopeptide biosurfactant purified from Bacillus natto TK-1 was able to inhibit the proliferation of MCF-7 human breast-cancer cells in a dose- and time-dependent manner. The activity of lactate dehydrogenase release showed no significant difference between MCF-7 cells treated with lipopeptide and untreated controls. The antitumour activity of the lipopeptide in MCF-7 cells was associated with cell apoptosis determined by typical morphological changes and sub-G(1) peak in cell growth-phase distribution. The cell cycle was arrested at G(2)/M phase. In addition, the caspase activity assay revealed that lipopeptide-induced apoptosis in MCF-7 cells was associated with caspase 3.

Evaluation of a lipopeptide biosurfactant from Bacillus natto TK-1 as a potential source of anti-adhesive, antimicrobial and antitumor activities.

A lipopeptide biosurfactant produced by Bacillus natto TK-1 has a strong surface activity. The biosurfactant was found to be an anti-adhesive agent against several bacterial strains, and also showed a broad spectrum of antimicrobial activity. The biosurfactant induced a significant reduction in tumor cells viability in a dose-dependent manner.