TM-Score predicts immunotherapy efficacy and improves the performance of the machine learning prognostic model in gastric cancer.

Immunotherapy is becoming increasingly important, but the overall response rate is relatively low in the treatment of gastric cancer (GC). The application of tumor mutational burden (TMB) in predicting immunotherapy efficacy in GC patients is limited and controversial, emphasizing the importance of optimizing TMB-based patient selection. By combining TMB and major histocompatibility complex (MHC) related hub genes, we established a novel TM-Score. This score showed superior performance for immunotherapeutic selection (AUC = 0.808) compared to TMB, MSI status, and EBV status. Additionally, it predicted the prognosis of GC patients. Subsequently, a machine learning model adjusted by the TM-Score further improved the accuracy of survival prediction (AUC > 0.8). Meanwhile, we found that GC patients with low TM-Score had a higher mutation frequency, higher expression of HLA genes and immune checkpoint genes, and higher infiltration of CD8+ T cells, CD4+ helper T cells, and M1 macrophages. This suggests that TM-Score is significantly associated with tumor immunogenicity and tumor immune environment. Notably, based on the RNA-seq and scRNA-seq, it was found that AKAP5, a key component gene of TM-Score, is involved in anti-tumor immunity by promoting the infiltration of CD4+ T cells, NK cells, and myeloid cells. Additionally, siAKAP5 significantly reduced MHC-II mRNA expression in the GC cell line. In addition, our immunohistochemistry assays confirmed a positive correlation between AKAP5 and human leukocyte antigen (HLA) expression. Furthermore, AKAP5 levels were higher in patients with longer survival and those who responded to immunotherapy in GC, indicating its potential value in predicting prognosis and immunotherapy outcomes. In conclusion, TM-Score, as an optimization of TMB, is a more precise biomarker for predicting the immunotherapy efficacy of the GC population. Additionally, AKAP5 shows promise as a therapeutic target for GC.

A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice.

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.

Correlation between maximum heart distance and thoracic diameter changes and diaphragmatic descent in left-sided breast cancer patients during deep inspiration breath-hold (DIBH).

BACKGROUND: Cardioprotection is valued in radiotherapy for patients with left-sided breast cancer. Deep inspiration breath-hold (DIBH) technique can achieve cardioprotection well. However, during DIBH, the extent to which the heart enters the radiation field is affected by the movement of the thorax and diaphragm. The aim of this study was to analyze the correlation between the maximum distance of the heart entering the field (maximum heart distance, MHD) and thoracic diameter changes and diaphragmatic descent in left-sided breast cancer patients during DIBH. PATIENTS AND METHODS: Ninety-eight patients with left-sided breast cancer were included in this retrospective study. They performed simulation in Sentinel-guided DIBH, and two sets of CT images were collected under both free breathing (FB) and DIBH, and diaphragm positions, anteroposterior thoracic diameter (ATD), transverse thoracic diameter (TTD), gating window level (GWL), and MHD were measured, and the change (Δ) of each parameter in DIBH relative to that in FB were calculated. Pearson or Spearman test were used to analyze the correlation between ΔMHD and the changes in other parameters. RESULTS: For all patients with DIBH, the average of ΔMHD was -8.3 mm, and the average of ΔATD and ΔTTD were 11.0 and 8.6 mm, and the median of both left diaphragmatic descent (LDD) and right diaphragmatic descent (RDD) were 35.0 mm, and the median of GWL was 11.1 mm. The correlation coefficients between MHD decrease (ΔMHD) and LDD, RDD, and ΔTTD were -0.430 (p = 0.000), -0.592 (p = 0.000) and 0.208 (p = 0.040), respectively, but not significantly correlated with ΔATD or GWL. CONCLUSIONS: The MHD decrease showed a moderate correlation with diaphragmatic descent In Sentinel-guided DIBH for patients with left-sided breast cancer, while there was a weak or no correlation with thoracic diameter changes or GWL. Abdominal breathing can lower diaphragm more and may be more beneficial to the heart stay away from tangential field.

Space Charge Characteristics and Breakdown Properties of Nanostructured SiO2/PP Composites.

Polypropylene (PP) has gained attention in the industry as an environmentally friendly material. However, its electrical properties are compromised due to space charge accumulation during operation, limiting its application in high-voltage DC cable insulation. This study investigates the effect and mechanism of SiO2 with a DDS surface hydrophobic treatment on space charge suppression and the electrical properties of PP composites. The PP matrix was doped with SiO2 nanostructures, both with a DDS surface hydrophobic treatment and untreated as a control group. The functional group structure and dispersion of nanostructured SiO2 in the matrix were characterized. The findings reveal that the incorporation of SiO2 nanostructures effectively mitigates charge accumulation in PP composites. However, a high concentration of unsurfaced nanostructures tends to agglomerate, resulting in inadequate space charge suppression and a diminished DC breakdown field strength. Nonetheless, surface treatment improves the dispersion of SiO2 within the matrix. Notably, the composite containing 1.0 wt% of surface hydrophobic SiO2 exhibits the least space charge accumulation. Compared to the base material PP, the average charge density is reduced by 83.9% after the 1800 s short-circuit discharges. Moreover, its DC breakdown field strength reaches 3.45 × 108 V/m, surpassing pure PP by 19.4% and untreated SiO2/PP composites of the same proportion by 24.0%.

The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections.

Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.

Rare pulmonary embolism in a pregnant patient: A primary diffused pulmonary artery myxofibrosarcoma case report.

A 37-year-old female patient presented with shortness of breath, cough, and chest pain complaints from the 12th week of her first pregnancy. At the 28th week, labor induction had to be performed because of severe dyspnea and hyoxemia. Thereafter, a diffused pulmonary embolism was detected by echocardiography and CT angiography, without histological diagnosis. Pulmonary endarterectomy was performed, and it was found during operation that a huge, lobular mass originated in the posterior wall and extended throughout the vasculature of both lungs, and a mucinous pellicle covered the entire pulmonary endothelium. Pathology revealed a low-grade myxofibrosarcoma with positive vimentin and SMA, partially positive CD-34.

The Correlation Between MicroRNAs and Diabetic Retinopathy.

Micro ribonucleic acids (miRNAs), as a category of post-transcriptional gene inhibitors, have a wide range of biological functions, are involved in many pathological processes, and are attractive therapeutic targets. Considerable evidence in ophthalmology indicates that miRNAs play an important role in diabetic retinopathy (DR), especially in inflammation, oxidative stress, and neurodegeneration. Targeting specific miRNAs for the treatment of DR has attracted much attention. This is a review focusing on the pathophysiological roles of miRNAs in DR, diabetic macular edema, and proliferative DR complex multifactorial retinal diseases, with particular emphasis on how miRNAs regulate complex molecular pathways and underlying pathomechanisms. Moreover, the future development potential and application limitations of therapy that targets specific miRNAs for DR are discussed.

Green Synthesis of Metallic Nanoparticles and Their Potential Applications to Treat Cancer.

Nanoparticle synthesis using microorganisms and plants by green synthesis technology is biologically safe, cost-effective, and environment-friendly. Plants and microorganisms have established the power to devour and accumulate inorganic metal ions from their neighboring niche. The biological entities are known to synthesize nanoparticles both extra and intracellularly. The capability of a living system to utilize its intrinsic organic chemistry processes in remodeling inorganic metal ions into nanoparticles has opened up an undiscovered area of biochemical analysis. Nanotechnology in conjunction with biology gives rise to an advanced area of nanobiotechnology that involves living entities of both prokaryotic and eukaryotic origin, such as algae, cyanobacteria, actinomycetes, bacteria, viruses, yeasts, fungi, and plants. Every biological system varies in its capabilities to supply metallic nanoparticles. However, not all biological organisms can produce nanoparticles due to their enzymatic activities and intrinsic metabolic processes. Therefore, biological entities or their extracts are used for the green synthesis of metallic nanoparticles through bio-reduction of metallic particles leading to the synthesis of nanoparticles. These biosynthesized metallic nanoparticles have a range of unlimited pharmaceutical applications including delivery of drugs or genes, detection of pathogens or proteins, and tissue engineering. The effective delivery of drugs and tissue engineering through the use of nanotechnology exhibited vital contributions in translational research related to the pharmaceutical products and their applications. Collectively, this review covers the green synthesis of nanoparticles by using various biological systems as well as their applications.

Down-regulation of ETS2 inhibits the invasion and metastasis of renal cell carcinoma cells by inducing EMT via the PI3K/Akt signaling pathway.

V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2), belonging to the ETS family of transcription factors, is implicated in a broad range of cellular functions. Recently, ETS2 has been found playing an important role in the progression of some types of cancers. However, it remains unclear whether ETS2 has any effects on renal cell carcinoma (RCC). In this study, we investigated the biological functions of ETS2 in RCC. The results showed that ETS2 was highly expressed in RCC tissues and cell lines and its expression had an association with clinicopathological characteristics of RCC patients. In addition, down-regulation of ETS2 significantly inhibited RCC cell invasion in vitro and metastasis in vivo as well as suppressed the epithelial-mesenchymal transition (EMT) process. We also found that ETS2 down-regulation significantly reduced the levels of PI3K and Akt phosphorylation in RCC cells. Taken together, we suggest that ETS2 is of potential value as a molecular target for RCC treatment.

Sevoflurane preconditioning promotes activation of resident CSCs by transplanted BMSCs via miR-210 in a rat model for myocardial infarction.

OBJECTIVE: To assess the effect of sevoflurane preconditioning (SFpre) on bone marrow mesenchymal stem cells (BMSCs) for the treatment of acute myocardial infarction. RESULTS: 24 hours after the transplantation, decreased apoptosis of implanted BMSCs and up-regulation of cytokines expression were found within the ischemic area in SFpreBMSCs group compared with BMSCs group (P < 0.05). 4 weeks later, SFpreBMSCs group showed more viable implanted BMSCs, CSC-derived cardiomyocytes, and higher vessel and myocardial density within the infarcted region and improved cardiac function, compared with control and BMSCs groups (P < 0.05). Compared with untreated BMSCs, promoted migration, inhibited apoptosis, increased cytokine secretion, and enhanced activation to CSCs were detected in SFpreBMSCs exposed to profound hypoxia and serum deprivation, via up-regulating miR-210 expression (P < 0.05). CONCLUSIONS: Sevoflurane preconditioning can protect BMSCs against hypoxia by activating miR-210 expression and promote their paracrine functions and effects on resident CSCs. METHODS: After the preconditioning, rat BMSCs (SFpreBMSCs group) were transplanted into rat AMI models, while BMSCs group received unconditioned BMSCs. Apoptosis and paracrine functions of the transplanted BMSCs, angiogenesis, resident cardiac stem cells (CSCs) derived myocardial regeneration, cardiac function and remodeling were assessed at various time points. In vitro experiments were performed to determine the expression of miR-210 in BMSCs exposed to sevoflurane and the effect of sevoflurane on BMSCs' migration, apoptosis and secretion of cytokines under hypoxic condition, as well as cytokine-induced CSCs activation.

Edaravone promotes activation of resident cardiac stem cells by transplanted mesenchymal stem cells in a rat myocardial infarction model.

OBJECTIVE: To explore the effect of edaravone on bone marrow mesenchymal stem cells (BMSCs) transplanted to treat acute myocardial infarction (AMI) and the underlying mechanism. METHODS: After pretreatment or treatment with edaravone under conditions of deep hypoxia and serum deprivation, the rat BMSCs were evaluated for reactive oxygen species (ROS), Akt pathway, apoptosis, migration, and paracrine function mediating cardiac stem cell (CSC) activation. Edaravone-pretreated BMSCs, control-released edaravone, and BMSCs were respectively transplanted into a rat AMI model. Apoptosis and paracrine functions of the BMSCs, resident CSC activation, and myocardial regeneration and function were measured at various time points. RESULTS: Compared with the control and edaravone pretreatment, edaravone treatment showed significantly increased apoptosis inhibition, migration, and cytokine secretion of BMSCs under an in vitro deep hypoxia and serum deprivation condition (P < .05), via inhibiting intracellular accumulation of ROS and prolonging the Akt pathway activation. At 24 hours postoperatively, up-regulated expression of cytokines within the transplanted area, and decreased apoptotic BMSCs, were detected in the BMSC + edaravone group, compared with the BMSCs and edaravone pretreatment BMSC groups (n = 10 for each group, P < .05). Four weeks later, the BMSCs + edaravone group showed more CSCs, CSC-derived cardiomyocytes, new vessels, and myocardial density within the ischemic area, and improved ejection fraction, compared with the other groups (n = 10 in each group, P < .05). CONCLUSIONS: Edaravone can protect the BMSCs against hypoxia and activate their potential to activate CSCs via the Akt pathway. The combined treatment can promote angiogenesis, resident CSC-mediated myocardial regeneration, and cardiac function after AMI, providing a new strategy for cell therapy.

Clinicopathological significance of matrix metalloproteinase 2 protein expression in patients with renal cell carcinoma: A case-control study and meta-analysis.

BACKGROUND: Numerous previous studies explored the influence of matrix metalloproteinase 2 (MMP-2) expressions on renal cell carcinoma (RCC), yet inconsistent results were reported. OBJECTIVE: This study aims to derive a more precise estimation of the associations between MMP-2 and RCC. METHODS: A total of 115 patients with RCC were selected; meanwhile, 45 patients with traumatic rupture of renal cysts or renal calculi were recruited and normal kidney tissues were collected as control group. The expression level of MMP-2 protein was detected by using immunohistochemistry. A meta-analysis was performed by using Comprehensive Meta-analysis 2.0 (CMA 2.0). RESULTS: The positive expression rate of MMP-2 protein in the RCC tissues was evidently higher than that in the normal renal tissues (P < 0.001). The positive expression rate of MMP-2 protein in patients with tumor size > 5 cm, with lymph node metastasis (LNM), with well-differentiated RCC, and stage III-IV RCC was significantly higher, compared with the patients with tumor size ≤ 5 cm, without LNM, with moderate/low-differentiated RCC, and with stage I-II RCC, respectively (all P < 0.05). There was statistical significance in the 5-year survival rate between the patients with positive MMP-2 protein expression and those with negative MMP-2 protein expression (P = 0.037). These results were further confirmed by the meta-analysis. CONCLUSION: MMP-2 protein expression is significantly associated with historical grade, TNM stage, tumor size and LNM in RCC, suggesting that MMP-2 may serve as a biological marker for the prognosis in RCC.

bFGF binding cardiac extracellular matrix promotes the repair potential of bone marrow mesenchymal stem cells in a rabbit model for acute myocardial infarction.

To assess the effect of basic fibroblast growth factor-binding extracellular matrix (bFGF-ECM) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation on acute myocardial infarction (AMI) and explore the underlying mechenisms. Rabbit hearts were processed by decellularization with sodium dodecyl sulfate (SDS) perfusion, heparin immobilization, bFGF-binding and homogenization, for preparation of bFGF-binding cardiac ECM suspension (bFGF-ECM). Thereafter, the characteristics of bFGF release were analyzed in vitro. Following ligation of the mid-third of the left anterior descending artery, the rabbits were divided into a control group (no treatment), BMSCs group (BMSCs transplantation), bFGF-ECM group (bFGF-ECM implantation), and BMSCs + bFGF-ECM group (BMSCs and bFGF-ECM implantation). Apoptosis and differentiation of implanted BMSCs, and the left ventricular (LV) remodeling and function were assessed. The ex vivo proliferation, apoptosis, migration and differentiation of BMSCs were determined after exposure to bFGF and/or ECM. The ECM could sustainably release bFGF. 24 h and 6 weeks after the operation, improved viability and differentiation of the implanted BMSCs, as well as inhibited dilatation and preserved function of the left ventricle (LV), were significant in the BMSCs + bFGF-ECM group compared with other groups (P < 0.05), although BMSCs and ECM-bFGF groups also showed better results than control group (P < 0.05). Additionally, ECM and bFGF showed a synergistic effect on BMSCs proliferation, viability, migration and differentiation. The combination of bFGF-binding ECM and BMSCs implantation may promote myocardial regeneration and LV function, and become a new strategy for the treatment of AMI.

HGF and IGF-1 promote protective effects of allogeneic BMSC transplantation in rabbit model of acute myocardial infarction.

OBJECTIVES: To explore effects of hepatocyte growth factor (HGF) combined with insulin-like growth factor 1 (IGF-1) on transplanted bone marrow mesenchymal stem cells (BMSCs), for treatment of acute myocardial ischaemia. MATERIALS AND METHODS: After ligation of the left anterior descending artery, rabbits were divided into a Control group, a Factors group (HGF+IGF-1), a BMSC group and a Factors+BMSCs group. Allogenous BMSCs (1 × 10(7)) and/or control-released microspheres of 2 µg HGF+2 µg IGF-1 were intramyocardially injected into infarcted regions. Apoptosis and differentiation of implanted BMSCs, histological and morphological results, and cardiac remodelling and function were evaluated at different time points. In vitro, BMSCs were exposed to HGF, IGF-1 and both (50 ng/ml) and subsequently proliferation, migration, myocardial differentiation and apoptosis induced by hypoxia, were analysed. RESULTS: Four weeks post-operatively, the above indices were significantly improved in Factors+BMSCs group compared to the others (P < 0.01), although Factors and BMSCs group also showed better results than Control group (P < 0.05). In vitro, HGF promoted BMSC migration and differentiation into cardiomyocytes, but inhibited proliferation (P < 0.05), while IGF-1 increased proliferation and migration, and inhibited apoptosis induced by hypoxia (P < 0.05), but did not induce myocardial differentiation. Combination of HGF and IGF-1 significantly promoted BMSCs capacity for migration, differentiation and lack of apoptosis (P < 0.05). CONCLUSIONS: Combination of HGF and IGF-1 activated BMSCs complementarily, and controlled release of the two factors promoted protective potential of transplanted BMSCs to repair infarcted myocardium. This suggests a new strategy for cell therapies to overcome acute ischemic myocardial injury.

Delayed enrichment for c-kit and inducing cardiac differentiation attenuated protective effects of BMSCs' transplantation in pig model of acute myocardial ischemia.

OBJECTIVE: To investigate the effects of immature cardiomyocytes differentiated from c-kit(+) bone marrow mesenchymal stem cells (BMSCs) against acute myocardial infarction (AMI). METHODS: Miniswine passage 8 BMSCs were enriched for c-kit and induced by 5 µM 5-azacytidine (AZA) for 14 days, and a second enrichment for the dihydropyridine receptor subunit α2δ1 was performed (enriched BMSCs). Thereafter, enriched BMSCs were analyzed by determining cardiac differentiation, secretion function, and the effects of these secreted factors on cardiac stem cells (CSCs). Miniswine with AMI were divided into control, primary BMSCs' (PB), and enriched BMSCs' (EB) groups. Autologous BMSCs were intramyocardially injected into the ischemic regions in PB and EB groups. The following indices were evaluated at different time points, including paracrine of implanted BMSCs, histological and morphological analysis, myocardial perfusion, and cardiac function. RESULTS: As shown by in vitro study, enrichment + AZA significantly promoted BMSCs to express cardiac-specific markers and format action potential, but down-regulated the expression of VEGF and bFGF, consequently attenuated BMSCs-inducing CSCs proliferation, migration, and differentiation. The in vivo experiments revealed similar results like the in vitro 6 weeks postoperatively. And in EB group, there were decreased angiogenesis and myocardial perfusion, attenuated resident CSCs-mediated myocardial regeneration, and consequently impaired cardiac function compared with PB group. CONCLUSIONS: This pretreatment promoted BMSCs to differentiate into myocardiocytes both in vitro and in vivo, but impaired their paracrine function and effects on resident CSCs, suggesting that inducing cardiac differentiation alone may not improve protective effects of BMSCs transplantation on AMI.

Steroidal saponins from Paris polyphylla suppress adhesion, migration and invasion of human lung cancer A549 cells via down-regulating MMP-2 and MMP-9.

BACKGROUND: Tumor metastases are the main reasons for oncotherapy failure. Paris polyphylla (Chinese name: Chonglou) has traditionally been used for its anti-cancer actions. In this article, we focus on the regulation of human lung cancer A549 cell metastases and invasion by Paris polyphylla steroidal saponins (PPSS). MATERIALS AND METHODS: Cell viability was evaluated in A549 cells by MTT assay. Effects of PPSS on invasion and migration were investigated by wound-healing and matrigel invasion chamber assays. Adhesion to type IV collagen and laminin was evaluated by MTT assay. Expression and protease activity of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, were analyzed by Western blotting and gelatin zymography, respectively. RESULTS: PPSS exerted growth inhibitory effects on A549 cells, and effectively inhibited A549 cell adhesion, migration and invasion in a concentration-dependent manner. Western blotting and gelatin zymography analysis revealed that PPSS inhibited the expression and secretion of MMP-2 and MMP-9 in A549 cells. CONCLUSIONS: PPSS has the potential to suppress the migration, adhesion and invasion of A549 cells. PPSS could be a potential candidate for interventions against lung cancer metastases.

Exogenous basic fibroblast growth factor promotes cardiac stem cell-mediated myocardial regeneration after miniswine acute myocardial infarction.

OBJECTIVE: To investigate the effects of exogenous basic fibroblast growth factor (bFGF) on myocardial regeneration after acute myocardial infarction (AMI). METHODS: AMI models were established by ligating the mid-third of left anterior descending artery, thereafter, miniswines were randomly divided into control (none treatment, n = 6) and bFGF groups (n = 6). For the bFGF group, bFGF (100 µg) was injected with a sterile microinjection at five sites within the ischemic region. 5-Bromo-2-deoxyuridine (250 mg) was administrated intravenously twice a week after the operation, to label cells undergoing DNA replication. The expression of stromal cell-derived factor-1α (SDF-1α) and CXC chemokine receptor 4 (CXCR4), cardiac stem cell-mediated myocardial regeneration, myocardial apoptosis, histological and immunohistochemical analyses, and cardiac function were evaluated at different time points. RESULTS: Four weeks after bFGF therapy, it showed an increased vessel density and myocardial perfusion (P < 0.001), upregulative expression of SDF-1α and CXCR4 (P < 0.001), increased c-kit and 5-bromo-2-deoxyuridine-positive cells (P < 0.001), enhanced myocardial viability (P < 0.001), and improved left ventricular ejection fraction (P = 0.007), compared with the control. CONCLUSION: Exogenous bFGF was shown to have increased angiogenesis and myocardial perfusion, promoted myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improved the cardiac function, which may provide a new therapeutic strategy for AMI.

Mechanisms of the protective effects of BMSCs promoted by TMDR with heparinized bFGF-incorporated stent in pig model of acute myocardial ischemia.

This study investigates the mechanism by which transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor incorporated degradable stent implantation (TMDRSI) enhanced effects of bone marrow mesenchymal stem cells (BMSCs) transplantation against acute ischemic myocardial injury. After the mid-third of left anterior descending artery was ligated, miniswine were divided into none-treatment group (control, n = 6), BMSCs implantation group (C, n = 6), TMDRSI group (TS, n = 6) and TMDRSI and BMSCs implantation group (TSC, n = 6). Two channels of 3.5 mm diameter were established by a self-made drill in the ischemic region, into which a stent was implanted for the TS and TSC groups. Autologous BMSCs were transplanted into the ischemic region in C group or around the channels in TSC group. Expression of von Willebrand factor, vascular endothelial growth factor, interleukin-1ß, transforming growth factor-ß(3) , cell proliferation and apoptosis, histological and morphological analyses, myocardial remodelling and cardiac function were evaluated at different time-points. Six weeks after the operation, the above indices were significantly improved in TSC group compared with others (P < 0.05), though C and TS groups also showed better results than the control group (P < 0.05). The new method was shown to have activated paracrine pathway of transplanted BMSCs, increased survival and differentiation of such cells, and enhanced effects of BMSCs transplantation on myocardial remodelling, which may provide a new strategy for cell therapies against acute ischemic myocardial injury.

Mid-term effect of stem cells combined with transmyocardial degradable stent on swine model of acute myocardial infarction.

BACKGROUND: We aimed to confirm the mid-term results of the new method combined with bone marrow-derived mesenchymal stem cells (MSCs) transplantation and transmyocardial drilling revascularization (TMDR) with degradable stent incorporated with basic fibroblast growth factor and heparin. METHODS: The miniswine underwent acute myocardial infarction by ligation of the left anterior descending coronary artery. Transmyocardial channels with 3.5 mm diameter (TMDR) were made by mechanical drilling in the infarction territory and basic fibroblast growth factor stents were implanted into the channels. Animals were randomly divided into the following four groups (n=6 in each): control; II: MSCs implantation; III: TMDR+stent implantation; IV: TMDR+stent implantation+MSCs implantation. Three months postoperatively, ECG-gated single photon emission computed tomography, histopathological examination, and reverse transcription-polymerase chain reaction were carried out. RESULTS: Left ventricular ejection fraction and myocardial perfusion were significantly improved in group IV than that in other groups (P<0.05). Compared with other groups, vessel density was augmented and cell apoptosis was reduced in group IV (P<0.01). Reverse transcription-polymerase chain reaction results showed that the expression levels of von Willebrand factor, transforming growth factor-beta3, vascular endothelial growth factor, and interleukin-1beta were much higher in group IV than that in other groups (P<0.05). CONCLUSION: Three months after operation, MSCs transplantation combined with TMDR and degradable stent significantly improved cardiac function, enhanced neovascular density, reduced infarcted size, improved ventricular remodeling, and reduced cardiac myocyte apoptosis, and therefore provides strong information for clinical trial.

A new transmyocardial degradable stent combined with growth factor, heparin, and stem cells in acute myocardial infarction.

AIMS: We developed a new method-transmyocardial drilling revascularization (TMDR) with absorbable stent incorporated with basic fibroblast growth factor (bFGF) and heparin. The present study tested the effect of this method with transplantation of bone marrow-derived stem cells (BMSCs) in acute myocardial infarction. METHODS AND RESULTS: Infarction was produced in mini-swine by ligating the left anterior descending (LAD) coronary artery. TMDR of 3.0 mm in diameter was made by mechanical drilling in the infarcted area. The animals that had LAD ligation were divided into six groups according to the procedures followed (n = 6 in each): control; T (TMDR); C (cell implantation); TS (TMDR+stent implantation); TC (TMDR+cell implantation); TSC (TMDR+stent implantation+cell implantation). Left ventricular (LV) function, myocardial perfusion, vascular density, and histological and morphological analyses were evaluated pre-operatively and at 30 min and 6 weeks post-operatively. Six weeks after operation, the above indices were significantly better in the TSC group than in other groups (P < 0.001 compared with the control group, and P < 0.05 or 0.01 compared with the TS and TC groups), although TS and TC also showed better results than the control group (P < 0.05). CONCLUSION: We have demonstrated in a pig model that an intramyocardial stent implanted with slow release of bFGF, heparin, and BMSC transplantation may significantly increase LV function, cardiac blood flow, and vascular density. Therefore, the present study may provide a new method for the surgical treatment of myocardial infarction.