Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

[Intervention effects of estradiol on myocardial ischemia- reperfusion injury of rat and its mechanisms].

Objective: To study the effects of estradiol (E2) on alleviating myocardial ischemia/reperfusion(I/R) injury through estrogen receptorß(ERß) mediated extracellular regulated protein kinases(ERK) pathway activation. Methods: Eighty-four adult female SD rats were ovariectomized and randomly divided into control group, NC siRNA adeno-associated virus (AAV) group received sham operation, the myocardial I/R injury model was prepared by ligation of the left anterior descending coronary artery in I/R group, E2+I/R group, NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group and ERß-siRNA AAV+E2+I/R group. E2+I/R group, NC siRNA AAV+E2+I/R group and ERß-siRNA AAV+E2+I/R group were treated with E2 0.8 mg/kg by gavage for 60 days before modeling. NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group, and ERß-siRNA AAV+E2+I/R group were treated with AAV by caudal vein injection 24 h before modeling. After 120 min of reperfusion, the contents of serum lactate dehydrogenase (LDH), phosphocreatine kinase (CK), phosphocreatine kinase isoenzyme (CK-MB), myocardial infarction area and the expressions of ERß, p-ERK, the contents of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1 ß), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) in myocardium were measured. Results: The contents of serum LDH, CK, CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 ß, MDA in myocardium of I/R group were higher than those of the control group, the expression levels of ERß and p-ERK and the content of T-AOC were lower than those in the control group (P＜0.05). The contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 ß and MDA in myocardium of E2+I/R group were lower than those of the I/R group, the expression levels of ERß and p-ERK and the content of T-AOC were higher than those of the I/R group(P＜0.05). After knockdown ERß by caudal vein injection of ERß-siRNA AAV, the contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 ß and MDA in myocardium of ERß-siRNA AAV+E2+I/R group were higher than those of NC-siRNA AAV+E2+I/R, the expression levels of ERß and p-ERK and the content of T-AOC were lower than those of NC-siRNA AAV+E2+I/R(P＜0.05). Conclusion: E2 has protective effects on myocardial I / R injury in ovariectomized rats, which are related to the promotion of ERß mediating the activation of ERK pathway, reducing inflammatory and oxidative stress responses.

The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer.

Colorectal cancer (CRC) is the third most common diagnosed cancer of which risk factors include unhealthy diet, smoking, and chronic inflammation. Weakening the inflammatory response emerges as an effective therapeutic strategy to prevent the progression of CRC. Inflammatory macrophages produce substantial amounts of immunoregulatory metabolite itaconate, which is synthesized by the immune response gene 1 (Irg1). In this study, we use a membrane-permeable itaconate derivative, dimethyl itaconate (DI), for the protection against CRC in mouse model. DI decreased the high inflammatory state of ulcerative colitis and reduced the colitis-associated cancer (CAC) risk. Mechanistically, DI inhibited the secretion of the cytokines IL-1ß and CCL2 from intestinal epithelial cells, and therefore reduced the recruitment of macrophages into tumor microenvironment. Meanwhile, the decrease of macrophage infiltration was accompanied by a decrease of myeloid-derived suppressor cell (MDSC) infiltration and the differentiation of T cell subsets into cytotoxic T cells. We showed that itaconate derivative limits inflammatory response, indicating a negative feedback loop that involves an inflammatory agent and itaconate. Our findings demonstrate the potential application of DI for the prevention of colitis-associated CRC. KEY MESSAGES: Dimethyl itaconate (DI) suppresses ulcerative colitis and colitis-associated colorectal cancer DI decreases infiltration of macrophages and myeloid-derived suppressor cells into tumor DI weakens the inflammatory response via inhibiting the secretion of IL-1ß and CCL2.

Actin­like protein 8 executes a promoting function in the malignant progression of endometrial cancer: identification of a promising biomarker.

Endometrial cancer (EC) is generally considered as a disease that affects older women. We attempt to explore the role of actin­like protein 8 (ACTL8) in EC and how it achieves its function. Based on the data from The Cancer Genome Atlas (TCGA), we found that ACTL8 expression was up-regulated in EC tissues and correlated with shorter overall survival of EC patients. ACTL8 expression was significantly associated with age, clinical-stage, or grade. Cox proportional hazards model analysis revealed that ACTL8 expression, grade, and clinical-stage were promising independent prognostic factors of EC. Knockdown of ACTL8 repressed the proliferative, migrating and invading capabilities of human EC cell lines KLE and Ishikawa. Silencing ACTL8 up-regulated the negative cell cycle regulator p21 and epithelial marker E-cadherin, and down-regulated the positive cell cycle regulator Cyclin A, mesenchymal markers MMP-9 and N-cadherin in KLE cells. Collectively, these outcomes illustrated that ACTL8 might act as a tumor facilitator during EC progression.

Intracavitary/Interstitial Applicator Plus Distal Parametrial Free Needle Interstitial Brachytherapy in Locally Advanced Cervical Cancer: A Dosimetric Study.

PURPOSE: To explore the dosimetric advantage of combining intracavitary/interstitial applicator with distal parametrial free needle interstitial brachytherapy (IC/IS+ISBT DP) based on MRI for locally advanced cervical cancer. METHODS AND MATERIALS: 77 IC/IS+ISBT DP treatment plans were developed for 34 patients with locally advanced cervical cancer from June 2016 to January 2020 in this study. We removed the free needles and devised a new IC/ISBT treatment plan based on the same principle. We then compared the dosimetric differences of D90, D98, V100, V150, V200 for HR-CTV (high-risk clinical target volume), D90 for IR-CTV (Intermediate risk-CTV) and D2cc for OARs (organs at risk) between the two groups of treatment plans for the same patient, and the paired T test was performed in parallel. Further, the dosage differences between the two group plans under different parametrial extension widths (the maximum distance of HR-CTV from the vertical direction of the uterine tandem at coronal position) were compared. The survival rate was calculated using the Kaplan-Meier method. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined by Cox regression method. RTOG/EORTC criteria were used to grade toxicities. RESULTS: A total of 297 free needles were used, with a weight ratio of 15.8% ± 0.11, and a mean insertion depth of 6.52cm ± 2.8cm. D90, D98, V100 for HR-CTV, and D90 for IR-CTV for IC/IS+ISBT DP were significantly higher than IC/ISBT for which free needles were removed (p<0.05). And the V200 for HR-CTV and D2cc for bladder, rectum and sigmoid were decreased (p<0.05). When the parametrial extension widths were greater than 3cm, the HR-CTV D90 and the D2CC for rectum, bladder and sigmoid colon for IC/IS-ISBT DP were advantageous compared to IC/ISBT (p<0.05). The 2-yr OS, PFS and local control rate (LC) were 82.3, 66.8, and 93.1%, respectively. Parametrial extension widths was the only statistically prognostic factors for PFS (p = 0.002) on univariate analysis. No grade 3 or 4 Treatment-related toxicities were observed. CONCLUSION: Our institutional experiences showed that IC/IS+ISBT DP is an effective treatment for cervical cancer patients with distal parametrial extension. IC/IS-ISBT DP had dosage advantage and clinical feasibility in locally advanced cervical cancer with distal parametrial extension when the parametrial extension widths were greater than 3cm.

Impact of cross-correlated sine-Wiener noises in the gene transcriptional regulatory system.

We studied fluctuation-induced switching processes in the gene transcriptional regulatory system under cross-correlated sine-Wiener (CCSW) noises. It is numerically demonstrated that the increase of the multiplicative noise intensity A and cross-correlation time τ in CCSW noises can reduce the concentration of the TF-A monomer and switch to an "off" state. In addition, when the cross-correlation time τ is small, the increase of the additive noise intensity B leads to a switch of the process from "off"→"on". Simultaneously, the increase of the cross-correlation intensity λ of CCSW noises contributes to maintaining the current state. When the cross-correlation time is large, the high concentration state has two peaks and the stationary probability distribution presents a three-peak structure.

Effect of Cross-Linked Hyaluronate Scaffold on Cartilage Repair: An In Vivo Study.

OBJECTIVE: To determine the safety and effectiveness of a cross-linked sodium hyaluronate (CHA) scaffold in cartilage repair. METHODS: Physicochemical properties of the scaffold were determined. The safety and effectiveness of the scaffold for cartilage repair were evaluated in a minipig model of a full-thickness cartilage defect with microfracture surgery. Postoperative observation and hematological examination were used to evaluate the safety of the CHA scaffold implantation. Pathological examination as well as biomechanical testing, including Young's modulus, stress relaxation time, and creep time, were conducted at 6 and 12 months postsurgery to assess the effectiveness of the scaffold for cartilage repair. Furthermore, type II collagen and glycosaminoglycan content were determined to confirm the influence of the scaffold in the damaged cartilage tissue. RESULTS: The results showed that the routine hematological indexes of the experimental animals were within the normal physiological ranges, which confirmed the safety of CHA scaffold implantation. Based on macroscopic observation, it was evident that repair of the defective cartilage in the animal knee joint began during the 6 months postoperation and was gradually enhanced from the central to the surrounding region. The repair smoothness and color of the 12-month cartilage samples from the operation area were better than those of the 6-month samples, and the results for the CHA scaffold implantation group were better than the control group. Greater cell degeneration and degeneration of the adjacent cartilage was found in the implantation group compared with the control group at both 6 and 12 months postoperation, evaluated by O'Driscoll Articular Cartilage Histology Scoring. Implantation with the CHA scaffold matrix promoted cartilage repair and improved its compression capacity. The type II collagen level in the CHA scaffold implantation group tended to be higher than that in the control group at 6 months (2.33 ± 1.50 vs 1.68 ± 0.56) and 12 months postsurgery (3.37 ± 1.70 vs 2.06 ± 0.63). The GAG content in the cartilage of the control group was significantly lower than that of the experimental group (2.17 ± 0.43 vs 3.64 ± 1.17, P = 0.002 at 6 months and 2.27 ± 0.38 vs 4.12 ± 1.02, P = 0.002 at 12 months). Type II collagen and glycosaminoglycan content also demonstrated that CHA was beneficial for the accumulation of both these vital substances in the cartilage tissue. CONCLUSIONS: The CHA scaffold displayed the ability to promote cartilage repair when applied in microfracture surgery, which makes it a promising material for application in the area of cartilage tissue engineering.

Utrecht Interstitial Applicator Shifts and DVH Parameter Changes in 3D CT-based HDR Brachytherapy of Cervical Cancer.

BACKGROUND: For brachytherapy of cervical cancer, applicator shifts can not be avoided. The present investigation concerned Utrecht interstitial applicator shifts and their effects on organ movement and DVH parameters during 3D CT-based HDR brachytherapy of cervical cancer. MATERIALS AND METHODS: After the applicator being implanted, CT imaging was achieved for oncologist contouring CTVhr, CTVir, and OAR, including bladder, rectum, sigmoid colon and small intestines. After the treatment, CT imaging was repeated to determine applicator shifts and OARs movements. Two CT images were matched by pelvic structures. In both imaging results, we defined the tandem by the tip and the base as the marker point, and evaluated applicator shift, including X, Y and Z. Based on the repeated CT imaging, oncologist contoured the target volume and OARs again. We combined the treatment plan with the repeated CT imaging and evaluated the change range for the doses of CTVhr D90, D2cc of OARs. RESULTS: The average applicator shift was -0.16 mm to 0.10 mm for X, 1.49 mm to 2.14 mm for Y, and 1.9 mm to 2.3 mm for Z. The change of average physical doses and EQD2 values in Gyα/ß range for CTVhr D90 decreased by 2.55 % and 3.5 %, bladder D2cc decreased by 5.94 % and 8.77 %, rectum D2cc decreased by 2.94 % and 4 %, sigmoid colon D2cc decreased by 3.38 % and 3.72 %, and small intestines D2cc increased by 3.72 % and 10.94 %. CONCLUSIONS: Applicator shifts and DVH parameter changes induced the total dose inaccurately and could not be ignored. The doses of target volume and OARs varied inevitably.

Therapeutic effects of baicalin on monocrotaline-induced pulmonary arterial hypertension by inhibiting inflammatory response.

BACKGROUND: Baicalin has been shown to possess various pharmacological actions, a recent study revealed that baicalin can attenuate pulmonary hypertension and pulmonary vascular remodeling through the inhibition of pulmonary artery smooth muscle cell proliferation, however, the potential mechanism remains unexplored. In this study, we investigated the therapeutic effect of baicalin on a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and attempted to further clarify the possible mechanisms underlying the anti-inflammatory. METHODS AND RESULTS: Our research showed that compared with MCT-induced PAH model rats, rats administered intragrastically with 100mg/kg baicalin showed the following after two weeks: the right ventricular systolic pressure (RVSP) and the right ventricle/left ventricle plus septum (RV/LV+S) ratio were lower (P<0.05); the intima thickening and luminal stenosis were improved (P<0.05); the mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin-11ß (IL-1ß), IL-6, and endothelin-1 (ET-1) were obviously reduced by quantitative reverse transcription-polymerase chain reaction (qRT-PCR); the protein expression of transforming growth factor-ß1 (TGF-ß1), intercellular cell adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) were significantly decreased (P<0.05); and the expression of inhibitor of NF-κB (I-κB) was increased (P<0.05) through immunohistochemical and western blot. CONCLUSION: We studied the protective effects of baicalin against the lung and heart damage in experimental PAH rats; the therapeutic effects maybe through inhibiting vascular endothelial inflammatory response.

Bone marrow mesenchymal stem cells improve myocardial function in a swine model of acute myocardial infarction.

The aim of the current study was to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in acute myocardial infarction (AMI). AMI was induced in mini­swine by ligating the left anterior descending coronary artery, and BMSCs (1x107) were injected via a sterile microinjection into the ischemic area. Six months postoperatively, electrocardiograph­gated single photon emission computed tomography revealed that the myocardial filling defect was reduced and the left ventricular ejection fraction was improved in the BMSC group compared with the control group (P<0.05). Histopathological examination indicated that, in the BMSC treatment group, the percentage of survived myocardial tissue and the vessel density were increased, and the percentage of apoptosis was decreased compared with controls (P<0.05). Reverse transcription­polymerase chain reaction results indicated that the expression levels of multiple inflammatory factors were significantly upregulated in the BMSC group compared with levels in the control group (P<0.05). In conclusion, the present study demonstrated that BMSC injection significantly improved cardiac function and reduced infarct size in six months, indicating that this method may be valuable for future study in clinical trials.

Role of PLC-PIP2 and cAMP-PKA signal pathways in radiation-induced immune-suppressing effect.

OBJECTIVE: The purpose of the present study was to observe the changes in CD4+CD25+Nrp1+Treg cells after irradiation with different doses and explore the possible molecular mechanisms involved. METHODS: ICR mice and mouse lymphoma cell line (EL-4 cells) was used. The expressions of CD4, CD25, Nrp1, calcineurin and PKC-α were detected by flow cytometry. The expressions of TGF-ß1, IL-10, PKA and cAMP were estimated with ELISA. RESULTS: At 12 h after irradiation, the expression of Nrp1 increased significantly in 4.0 Gy group, compared with sham-irradiation group (P<0.05) in the spleen and thymus, respectively, when ICR mice received whole-body irradiation (WBI). Meanwhile the synthesis of Interleukin 10 (IL-10) and transforming growth factor-ß1 (TGF-ß1) increased significantly after high dose irradiation (HDR) (> or = 1.0 Gy). In addition, the expression of cAMP and PKA protein increased, while PKC-α, calcineurin decreased at 12h in thymus cells after 4.0 Gy X-irradiation. While TGF-ß1 was clearly inhibited when the PLC-PIP2 signal pathway was stimulated or the cAMP-PKA signal pathway was blocked after 4.0 Gy X-irradiation, this did not limit the up-regulation of CD4+CD25+Nrp1+Treg cells after ionizing radiation. CONCLUSION: These results indicated that HDR might induce CD4+CD25+Nrp1+Treg cells production and stimulate TGF-ß1 secretion by regulating signal molecules in mice.

Long-term research of stem cells in monocrotaline-induced pulmonary arterial hypertension.

Our previous studies have shown that bone marrow mesenchymal stem cells (BMSCs) can inhibit the progression of pulmonary artery hypertension (PAH) in the monocrotaline (MCT) model in the short term. The aim of this study was to further investigate the long-term effect of BMSCs on PAH and to explore the mechanism of the protective effect including the pulmonary vascular remodeling and cell differentiation. PAH model was established by subcutaneous injection of 50 mg/kg MCT as previously study. Postoperatively, the animals were randomly divided into three groups (n = 10 in each group): control, PAH group, and BMSCs implantation group. Six months after injection, immunology and immunohistochemistry analysis indicated the MCT-induced intima-media thickness in muscular arteries was reduced (P < 0.05); the area of collagen fibers in lung tissue was lower (P < 0.05), and the proliferating cell nuclear antigen level in pulmonary artery smooth muscle cells was decreased (P < 0.05). Immunofluorescence showed that the cells have the ability to differentiate between von Willebrand factor and vascular endothelial growth factor. Six months after intravenous injection, BMSCs could significantly improve pulmonary function by inhibiting the ventricular remodeling and the effect of cell differentiation.

Baicalin protects the myocardium from reperfusion-induced damage in isolated rat hearts via the antioxidant and paracrine effect.

The aim of the present study was to investigate the protective effect of baicalin (BA) against ischemia-reperfusion (I/R) injury in isolated rat hearts. Sprague-Dawley rat hearts were rapidly removed, mounted on a Langendorff apparatus and subjected to 30 min ischemia followed by 30 min reperfusion with Krebs-Henseleit (K-H) solution at 37°C to establish the isolated I/R injury model. All animals (n=50) were randomly divided into five groups (n=10 in each): I, normal control; II, I/R; III, I/R plus 20 mg/kg BA; IV, I/R plus 40 mg/kg BA; and V, I/R plus 80 mg/kg BA. The degree of heart injury caused by the I/R was assessed by evaluating left ventricular function and by detecting the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent and the myocardial superoxide dismutase (SOD) and malondialdehyde (MDA) levels in the isolated rat hearts. Myocardial infarct size and vascular density were assessed using histology and immunohistochemistry. The apoptotic cardiomyocytes were determined using flow cytometry (FCM). Compared with group II, the BA groups demonstrated improved left ventricular function, reduced CK and LDH release in the coronary effluent and increased SOD and MDA activity (P<0.05). Furthermore, histology and immunohistochemistry results showed that the infarct size was reduced and vessel density was augmented in the BA groups (P<0.01) compared with group II. The FCM results indicated that apoptosis was significantly lower in the BA groups than in group II (P<0.05) and that the protective effect was dose-dependent. In conclusion, these results demonstrated that BA exerts a dose-dependent protective effect on I/R injury in isolated rat hearts, the mechanisms of which may be associated with antioxidant and anti-apoptosis properties. To the best of our knowledge, this study is the first evaluation of the efficacy of BA in isolated rat hearts using histology and immunohistochemistry, providing a foundation for the use of BA in the treatment of acute myocardial infarction.

siRNA Suppression of NEDD9 Inhibits Proliferation and Enhances Apoptosis in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies. NEDD9/HEF1/Cas-L is a member of the Cas protein family and is known as a biomarker in multiple cancer types. In this study, we demonstrate for the first time that NEDD9 was upregulated in RCC tissue and cell lines. Immunohistochemical analysis and quantitative RT-PCR analysis showed low expression of NEDD9 in normal renal tissues and high expression in RCC tissues. In addition, in vitro experiments show that expression of NEDD9 was upregulated in RCC cell lines. Through MTT assay, we observed that NEDD9 knockdown inhibited cell proliferation. Furthermore, flow cytometry analysis showed that NEDD9 downregulation induced apoptosis. Together, our data suggest that abnormal NEDD9 protein expression may be a marker for RCC, and NEDD9 knockdown suppresses cell growth.

MUTYH association with esophageal adenocarcinoma in a Han Chinese population.

Adenocarcinoma of esophagus (AE) is a complex disease, affected by a variety of genetic and environmental factors. Much evidence has shown that the MutY glycosylase homologue (MUTYH) plays a key role in the pathogenesis of many cancers. However, there have been no reports on influence on AE in the Han Chinese population. The objective of this study was to investigate this issue. A gene-based association study was conducted using three single nucleotide polymorphisms(SNPs) reported in previous studies. The three SNPs (rs3219463, rs3219472, rs3219489) were genotyped in 207 unrelated AE patients and 249 healthy controls in a case-control study using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The results revealed that the genotype distribution of rs3219472 differed between the case and control groups (OR=1.66,95%CI=1.11-2.48, P=0.012 ), indicating that an association may exist between MUTYH and AE. These findings support a signifcant role for MUTYH in AE pathogenesis in the Han Chinese population.

Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism.

UNLABELLED: Pulmonary arterial hypertension (PAH) is characterized by functional and structural changes in the pulmonary vasculature, and despite the drug treatment that made significant progress, the prognosis of patients with advanced PH remains extremely poor. In the present study, we investigated the early effect of bone marrow mesenchymal stem cells (BMSCs) on experimental high blood flow-induced PAH model rats and discussed the mechanism. BMSCs were isolated, cultured from bone marrow of Sprague-Dawley (SD) rat. The animal model of PAH was created by surgical methods to produce a left-to-right shunt. Following the successful establishment of the PAH model, rats were randomly assigned to three groups (n=20 in each group): sham group (control), PAH group, and BMSC group (received a sublingual vein injection of 1-5 × 10(6) BMSCs). Two weeks after the administration, BMSCs significantly reduced the vascular remodeling, improved the hemodynamic data, and deceased the right ventricle weight ratio to left ventricular plus septal weight (RV/LV+S) (P<0.05). Real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry analysis results indicated that the inflammation factors such as interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) were reduced (P<0.05); the expression of matrix metallo proteinase-9 (MMP-9) was lower (P<0.05); vascular endothelial growth factor (VEGF) was higher in BMSC group than those in PAH group (P<0.05). CONCLUSION: Sublingual vein injection of BMSCs for 2 weeks, significantly improved the lung and heart injury caused by left-to-right shunt-induced PAH; decreased pulmonary vascular remodeling and inflammation; and enhanced angiogenesis.

Association of common polymorphisms in the LRP6 gene with sporadic coronary artery disease in a Chinese population.

BACKGROUND: Genetic factors contribute to the development of coronary artery disease (CAD). Recently, a missense mutation in the low density lipoprotein receptor related protein 6 (LRP6) gene, encoding low density lipoprotein receptor related protein 6, has been implicated in an autosomal dominant form of early-onset CAD. The aim of this study was to determine whether the common variants in LRP6 are associated with sporadic CAD in Chinese. METHODS: A total of 766 CAD patients and 806 healthy controls were included in this study. The presence of angiographic CAD was determined by coronary angiographic analysis. Six signal nucleotide polymorphisms (SNPs) were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: A significant association was detected between rs11054731 in LRP6 intron 2 and CAD in our cohort (P = 0.001). The CC genotype and C allele frequency in the case group were 52% and 72%. Using a dominant model of inheritance, the C allele of rs11054731 was shown to be an independent risk factor for CAD with an OR of 1.45 (95%CI: 1.19 - 1.77, P = 0.0002). With the stratification according to the number of affected coronary arteries, an association was observed between rs11054731 and CAD (P = 0.0002). No significant association was observed between any other SNPs and the risk of CAD. CONCLUSION: The C allele of the rs11054731 within the LRP6 gene was associated with increased risk and extent of CAD in Chinese.

Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension.

INTRODUCTION: Pulmonary hypertension (PH) is a rapidly progressive and fatal disease. In recent years, despite drug treatment made significant progress, the prognosis of patients with advanced PH remains extremely poor. The authors implanted bone marrow-derived mesenchymal stem cells (BMSCs) intravenously into the PH model rats and observed the effect of MSCs on right ventricular (RV) impairments. METHODS: BMSCs were isolated, cultured from bone marrow of rats and stained with the cross-linkable membrane dye in vitro. One week after, a PH model was induced by subcutaneous injection of monocrotaline, the animals were randomly divided into 4 groups (n = 20 in each group): I, control; II, MSCs implantation; III, PH and IV, PH + MSCs implantation. Two weeks after MSCs implantation, the authors observed the MSC survival and transformation by immunofluorescence microscopy. On the other hand, RV hypertrophy and the elevation of systolic pressure were detected by echocardiography. RESULT: Three weeks after monocrotaline injection, RV systolic pressure, mean right ventricular pressure and mean pulmonary arterial pressure were significantly elevated in group III than in group I and II (P < 0.05) but significantly lower in group IV than in group III (P < 0.05). These results showed that implantation of MSCs could improve RV impairments caused by experimental PH. Histochemical results confirmed that transplanted MSCs were still alive after 2 weeks and part of the cells could differentiate into pulmonary vascular endothelial cells. CONCLUSION: Intravenous implantation of MSCs could significantly reduce or even reverse the progression of MCT-induced PH, improve cardiac function and hemodynamics.

[Association study between TNFSF4 and coronary heart disease].

Previous studies suggest that TNFSF4 is a susceptibility gene of atherosclerosis. But case-control association analysis in Swedish population and German population provided inconsistent, even opposite results. In order to explore the relationship between this gene and coronary heart disease (CHD) in Chinese Han population, we collected 498 cases and 509 controls from Qilu hospital of Shandong University and analyzed the association between five single-nucleotide polymorphisms (SNPs) (rs1234314, rs45454293, rs3850641, rs1234313, and rs3861950) of TNFSF4 and CHD. On the basis of using traditional statistical analysis methods based on single SNP and haplotypes, we introduced principal component score-based logistic regression analysis to deal with the data. The results suggested that in Armitage trend test, only rs3861950 was significant, when used the Bonferroni correction, and all of the five SNPs were not statistically significant. In the logistic regression analysis which adjusts the confounding factors, all of the five SNPs were not statistically significant. In haplotype analysis, the frequencies of six haplotypes were significantly different in cases and controls (CTAGT (P=0.0006), CTAAC (P=0.0123), CCAGT (P=0.0004), GTGGT (P=0.0329), GCGAC (P<0.0001), and GCAAC (P=0.0173)). In principal component score-based logistic regression analysis, the first principal component has statistical significance (P=0.0236). These results indicate that TNFSF4 is a susceptibility gene of CHD in Chinese Han population.

[Association of the ABCG1 gene polymorphism with the susceptibility and severity of coronary atherosclerotic disease].

OBJECTIVE: To investigate the association of the ATP-binding cassette sub-family G member 1 (ABCG1) gene polymorphisms with coronary atherosclerotic disease (CAD) in Chinese Han population. METHODS: A population based case-control association study was carried out in 541 patients with CAD and 649 healthy controls from Chinese Han population. Two single nucleotide polymorphisms (SNPs) of the ABCG1 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Logistic regression was used to compare the genotypic and allelic frequency difference. RESULTS: The frequency of allele C of rs225374 was significantly higher in the CAD patients than that in the healthy controls (OR=1.186, 95%CI: 1.009-1.394, P=0.039), while the difference was also significant in the male subgroup (OR=1.236, 95%CI: 1.014-1.506, P=0.036). A statistically higher frequency of rs1044317 allele A was found in the CAD patients in comparison to the healthy controls (OR=1.187, 95%CI: 1.009-1.397, P=0.039). In case-only association study, rs225374 showed significant association in the high Gensini score group compared with the low Gensini score group (OR=1.303, 95%CI: 1.024-1.657, P=0.031). CONCLUSION: The two SNPs of the ABCG1 gene might be associated with the susceptibility and severity of CAD in Chinese Han population.