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Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

Activation of adventitial fibroblasts (AFs) on vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-β1 (TGF-β1)-induced activation of AFs and, if so, to determine the underlying molecular mechanisms. Immunofluorescent staining and western blot were used to determine the expression of collagen I and α-smooth muscle actin. The proliferation and migration of AFs were performed by using cell counting Kit-8 and transwell assay, respectively. The mitochondrial morphology was assessed by using MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-β1-induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and regulated mitochondrial reactive oxygen species generation. Moreover, exogenous H2S reversed TGF-β1-induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1-dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-β1-induced AF activation through suppression of Drp1-mediated mitochondrial fission in a Rho-associated protein kinase 1-dependent fashion.

Aims Hyperglycemia induces endothelial cell apoptosis and blood vessel damage, while diallyl trisulfide (DATS) has shown cardiovascular protection in animal models and humans. The aim of this study was to investigate the effects of DATS on inhibition of high glucose-induced endothelial cell apoptosis and the underlying molecular events. Methods Human umbilical vein endothelial cells (HUVECs) were incubated with DATS (100 μM) for 30 min and then cultured in high-glucose medium (HG, 33 mM) for 24 h for assessment of apoptosis, glutathione (GSH), reactive oxygen species (ROS), superoxide dismutase (SOD), and gene expression using the terminal deoxyuridine triphosphate nick end labeling (TUNEL), flow cytometry, caspase-3 activity, ROS, SOD, and western blot assays as well as JC-1 and MitoTracker Red staining, respectively. Results DATS treatment significantly inhibited high glucose-induced HUVEC apoptosis by blockage of intracellular and mitochondrial ROS generation, maintenance of the mitochondrial membrane potential, and suppression of high glucose-induced dynamin-related protein 1 (Drp1) expression. Furthermore, DATS blockage of high glucose-induced mitochondrial fission and apoptosis was through adenosine monophosphate-activated protein kinase (AMPK) activation-inhibited Drp1 expression in HUVECs. Conclusions DATS demonstrated the ability to inhibit high glucose-induced HUVEC apoptosis via suppression of Drp1-mediated mitochondrial fission in an AMPK-dependent fashion.

Selenium (Se), an essential nutrient for humans, has been reported to possess cardioprotective effect. However, the protective effects of Se against doxorubicin (DOX)-induced cardiotoxicity and the underlying mechanism are rarely reported. In this study, we sought to explore whether Se protected against DOX-induced cardiotoxicity by inhibiting Nrf2-NLRP3 pathway. We found that Se treatment effectively alleviated DOX-induced myocardial dysfunctions, decreasing plasma markers associated with myocardial injury. Moreover, Se treatment significantly inhibited DOX-induced oxidative damages and pro-inflammatory cytokine expression in heart tissues. Furthermore, Se treatment markedly promoted the expression of Nrf2 and prevented the activation of NLRP3 inflammasome. Importantly, suppression of Nrf2 abolished the cardioprotective effects of Se and diminished the inhibition of Se on NLRP3 inflammasome. Collectively, our study demonstrated that Se might protect against DOX-induced cardiotoxicity via regulating Nrf2-NLRP3 pathway. Se supplementation may be a potential therapeutic strategy to protect against DOX-induced cardiac injury.

Normal or “good” inflammation process starts from a local cellular response against injury or any infectious agent, with the activation of neutrophils, macrophages, Langerhans cells, dendritic cells, and innate immune cells. Cytokines and chemokines are produced to amplify the local inflammatory process followed by the migration of immune cells to the regional lymph nodes where adaptive immune response is initiated. Systemic inflammation enhances the biological response to mobilize additional cells from central and peripheral immune/hematopoietic system. Local mechanisms to limit inflammation are initiated and lead to healing. During the normal inflammatory process, there is a balance between the production of inflammatory chemokines/cytokines such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6 and IL-1 and the production of compounds that limit inflammation and have an immune suppressive effect, such as IL-10 and Transforming Factor (TGF) β. IL-6 and IL-6/soluble IL-6 Receptor (R) complex stimulate liver cells to produce inflammatory proteins, which represents the systemic inflammation response. The magnitude and the duration of the systemic inflammatory response are linked to the cause, under genetic and epigenetic control. Significant inflammation as seen in septic shock, in severe forms of infections or in certain active cancers, represents the “bad inflammation”, correlated with a poor prognosis. In addition, the persistence of a chronic smoldering inflammation may lead to pathological situations which are observed in the majority of inflammatory, degenerative, dysmetabolic, or dysimmune diseases and cancer. Chronic smoldering inflammation is a cross between different pathological situations possibly linked. In addition, within the tumor microenvironment, inflammatory process results from different cellular mechanisms modulated by metabolic and vascular changes. On the contrary, a limited and balanced inflammation initiates the normal immune response, including the adaptive response which amplifies any immunotherapy, including vaccines. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells are associated with cytokine release syndrome, a clinical risk leading to the use of anti-cytokine drugs. Nowadays, it is time to monitor the dynamic inflammatory process for a better immune precision medicine in both infections and cancer.

We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.

Sepsis-induced myocardial dysfunctions are associated with high morbidity and mortality. Selenium, an essential trace element, has been reported to exert anti-inflammation, anti-oxidative stress, and anti-apoptosis. However, the protective effects of selenium on LPS-induced heart injury are still poorly illustrated. Therefore, in the present study, we sought to explore the effects of selenium pretreatment on LPS-induced myocardial injury in mice. We firstly found that selenium pretreatment significantly improved markers of myocardial injury and alleviated LPS-induced myocardial dysfunctions. Moreover, selenium supplementation reduced pro-inflammatory cytokines expression, decreased oxidative stress, and inhibited myocardial apoptosis. In addition, selenium supplementation inactivated the Sting pathway. In conclusion, our study suggests that selenium exerts protective effects on LPS-induced myocardial injury, and the underlying molecular mechanism may be related to the inactivation of Sting pathway, implying a potential therapy for sepsis-induced myocardial dysfunctions.

Background and objective Allitridin [diallyl trisulfide (DATS)] is an extract from garlic (Allium sativum) that putatively improves endothelial function and is protective against cardiovascular diseases. Endothelial dysfunction after tissue ischemia in diabetic patients is partially due to poor angiogenic response. This study investigated whether DATS may improve angiogenesis in a diabetic mouse model with hind limb ischemia. Methods Streptozotocin was administered by intraperitoneal injection to establish the model of diabetes in male C57BL/6 mice. After 14 days, nondiabetic and diabetic mice (n = 24, each) underwent unilateral hind limb ischemia by femoral artery ligation. The mice were apportioned to 4 groups: nondiabetic treated (or not) with DATS and diabetic treated (or not) with DATS. DATS treatment consisted of a single daily intraperitoneal injection of 500 μg·kg·d for 14 days, beginning on the day of induced ischemia. Ischemia was scored by standard criteria. Blood perfusion was determined using thermal infrared imaging. Tissue capillary density and oxidative stress levels were measured by immunohistochemistry and immunofluorescence, respectively. Serum lipids were measured by enzymatic colorimetric assay. Fasting serum insulin was detected using an insulin enzyme-linked immunosorbent assay kit. Nitric oxide (NO) metabolites and protein carbonyls in tissues were determined by enzyme-linked immunosorbent assay. Targeted protein concentrations were measured by western blotting. Results At 14 days after ligation, the ischemic skeletal muscle of the streptozotocin-induced diabetic mice had lower levels of endothelial NO synthase, phosphorylated endothelial NO synthase, and vascular endothelial growth factor compared with nondiabetic group. In addition, the hind limb blood perfusion, capillary density, and NO bioactivity were lower in the diabetic group, whereas oxidative stress and protein carbonyl levels were higher. These changes were ameliorated by DATS treatment. Conclusions DATS treatment of diabetic mice promoted revascularization in ischemic tissue.

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6; Fig 1). In patients with low baseline CRP levels (40 mg/l; n=17), CRP levels were significantly reduced on day 8 (n=17; P Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment strategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. Figure 1 Figure 1. Disclosures Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc ; EUSA Pharma: Consultancy; LEO Pharma: Consultancy; NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'; Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

Introduction CF-sensing catheter emerged as a novel ablation technology and was increasingly used in clinical practice. Nonetheless, available evidence of efficacy and safety comparison between CF-guided RF catheter ablation and non-CF-guided ablation for treatment of AF was still lacking. Methods and results Twenty-two eligible studies were included after systematic review through the MEDLINE, Google Scholar, the Cochrane Library and PubMed databases. AF/atrial tachycardia-free survival was markedly improved in CF-guided catheter ablation compared with non-CF-guided ablation at a median 12-month follow-up (RR: 1.12, 95% CI: 1.06 to 1.19, p = 0.000, fixed). Notably, CF-guided catheter ablation presented a robust survival benefit for treatment of paroxysmal AF (RR: 1.10, 95% CI: 1.03 to 1.18, p = 0.005, fixed), but not persistent AF (RR: 1.07, 95% CI: 0.89 to 1.28, p = 0.466, fixed). Moreover, procedure time (WMD: -23.87, 95% CI: -33.83 to -13.91, p = 0.000, random), fluoroscopy time (WMD: -7.78, 95% CI: -13.93 to -1.63, p = 0.013, random) and RF time (WMD: -3.98, 95% CI: -7.78 to -0.17, p = 0.040, random) were significantly reduced in CF-guided catheter ablation. The incidence of procedure-related complications did not differ between these two technologies (RR: 0.83, 95% CI: 0.59 to 1.16, p = 0.271, fixed). Conclusion CF-guided RF catheter ablation was associated with a significant AF/atrial tachycardia-free survival benefit compared with non-CF-guided ablation in patients with paroxysmal AF rather than persistent AF. In addition, CF-guided ablation strategy also reduced the procedure time, fluoroscopy time, as well as RF time despite no distinct effect on the alleviation of procedure-related complications. This article is protected by copyright. All rights reserved

// An Hu 1 , Jing-Juan Huang 2 , Jing-Fei Zhang 1 , Wei-Jun Dai 1 , Rui-Lin Li 3 , Zhao-Yang Lu 3 , Jun-Li Duan 3 , Ji-Ping Li 4 , Xiao-Ping Chen 1 , Jing-Ping Fan 1, 5 , Wei-Hua Xu 1 and Hong-Liang Zheng 6 1 Department of Otolaryngology, Gongli Hospital, Second Military Medical University, Pudong New Area, Shanghai, 200135, China 2 Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China 3 Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China 4 Department of Otolaryngology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Pudong New Area, Shanghai, 200127, China 5 Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China 6 Department of Otolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China Correspondence to: Jing-Juan Huang, email: hjjxinhua@163.com Keywords: cell cycle arrest, apoptosis, ATM/Chk2/p53 signal pathway, head and neck squamous cell carcinoma, curcumin Received: March 20, 2016 Accepted: March 31, 2017 Published: April 13, 2017 ABSTRACT Studies have demonstrated that curcumin (CUR) exerts its tumor suppressor function in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). However, the exact underlying molecular mechanisms remain obscure. Here, we aim to test whether CUR affects ATM/Chk2/p53 signaling pathway, leading to the induction of cell cycle arrest, inhibition of angiogenesis of HNSCC in vitro and in vivo . To this end, we conducted multiple methods such as MTT assay, Invasion assay, Flow cytometry, Western blotting, RT-PCR, and transfection to explore the functions and molecular insights of CUR in HNSCC. We observed that CUR significantly induced apoptosis and cell cycle arrest, inhibited angiogenesis in HNSCC. Mechanistically, we demonstrated that CUR markedly up-regulated ATM expression and subsequently down-regulated HIF-1α expression. Blockage of ATM production totally reversed CUR induced cell cycle arrest as well as anti-angiogenesis in HNSCC. Moreover, our results demonstrated that CUR exerts its antitumor activity through targeting ATM/Chk2/p53 signal pathway. In addition, the results of xenograft experiments in mice were highly consistent with in vitro studies. Collectively, our findings suggest that targeting ATM/Chk2/p53 signal pathway by CUR could be a promising therapeutic approach for HNSCC prevention and therapy.

120 main industrial installations were screened based on the emissions inventory of 2016 in Cangzhou City, and the air pollution effect of PM

Aims Adventitial remodelling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signalling and transcriptional pathways in vascular smooth muscle cells; however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin (CN), a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodelling in AngII-induced hypertensive mice. Methods and results In primary mouse AFs, we found that CN-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial reactive oxygen species production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and CN in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the CN-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodelling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by CN/Drp1 signalling pathways. Conclusions Our study suggests that CN/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodelling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodelling-related diseases.

Nanostructured calcium phosphate (CaP) and magnesium phosphate (MgP) are promising for the application as the nanocarriers in drug delivery. However, the difference between CaP and MgP nanocarriers in drug delivery is rarely investigated. In this work, we comparatively investigated nanostructured CaP, MgP and calcium magnesium phosphate (CMP) for the delivery of SRT1720, which is a silent information regulator (SIRT1) specific activator with pro-angiogenic and anti-aging properties in response to hydrogen peroxide (H

A major concern in aerial video surveillance today is to improve the processing speed continuously. This work introduces a joint visual constraints method for high speed aerial video stitching. To obtain real-time and accurate performance, we first select the compact and efficient ORB (Oriented FAST and Rotated BRIEF) for fast local feature description and matching, and then adopt the dynamic key frame based video stitching framework to reduce the accumulation errors. To further achieve high speed performance, we improve the above framework by fusing spatial and temporal constraints of ORB keypoints during online stitching, and increase the processing speed to 150 fps successfully. The results with public available UAV datasets demonstrate the superiority of joint constraints.

Aims Cryoablation is a promising alternative technique to RF ablation for treating paroxysmal AF with encouraging results. However, data about the efficacy and safety comparison between cryoablation and RF ablation is still lacking. Methods and results We systematically search the PubMed, the Cochrane Library, MEDLINE and Google Scholar databases, and finally identify 16 eligible studies including 7195 patients (2863 for cryoablation; 4332 for RF ablation). Freedom from AF/atrial tachycardial replase is slightly higher in cryoablation than RF ablation during a median 12 months of follow-up, with no statistical significant (RR: 1.05, 95% CI: 0.98–1.13, P = 0.159). In cryoablation, the procedure time is substantially shortened (WMD: −27.66, 95% CI: −45.24 to − 10.08, P = 0.002), whereas the fluoroscopy time is identical to RF ablation (WMD: −0.37, 95% CI: −2.78 to 2.04, P = 0.763). Procedure-related adverse events in cryoablation are parallel with that in RF ablation (RR: 1.08, 95% CI: 0.86–1.35, P = 0.159). Conclusions Compared with RF ablation, cryoablation present a comparable long-term AF/atrial tachycardial-free survival and procedure-related adverse events. Meanwhile, cryoablation markedly shorten the procedure time, nonetheless, with negligible impact on the fluoroscopy time.

Therapeutic ultrasound (TUS) has been demonstrated to improve endothelial nitric oxide synthase (eNOS) activity, which played a crucial role in the regulation of angiogenesis. Diabetes Mellitus (DM) impairs eNOS activity. We tested the hypothesis that DM may retard unilateral hindlimb ischemia-induced angiogenesis by inhibiting eNOS in high-fat diet (HFD)/streptozocin (STZ) induced diabetic mice, and that TUS may reverse DM-related impairment of angiogenesis. C57BL/6 mice were allocated to four groups: (A) mice were fed standard diet (control); (B) mice were fed standard diet and treated with TUS (control+TUS); (C) type-2 DM mice were induced by HFD/STZ (diabetic); and (D) type-2 DM mice and treated with TUS (dabetic+TUS). All mice were surgically induced unilateral limb ischemia. The ischemic skeletal muscles in groups B and D were irradiated with extracorporeal TUS for 9 minutes/day (frequency of 1 MHz, intensity of 0.3 W/cm2) for 14 consecutive days. The result showed that TUS augmented the blood perfusion, increased capillary density accompanied by an upregulation of angiogenic factors and a downregulation of apoptotic proteins in group D relative to group C. In vitro, TUS inhibited the apoptosis, promoted tubule formation, proliferation and migration capacities, increased angiogenic factors expression and reduced apoptotic protein levels in human umbilical vein endothelial cells (HUVECs). Furthermore, TUS can robust reverse the inhibiting effect induced by high glucose (HG) on HUVECs, and these benefits could be blocked by phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) or eNOS inhibitor (L-NAME). Together, TUS restored type-2 DM-mediated inhibition of ischemia-induced angiogenesis, partially via PI3K-Akt-eNOS signal pathway.

We examined the hypothesis that therapeutic ultrasound (TUS) treatment would rescue the hypertension-related inhibition of ischemia-induced angiogenesis. TUS protects against endothelial dysfunction, but it is little known that the effect of TUS treatment on angiogenesis inhibited by hypertension. 20-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were randomly allocated to 4 groups: SHR; TUS treated SHR (SHR-TUS); WKY and TUS treated WKY (WKY-TUS). After undergoing excision of the left femoral artery, the ischemic skeletal muscles were treated with extracorporeal TUS for 9 minutes of daily exposure (frequency of 1 MHz, intensity of 0.3 W/cm(2)) for 14 consecutive days. We found that TUS normalized the blood perfusion in SHR-TUS accompanied by elevated capillary density. Similar results were found in the protein expression of angiogenic factors. TUS treatment also enhanced peripheral capillary density in WKY rats and restored the capillary rarefaction in hypertension by elevating the protein levels of endothelial nitric oxide synthase (eNOS), hypoxic inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and phosphorylated Akt (p-Akt) in vivo. Our data demonstrated that TUS treatment ameliorated hypertension-related inhibition of ischemia-induced angiogenesis, at least in part, via an NO-dependent manner.

International audience; The leucocyte-specific phosphatase CD45 is present in two main isoforms: the large CD45RA and the short CD45RO. We have recently shown that distinctive expression of these isoforms distinguishes natural killer (NK) populations. For example, co-expression of both isoforms identifies in vivo the anti tumor NK cells in hematological cancer patients. Here we show that low CD45 expression associates with less mature, CD56 bright , NK cells. Most NK cells in healthy human donors are CD45RA + CD45RO-. The CD45RA-RO + phenotype , CD45RO cells, is extremely uncommon in B or NK cells, in contrast to T cells. However , healthy donors possess CD45RA dim RO-(CD45RA dim cells), which show immature markers and are largely expanded in hematopoietic stem cell transplant patients. Blood borne cancer patients also have more CD45RA dim cells that carry several features of immature NK cells. However, and in opposition to their association to NK cell progenitors, they do not proliferate and show low expression of the transferrin receptor protein 1/CD71, suggesting low metabolic activity. Moreover, CD45RA dim cells properly respond to in vitro encounter with target cells by degranulating or gaining CD69 expression. In summary, they are quies-cent NK cells, with low metabolic status that can, however, respond after encounter with target cells.

In this study, the performance of a typical Chinese industrial nitro-aromatic wastewater project (operational capacity: 3,000 m3d−1) was evaluated using chemical properties and toxicity data. Additionally, the relationship between the removal of organic pollutants and toxicity reduction was investigated throughout the whole-process wastewater treatment. Current advanced treatment reduced the dissolved organic carbon by 40% compared with biologically treated wastewater effluent (BTWE), but the acute toxicity and early life-stage toxicity increased significantly. For instance, the acute toxicity of the current advanced treated wastewater was 450% greater than that of the untreated BTWE. With the aim of effectively decreasing the toxicity of the effluent, several efficient adsorption technologies were assessed and compared for further treatment of BTWE. Coagulation and/or oxidation coupled with activated carbon adsorption, hypercrosslinked resin adsorption, or MIEX® technology was helpful for improving chemical indices and reducing toxicity. Among these adsorption treatment technologies, hypercrosslinked resin adsorption was more effective at removing most of the toxicants than MIEX® technology, and it also had better regeneration efficiency and mechanical properties compared with activated carbon. Therefore, hypercrosslinked resin adsorption may be a promising technology for enhancing organic pollutant removal and toxicity reduction of BTWE from nitro-aromatic factories.

The big differences of the texture and shapes in the same type and certain similarities among heterogeneous types result in the difficult classification of fabric defects. Compared with traditional global statistical method, we put up a new solution, which makes use of the fabric defect local region features to keep the defect property and defect classification by Support Vector Machines (SVM). Based on small-samples learning machine of SVM, we obtain a good performance of less computational load and high recognition rate.

Accumulation of foulants on adsorbents surface was regarded as the key problem inhibiting the repeated use of adsorbents for bio-treated wastewater reclamation. In the present research, the adsorption performance of aminated resin NDA80 was investigated in terms of anti-fouling from the theoretical comparison with its precursor resin NDA79, and its repeated use in practical application. After preloading with tannic acid (TA) as model background contaminants in biologically treated wastewater, the pore volume and specific surface area of the resins decrease obviously due to partial micropore blockage. However, on NDA80, the adsorption affinities (Ka) of phenol and p-nitrophenol increase by 76% and 67% after loaded with 120 μmol/g TA, respectively. Differently, the values of Ka on NDA79 remain almost constant before and after the same loading with TA. The special anti-fouling performance of aminated resin NDA80 was regarded as the contribution of functional groups containing nitrogen on the meso–macro-pore of the resin. The effluent from biologically treated coking wastewater was evaluated by NDA80 on a pilot-scale treatment. The removal of organic contaminants per specific surface area by NDA80 increased by about 35% due to its better anti-fouling property, which is corresponding to the theoretical experiment. The adsorption capacity of NDA80 was almost constant after 71 days of repeated use while the surface area and pore volume of NDA80 decreased by about 30%.

Nitrobenzene (NB) oxidation through conventional Fenton process produces a considerable amount of highly toxic 1,3-dinitrobenzene (1,3-DNB) as a byproduct. Aiming at significantly decreasing 1,3-DNB production in Fenton process, we developed a novel system integrating a reductive pretreatment via zero-valent iron (ZVI) with Fenton process to degrade NB in aqueous solution and industrial wastewater. The NB reduction efficiency of ZVI pretreatment could be controlled by adjusting the initial ZVI concentration and/or the initial pH of NB solution in a completely stirred ZVI reactor. After partial NB reduction by ZVI pretreatment, the residual NB was oxidized by a subsequent Fenton process. Aniline and ferrous irons were generated in ZVI pretreatment, producing an inhibitory effect on the formation of 1,3-DNB in Fenton process. While conventional Fenton process attained the NB removal efficiency of 95.0% and brought the relative 1,3-DNB yield (the molar concentration of 1,3-DNB in relation to that of converted NB) of 5.0%, the integrated system with the NB reduction efficiency of 48.1% achieved a similarly high NB removal efficiency (93.0%), but its relative 1,3-DNB yield was only 0.4%. Applied to the full-scale treatment of NB-rich industrial wastewater, the ZVI-Fenton integrated system with the NB reduction efficiency of 50.0% and conventional Fenton process produced dinitrobenzene isomers at the total concentrations of 0.005 mM and 0.060 mM, respectively. Accordingly, the integrated system increased the biodegradability and decreased the acute toxicity of the wastewater significantly more than conventional Fenton process. Therefore, the novel ZVI-Fenton integrated process is effective in the degradation of NB wastewater.

For comparing the adsorption of Synthetic Organic Chemicals (SOC) competing with background pollutants between a bifunctional resin and a commercial granular activated carbon (GAC), tannic acid (TA) was preloaded to the two adsorbents at quantities of 60 and 120 μmol/g. As a result, decreases of micropores volume in the resin were 75.5 and 98.9%, while those in the GAC were only 19.0 and 30.0%, respectively. Preloading attenuated surface heterogeneities and phenol’s capacities of two adsorbents distinctly. But maximumly, 1.0 mole TA’s preloading on GAC could decline 9.23 mole phenol’s adsorption. Under the same condition, the resin’s capacity of phenol was only descended at 2.68 times, when 98.9% micropores have been blocked. In kinetic tests, blockages in the resin were misapprehended to be much lighter than those in the GAC by the Homogeneous Surface Diffusion Model (HSDM). One steady operation engineering at micropore volume 37.8% decline was introduced. The conflicts were explained by quite a number of resin’s functional groups in the macroporous and mesoporous region could attract enough phenol molecular rapidly, even if almost all micropores were blocked.

Aiming at the limitations of traditional wavelet de-noising, multi-wavelet can possess symmetry, orthogonality, short support and high order vanish moments. However traditional single wavelet cannot possess all these properties at the same time. Analyze the principles of multi-wavelet method and the algorithm for image de-noising. The results prove that, multi-wavelet prior knowledge requirements for image signal is low, the suppression of noise interference at the same time. But it can preserve a more complete the useful signal.

In mice, the plasma cell (PC) niche in the bone marrow is close to the haematopoietic stem cell (HSC) niche. We investigated whether PCs can be mobilized into the peripheral blood (PB) in healthy donors receiving granulocyte colony-stimulating factor (G-CSF) for the induction of HSC mobilization into the PB. G-CSF increased the count of circulating PCs 6-fold, that of circulating B lymphocytes 4-fold and that of circulating HSCs 44-fold. Mobilized circulating PCs comprised CD138(-) (62·2%) and CD138(+) (37·8%) PCs, the latter being more mature based on increased CD27, CD38 and cytoplasmic immunoglobulin expression. Mobilized PCs had a phenotype close to that of steady-state PB PCs or in vitro generated PCs, but they expressed L-selectin only weakly. Finally, a median value of 0·4 × 10(6) /kg donor PCs - one-thirtieth of the overall PC count in a healthy adult - was grafted into patients, which could contribute to immune memory recovery.

The critical current versus tensile strain characteristics of mono- and multi-filament Bi-2223 tapes with Ag and AgMn and AgMg sheath has been studied. The strain tolerance ε0.9 of naked mono- and 37-filament Bi-2223 tapes were 0.13% and 0.20%, respectively. Ag sheath increased the strain tolerance ε0.9 of critical current by 0.08% and 0.16% for mono-filament and 37-filament Bi-2223/Ag tapes. The ε0.9 of Bi-2223 with Ag and AgMn and AgMg sheath increased with filament number. AgMn and AgMg sheath, increasing ε0.9 of Bi-2223 tapes by 0.07-0.09%, are effective to improve strain tolerance of critical current for multifilamentary Bi-2223 tapes.

The effects of bending strain on the critical current of 19-filament Ag/Bi-2223 and 121-filament AgMg/Bi-2223 tapes produced by powder-in-tube method have been studied by a pure-bending method at 77K. The I cn (e) curves are of two regimes, I cn does not decrease until bending strain increases to a limit e irr . The e 0.9 values of 19-filament Ag/Bi-2223 and 121-filament AgMg/Bi-2223 tapes are 0.32% (negative bending), 0.64% (positive bending) and 0.30%, respectively. The I cn (e) curves are fitted by the formulae I cn =1-(e/a) b , where a and b is the material parameters. The strain dependences of the I cn values for the pure-bending, modified RRT and bending-rig methods were nearly identical up to e irr .

SIRT1 is one of seven mammalian homologs of Sir2 that catalyzes NAD+-dependent protein deacetylation. The aim of the present study is to explore the effect of SIRT1 small molecule activator on the anticancer activity and the underlying mechanism. We examined the anticancer activity of a novel oral agent, curcumin, which is the principal active ingredient of the traditional Chinese herb Curcuma Longa. Treatment of FaDu and Cal27 cells with curcumin inhibited growth and induced apoptosis. Mechanistic studies showed that anticancer activity of curcumin is associated with decrease in migration of HNSCC and associated angiogenesis through activating of intrinsic apoptotic pathway (caspase-9) and extrinsic apoptotic pathway (caspase-8). Our data demonstrating that anticancer activity of curcumin is linked to the activation of the ATM/CHK2 pathway and the inhibition of nuclear factor-κB. Finally, increasing SIRT1 through small molecule activator curcumin has shown beneficial effects in xenograft mouse model, indicating that SIRT1 may represent an attractive therapeutic target. Our studies provide the preclinical rationale for novel therapeutics targeting SIRT1 in HNSCC.

High-dose cyclophosphamide (Cy) and G-CSF are widely used to mobilize hemopoietic stem cells for treating patients with high-dose chemotherapy and autologous stem cell transplantation (ASCT). Because lymphocyte count in the graft collected after Cy-G-CSF treatment is an independent survival factor after ASCT for patients with multiple myeloma, our purpose was to study how Cy-G-CSF treatment affects the phenotype and function of T cells in patients with multiple myeloma. Cy induced a 3-fold decrease of T cell counts with a slow and partial T cell recovery of one-third at the time of hemopoietic stem cell collection. Cy-G-CSF treatment did not affect the relative ratios of central memory, effector memory, and late effector CD4+ or CD8+ T cells, but a decrease in the percentage of naive CD4+ cells was observed. The percentages of CD25+ cells increased 2- to 3-fold in CD4+ and CD8+ T cells, the former including both activated CD25low and CD25high cells. CD4+CD25high cells were regulatory T cells (Treg) that expressed high levels of FOXP3, CTLA-4, and GITR and displayed in vitro suppressive properties. The recovery of Treg absolute counts after Cy-G-CSF treatment was higher than the recovery of other lymphocyte subpopulations. In conclusion, Cy-G-CSF treatment induces a severe T cell count decrease without deleting Treg, which are potent inhibitors of antitumor response. The present data encourage novel therapeutic strategies to improve T cell recovery following ASCT while limiting Treg expansion.

In this paper, we propose a new carrier frequency offset (CFO) estimation algorithm and a new CFO correction structure in the multi-stage synchronization strategy in time and frequency domain for OFDM. The new CFO estimation algorithm uses all pilots including continual pilots (CP) and scattered pilots (SP) to estimate the CFO in frequency domain, and it can acquire more accurate estimation results than the conventional algorithm only using CP. The new CFO correction structure is a double-loop structure, and in the double-loop synchronization structure, "fractional" frequency offset (FFO) is corrected using a long loop as conventional method, however, "integral" frequency offset (IFO) does not go back to the time domain, and it is recovered using a short loop in frequency domain, which can shorten the convergence time of frequency synchronization. The analysis and simulations show the improved performance of the proposed CFO estimation algorithm and the double-loop correction structure.

Factors influencing extramedullary relapse after allogeneic transplantation for multiple myeloma

Purpose: To investigate the regulatory mechanism of miR-218 in human hepatocellular carcinoma (HCC). Methods: qPCR was used to compare the expression levels miR-218 among six hepatocellular carcinoma cell lines and normal liver tissues. After transfecting MHCC97L cells with either miR-218 mimics or miR-218 inhibitor, western blotting was used to examine the expressing patterns of cyclinD1, p21, and PTEN/AKT/PI3K signaling pathway-related proteins. MTT and colony forming assay was used to assess the capability of cell proliferation. Bioinformatic method was applied to predict the binding of miR-218 on HoxA10, and western blotting was used to examine the modulatory effect of miR-218 AND HoxA10 on PTEN/AKT/PI3K pathway in HCC. Results: The expression levels of miR-218 were frequently lower in HCC cell lines than in normal liver tissues. Over-expression of miR-218 in HCC cells significantly decreased cell proliferation whereas inhibiting miR-218 promoted cancer cell proliferation. Western blotting analysis demonstrated that tumorigenesis related protein cyclin D1 and p21, as well as PTEN/AKT/PI3K signaling pathways were actively modulated by miR-218 in HCC cells. The expression of endogenous HoxA10 was also down-regulated by miR-218 over-expression, and silencing HoxA10 directly activated PTEN in HCC cells. Conclusion: Modulation of miR-218 actively affected HCC cancer cell development. The regulatory mechanism of miR-218 in HCC cells was acting through PTEN/AKT/PI3K pathway and possibly associated with HoxA10.

International audience; NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.

Non-myeloablative regimens have been proven to allow engraftment following allogeneic stem cells transplantation (allo-SCT) with minimal procedure-related toxicity. Conventional allo-SCT may produce remissions in patients with relapsed and refractory lymphoid malignancies (LM) but these good results may be achieved at the cost of high treatment-related morbidity and mortality. Application of allo-SCT using less intensive regimens may temper the frequency of these complications, allowing a potent graft-versus-tumor effect (GVT). We present our data on 11 patients with LM receiving allo-SCT with a reduced regimen. Ten patients had received previous high-dose therapy, and were at high risk for toxicity, thus precluding the use of allo-SCT. A fludarabine and low-dose busulfan combination facilitated engraftment while exerting GVT. Hematological recovery was quick, and full donor T cell chimerism preceded acute GVHD. GVHD and infections were the major problems. Spontaneous acute GVHD occurred in eight patients (72%). Five patients (45%) achieved complete remission, and the GVT effect was closely associated with GVHD. These results support the concept that GVT is effective against LM in patients who have been heavily pretreated. Further studies are needed to investigate strategies to generate more specific alloreactive effects providing optimal GVT and an acceptable risk of GVHD and infections.

We studied the role of interleukin (IL)-1β in patients with multiple myeloma. By in situ hybridization and immunochemistry, myeloid and megakaryocytic cells expressed high levels of the IL-1β gene and produced IL-1β. Myeloma cells less potently expressed the IL-1β gene and IL-1β protein. IL-1β gene expression was not constitutive since it was detected in the bone marrow myeloma cells of two patients, unlike circulating tumoural cells. In addition, nine myeloma cell lines failed to express the IL-1β gene and this expression could not be induced by 12 different cytokines. We demonstrated that IL-1 was mainly responsible for IL-6 production in the tumoural environment through a PGE2 loop. In fact, an IL-1 receptor antagonist (IL-1RA) blocked PGE2 synthesis and IL-6 production by 80%; this blockage could be reversed by adding synthetic PGE2. Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks PGE2 synthesis. Taken together, these data emphasize the possibility of blocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 production, which is a major tumoural survival and proliferation factor.