Renoprotection by remote ischemic conditioning during elective coronary revascularization: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Remote ischemic conditioning (RIC) has been recognized an emerging non-invasive approach for preventing acute kidney injury (AKI) in patients undergoing either elective coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). On the other hand, accumulating evidence has indicated the involving role of pre-CABG contrast usage for coronary angiography in post-surgery AKI risk. Along with the shortening time delay of CABG after coronary angiography, and the prevalent hybrid coronary revascularization (HCR), the AKI prevention by RIC has faced challenges following coronary revascuralization. METHODS: Randomized controlled trials (RCTs) were searched from Pubmed, EMBase, and Cochrane library (until May 2016). The primary outcome was postoperative AKI. The second outcomes were included the requirement for renal replacement therapy (RRT), and in-hospital or 30-day mortality. RESULTS: Twenty eligible RCTs (CABG, 3357 patients; PCI, 1501 patients) were selected. RIC significantly halved the incidence of AKI following PCI when compared with controls [n=1501; odds ratio (OR)=0.51; 95% CI, 0.32 to 0.82; P=0.006; I(2)=29.6%]. However, RIC did not affect the incidence of AKI following CABG (n=1850; OR=0.94; 95% CI, 0.73 to 1.19; P=0.586; I(2)=12.4%). The requirement for RRT and in-hospital mortality was not affected by RIC in CABG (n=2049, OR=1.04, P=0.87; n=1920, OR=0.89, P=0.7; respectively). CONCLUSIONS: Our meta-analysis suggests that RIC for preventing AKI following CABG has faced with challenges in terms of AKI, the requirement for RRT, and mortality. However, RIC shows a renoprotective benefit for PCI. Hence, our findings may infer the preserved renal effects of RIC in CABG with preconditioning before the coronary angiography, or in HCR

Optimal Homogenization of Perfusion Flows in Microfluidic Bio-Reactors: A Numerical Study

In recent years, the interest in small-scale bio-reactors has increased dramatically. To ensure homogeneous conditions within the complete area of perfused microfluidic bio-reactors, we develop a general design of a continually feed bio-reactor with uniform perfusion flow. This is achieved by introducing a specific type of perfusion inlet to the reaction area. The geometry of these inlets are found using the methods of topology optimization and shape optimization. The results are compared with two different analytic models, from which a general parametric description of the design is obtained and tested numerically. Such a parametric description will generally be beneficial for the design of a broad range of microfluidic bioreactors used for, e.g., cell culturing and analysis and in feeding bio-arrays

Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer

Topoisomerase IIb binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 30UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific Top- BP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95 % confidence interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

The Bulk Channel in Thermal Gauge Theories

We investigate the thermal correlator of the trace of the energy-momentum tensor in the SU(3) Yang-Mills theory. Our goal is to constrain the spectral function in that channel, whose low-frequency part determines the bulk viscosity. We focus on the thermal modification of the spectral function, $\rho(\omega,T)-\rho(\omega,0)$. Using the operator-product expansion we give the high-frequency behavior of this difference in terms of thermodynamic potentials. We take into account the presence of an exact delta function located at the origin, which had been missed in previous analyses. We then combine the bulk sum rule and a Monte-Carlo evaluation of the Euclidean correlator to determine the intervals of frequency where the spectral density is enhanced or depleted by thermal effects. We find evidence that the thermal spectral density is non-zero for frequencies below the scalar glueball mass $m$ and is significantly depleted for $m\lesssim\omega\lesssim 3m$.Comment: (1+25) pages, 6 figure

Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer

The usefulness of contrast during exercise echocardiography for the assessment of systolic pulmonary pressure

<p>Abstract</p> <p>Background</p> <p>The systolic pulmonary artery pressure (PAPs) can be accurately estimated, non-invasively, using continuous-wave Doppler (CWD) ultrasound measurement of the peak velocity of a tricuspid regurgitant (TR) jet.</p> <p>However, it is often difficult to obtain adequate tricuspid regurgitation signals for measurement of PAPs, what could lead to its underestimation. Therefore, utilization of air-blood-saline contrast has been implemented for the improvement of Doppler signal in several clinical contexts.</p> <p>It is now recommended in the evaluation of patients with pulmonary hypertension. Physical activity is severely restricted in patients with PAH, being exertional dypnea the most typical symptom. Exercise stress echo-Doppler imaging allows assessment of the response to exercise. It is an excellent screening test for patients with suspected PAH. Our purpose was to evaluate the value and accuracy of agitated saline with blood contrast echocardiography, in the improvement of the Doppler signal, to quantify PAPs during treadmill exercise-echocardiography.</p> <p>Purpose</p> <p>To evaluate the value of contrast echocardiography, using agitated saline with blood, in the improvement of the Doppler signal used to quantify the pulmonary artery systolic pressure during exercise.</p> <p>Methods</p> <p>From a total of 41 patients (pts), we studied 38 pts (93%), 35 women, aged 54 ± 12 years-old. 27 with the diagnosis of systemic sclerosis, 10 with history of pulmonary embolism and one patient with a suspected idiopathic PAH, who were referred to the Unity of Heart Failure and Pulmonary Hypertension for screening of PAH. According to the Unity protocol, a transthoracic echocardiogram was made, in left decubitus (LD), with evaluation of right ventricle-right atria gradient (RV/RAg). A peripheral venous access was obtained, with a 3-way stopcock and the patients were placed in orthostatism (O), with a new evaluation of RV/RAg. Exercise echocardiography (EE) was begun, with evaluation of RV/RAg at peak exercise (P) and afterwards agitated saline (8 cc with 1 cc of air and 1 cc of blood) was injected, followed by a new evaluation of RV/RAg (PC) and then the interruption of the EE. Pulmonary Hypertension was diagnosed when RV/RAg at the end of the exercise was superior to 40 mmHg.</p> <p>Results</p> <p>The quality of Doppler signal was deteriorated in 5 pts, maintained in 6 pts and improved in 26 pts, with the use of contrast. In one patient, an interventricular septal defect was diagnosed. In 6 pts, a Doppler signal was only obtained with the use of contrast. In 15 pts, a RV/RAg superior to 40 mmHg was only obtained with the use of contrast. Of these, 9 have already been submitted to right heart cathetherism, that confirmed the diagnosis of pulmonary hypertension in 5 of them (56%). RV/RAg (P) was 44 ± 11 mmHg and RV/RAg (PC) was 54 ± 11 mmHg, p < 0,001.</p> <p>Conclusion</p> <p>1. The method is applicable in a large number of patients. 2. RV/RA gradients obtained at peak exercise are higher with the use of contrast, and the clinical meaning of this difference should be evaluated in a larger number of pts submitted to right heart cathetherism. The high number of false positives should lead to a higher diagnostic threshold. 3. This method seems to have relevant clinical value in the diagnosis of pulmonary arterial hypertension.</p

Hot embossing for fabrication of a microfluidic 3D cell culture

Clinically relevant studies of cell function in vitro require a physiologically-representative microenvironment possessing aspects such as a 3D extracellular matrix (ECM) and controlled biochemical and biophysical parameters. A polydimethylsiloxane (PDMS) microfluidic system with a 3D collagen gel has previously served for analysis of factors inducing different responses of cells in a 3D microenvironment under controlled biochemical and biophysical parameters. In the present study, applying the known commercially-viable manufacturing methods to a cyclic olefin copolymer (COC) material resulted in a microfluidic device with enhanced 3D gel capabilities, controlled surface properties, and improved potential to serve high-volume applications. Hot embossing and roller lamination molded and sealed the microfluidic device. A combination of oxygen plasma and thermal treatments enhanced the sealing, ensured proper placement of the 3D gel, and created controlled and stable surface properties within the device. Culture of cells in the new device indicated no adverse effects of the COC material or processing as compared to previous PDMS devices. The results demonstrate a methodology to transition microfludic devices for 3D cell culture from scientific research to high-volume applications with broad clinical impact.National Cancer Institute (U.S.) (award R21CA140096)Charles Stark Draper Laboratory (IR&D Grant