Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation

BACKGROUND: Current evidence suggests that endothelial progenitor cells (EPC) contribute to ischemic tissue repair by both secretion of paracrine factors and incorporation into developing vessels. We tested the hypothesis that cell-free administration of paracrine factors secreted by cultured EPC may achieve an angiogenic effect equivalent to cell therapy. METHODOLOGY/PRINCIPAL FINDINGS: EPC-derived conditioned medium (EPC-CM) was obtained from culture expanded EPC subjected to 72 hours of hypoxia. In vitro, EPC-CM significantly inhibited apoptosis of mature endothelial cells and promoted angiogenesis in a rat aortic ring assay. The therapeutic potential of EPC-CM as compared to EPC transplantation was evaluated in a rat model of chronic hindlimb ischemia. Serial intramuscular injections of EPC-CM and EPC both significantly increased hindlimb blood flow assessed by laser Doppler (81.2+/-2.9% and 83.7+/-3.0% vs. 53.5+/-2.4% of normal, P<0.01) and improved muscle performance. A significantly increased capillary density (1.62+/-0.03 and 1.68+/-0.05/muscle fiber, P<0.05), enhanced vascular maturation (8.6+/-0.3 and 8.1+/-0.4/HPF, P<0.05) and muscle viability corroborated the findings of improved hindlimb perfusion and muscle function. Furthermore, EPC-CM transplantation stimulated the mobilization of bone marrow (BM)-derived EPC compared to control (678.7+/-44.1 vs. 340.0+/-29.1 CD34(+)/CD45(-) cells/1x10(5) mononuclear cells, P<0.05) and their recruitment to the ischemic muscles (5.9+/-0.7 vs. 2.6+/-0.4 CD34(+) cells/HPF, P<0.001) 3 days after the last injection. CONCLUSIONS/SIGNIFICANCE: Intramuscular injection of EPC-CM is as effective as cell transplantation for promoting tissue revascularization and functional recovery. Owing to the technical and practical limitations of cell therapy, cell free conditioned media may represent a potent alternative for therapeutic angiogenesis in ischemic cardiovascular diseases.

Regioselective Synthesis of 2-Amino-isophthalonitriles through a Ring Transformation Strategy

An expeditious synthesis of several 2-amino-isophthalonitriles and their biaryl compounds is described and illustrated by carbanion-induced ring transformation of functionalized 2H-pyran-2-ones with malononitrile in excellent yields. The strength of the reaction lies in the creation of an aromatic ring at room temperature from six membered-lactones under mild reaction conditions. This approach is an alternative to Diels-Alder reactions of 2H-pyran-2-ones with dienophiles, which require forcing thermal conditions to obtain benzene derivatives.

KNOWLEDGE-BASED MANUFACTURING STRATEGY AND METHODS FOR FOUNDRIES

The European foundry business is a traditional less RTD intensive industry which is dominated by SMEs and which forms a significant part of Europe’s manufacturing industry. The efficient design and manufacturing of cast components and corresponding tooling is a crucial success factor for these companies. To achieve this, information and knowledge around the design, planning and manufacturing of cast components needs to be accessible in a fast and structured way.

Transfer of spatial knowledge from a virtual environment to reality: Impact of route complexity and subject’s strategy on the exploration mode

The use of virtual reality as tool in the area of spatial cognition raises the question of the quality of learning transfer from a virtual to a real environment. It is first necessary to determine with healthy subjects, the cognitive aids that improve the quality of transfer and the conditions required, especially since virtual reality can be used as effective tool in cognitive rehabilitation. The purpose of this study was to investigate the influence of the exploration mode of virtual environment (Passive vs. Active) according to Route complexity (Simple vs. Complex) on the quality of spatial knowledge transfer in three spatial tasks. Ninety subjects (45 men and 45 women) participated. Spatial learning was evaluated by Wayfinding, sketch-mapping and picture classification tasks in the context of the Bordeaux district. In the Wayfinding task, results indicated that active learning in a Virtual Environment (VE) increased the performances compared to the passive learning condition, irrespective of the route complexity factor. In the Sketch-mapping task, active learning in a VE helped the subjects to transfer their spatial knowledge from the VE to reality, but only when the route was complex. In the Picture classification task, active learning in a VE when the route was complex did not help the subjects to transfer their spatial knowledge. These results are explained in terms of knowledge levels and frame/strategy of reference [SW75, PL81, TH82].

The Role of Ambidexterity in Marketing Strategy Implementation: Resolving the Exploration-Exploitation Dilemma

Formulating consistent marketing strategies is a difficult task, but successfully implementing them is even more challenging. This is even more pertinent as marketing strategies quite often incorporate inherent conflicts between major breakthroughs and consolidation. Consequently, marketers need to balance exploratory and exploitative strategies. However, the literature lacks concrete insights for marketing managers as to how exploratory and exploitative strategies can be best combined. This paper addresses this issue by introducing a framework of multiple types of ambidexterity. Based on qualitative research, tools and procedures are identified to overcome marketing dilemmas and support strategy implementation by drawing on ambidextrous designs.

Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis

BACKGROUND Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care-increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. METHODS We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPPbaseline, BEACOPPescalated, BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. FINDINGS We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9-6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ(2)=0·01). Overall survival was highest in patients who received six cycles of BEACOPPescalated (HR 0·38, 95% credibility interval [CrI] 0·20-0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPPescalated is 7% (95% CrI 3-10)-ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPPescalated has a 10% (95% CI 3-15) advantage over ABVD in overall survival. INTERPRETATION Six cycles of BEACOPPescalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care.

Multiplex strategy for multilocus sequence typing, fla typing, and genetic determination of antimicrobial resistance of Campylobacter jejuni and Campylobacter coli isolates collected in Switzerland

We present an optimized multilocus sequence typing (MLST) scheme with universal primer sets for amplifying and sequencing the seven target genes of Campylobacter jejuni and Campylobacter coli. Typing was expanded by sequence determination of the genes flaA and flaB using optimized primer sets. This approach is compatible with the MLST and flaA schemes used in the PubMLST database and results in an additional typing method using the flaB gene sequence. An identification module based on the 16S rRNA and rpoB genes was included, as well as the genetic determination of macrolide and quinolone resistances based on mutations in the 23S rRNA and gyrA genes. Experimental procedures were simplified by multiplex PCR of the 13 target genes. This comprehensive approach was evaluated with C. jejuni and C. coli isolates collected in Switzerland. MLST of 329 strains resulted in 72 sequence types (STs) among the 186 C. jejuni strains and 39 STs for the 143 C. coli isolates. Fourteen (19%) of the C. jejuni and 20 (51%) of the C. coli STs had not been found previously. In total, 35% of the C. coli strains collected in Switzerland contained mutations conferring antibiotic resistance only to quinolone, 15% contained mutations conferring resistance only to macrolides, and 6% contained mutations conferring resistance to both classes of antibiotics. In C. jejuni, these values were 31% and 0% for quinolone and macrolide resistance, respectively. The rpoB sequence allowed phylogenetic differentiation between C. coli and C. jejuni, which was not possible by 16S rRNA gene analysis. An online Integrated Database Network System (SmartGene, Zug, Switzerland)-based platform for MLST data analysis specific to Campylobacter was implemented. This Web-based platform allowed automated allele and ST designation, as well as epidemiological analysis of data, thus streamlining and facilitating the analysis workflow. Data networking facilitates the exchange of information between collaborating centers. The described approach simplifies and improves the genotyping of Campylobacter, allowing cost- and time-efficient routine monitoring.

Double arterial perfusion strategy for extensive thoracic aortic surgery to avoid lower body hypothermic circulatory arrest

OBJECTIVE To analyse our results of using a double arterial perfusion strategy to avoid lower body hypothermic circulatory arrest after extensive thoracic aortic surgery. METHODS We analysed the intra- and perioperative courses of 10 patients (median age 58 years, median logistic EuroSCORE 14.6) who underwent extensive thoracic aortic surgery with a double arterial perfusion strategy. The main goal of double arterial perfusion is to separate myocardial and supra-aortic from systemic perfusion. Aortic repair starts at the most distal level of the descending aorta, followed by reinsertion of the supra-aortic vessels, and ends with completion of the proximal anastomosis or by any kind of root repair as needed. RESULTS Seven of 10 patients had prior surgery of the thoracic aorta. Indications for surgery were post-dissection aneurysm in 4 patients, true aneurysm in 3, anastomotic aneurysms in 2 and Type B aortic dissection with pseudo-coarctation in 1. Surgical access was performed through median sternotomy with left hemi-clamshell extension in all cases. There was no in-hospital mortality, but perioperative neurological symptoms occurred in 2 patients. These 2 patients developed delayed stroke (after awaking) after an initial uneventful clinical course, and in 1 of them, neurological symptoms resolved completely during follow-up. The median follow-up was 7 (±13) months. There was no death and no need for additional redo surgery during this observational period. CONCLUSIONS Extensive surgery of the thoracic aorta using a double arterial perfusion technique in order to avoid lower body hypothermic circulatory arrest is an attractive option. Further refinements of this technique may enable the safe and effective simultaneous multisegmental treatment of thoracic aortic pathology in patients who would otherwise have to undergo a two-step surgical approach.

Transcatheter aortic valve implantation: the transfemoral access route is the default access

Transcatheter aortic valve implantation (TAVI) is a widely accepted alternative to surgical aortic valve replacement (SAVR) among non-operable patients or selected high-risk patients with degenerative, severe aortic stenosis. TAVI is considered less invasive when compared with SAVR; however, there remain significant differences between different TAVI access routes. The transfemoral approach is considered the least invasive access route, and can be performed as a fully percutaneous procedure in a spontaneously breathing patient under local anaesthesia and mild sedation only. Moreover, transfemoral TAVI patients are typically transferred to coronary care rather than to an intensive care unit after the procedure, and benefit from early ambulation and a reduction in overall length of hospital stay. Considering these patient-specific and health-economic advantages, several TAVI centres follow the least invasive strategy for their patients and have implemented the transfemoral access route as the default access in their institutions. This article provides an overview on the prerequisites for a successful transfemoral TAVI procedure, describes the procedural advantages compared to alternative access routes, and highlights differences in clinical outcomes.

Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival.

Histopathologic tumor regression grades (TRGs) after neoadjuvant chemotherapy predict survival in different cancers. In bladder cancer, corresponding studies have not been conducted. Fifty-six patients with advanced invasive urothelial bladder cancer received neoadjuvant chemotherapy before cystectomy and lymphadenectomy. TRGs were defined as follows: TRG1: complete tumor regression; TRG2: >50% tumor regression; TRG3: 50% or less tumor regression. Separate TRGs were assigned for primary tumors and corresponding lymph nodes. The prognostic impact of these 2 TRGs, the highest (dominant) TRG per patient, and competing tumor features reflecting tumor regression (ypT/ypN stage, maximum diameter of the residual tumor) were determined. Tumor characteristics in initial transurethral resection of the bladder specimens were tested for response prediction. The frequency of TRGs 1, 2, and 3 in the primary tumors were n=16, n=19, and n=21; corresponding data from the lymph nodes were n=31, n=9, and n=16. Interobserver agreement in determination of the TRG was strong (κ=0.8). Univariately, all evaluated parameters were significantly (P≤0.001) related to overall survival; however, the segregation of the Kaplan-Meier curves was best for the dominant TRG. In multivariate analysis, only dominant TRG predicted overall survival independently (P=0.035). In transurethral resection specimens of the chemotherapy-naive bladder cancer, the only tumor feature with significant (P<0.03) predictive value for therapy response was a high proliferation rate. In conclusion, among all parameters reflecting tumor regression, the dominant TRG was the only independent risk factor. A favorable chemotherapy response is associated with a high proliferation rate in the initial chemotherapy-naive bladder cancer. This feature might help personalize neoadjuvant chemotherapy.

Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin

UNLABELLED The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. METHODS To determine the effect of treatment with rapamycin and radiotherapy with a novel (177)Lu-labeled GRPr antagonist ((177)Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and (177)Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on (177)Lu-RM2 tumor uptake, in vivo small-animal PET studies with (68)Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of (177)Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with (177)Lu-RM2 alone or after pretreatment with rapamycin. RESULTS Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with (177)Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of (177)Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was observed. CONCLUSION Radiotherapy using a (177)Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.

Panel report ECIS 2012: publication strategy for junior researchers: quantity vs. quality, importance of the first authorship and collaboration

The publication record is a key component of a successful academic career in IS. Despite its importance, its definition - especially for junior researchers―remains unclear. Is it better to have one A-publication or three Bpublications? Does being the third author on an A-publication carry more weight than being the first author on a Bpublication? Is it better to publish with as few co-authors as possible to demonstrate ability for independent work or is publishing with others a sign of good teamwork and academic excellence? Faced with these uncertainties, young researchers increasingly question the choices they make regarding their publication strategy. If unaddressed, these issues are bound to interfere with the quality of the IS research and scholars’ job satisfaction. This article raises these concerns associated with a publication strategy for junior researchers and reports the views voiced by five academics at a panel session at the European Conference on Information Systems 2012. In particular, the following topics are discussed: quantity vs. quality, value of the first authorship, the “optimal” number of authors, and the issues of co-authorship with an academic supervisor.

Multi-scale micro-structure generation strategy for up-scaling transport in clays

Clays and claystones are used as backfill and barrier materials in the design of waste repositories, because they act as hydraulic barriers and retain contaminants. Transport through such barriers occurs mainly by molecular diffusion. There is thus an interest to relate the diffusion properties of clays to their structural properties. In previous work, we have developed a concept for up-scaling pore-scale molecular diffusion coefficients using a grid-based model for the sample pore structure. Here we present an operational algorithm which can generate such model pore structures of polymineral materials. The obtained pore maps match the rock’s mineralogical components and its macroscopic properties such as porosity, grain and pore size distributions. Representative ensembles of grains in 2D or 3D are created by a lattice Monte Carlo (MC) method, which minimizes the interfacial energy of grains starting from an initial grain distribution. Pores are generated at grain boundaries and/or within grains. The method is general and allows to generate anisotropic structures with grains of approximately predetermined shapes, or with mixtures of different grain types. A specific focus of this study was on the simulation of clay-like materials. The generated clay pore maps were then used to derive upscaled effective diffusion coefficients for non-sorbing tracers using a homogenization technique. The large number of generated maps allowed to check the relations between micro-structural features of clays and their effective transport parameters, as is required to explain and extrapolate experimental diffusion results. As examples, we present a set of 2D and 3D simulations and investigated the effects of nanopores within particles (interlayer pores) and micropores between particles. Archie’s simple power law is followed in systems with only micropores. When nanopores are present, additional parameters are required; the data reveal that effective diffusion coefficients could be described by a sum of two power functions, related to the micro- and nanoporosity. We further used the model to investigate the relationships between particle orientation and effective transport properties of the sample.

Antibodies targeting hepatoma-derived growth factor as a novel strategy in treating lung cancer.

Hepatoma-derived growth factor (HDGF) is overexpressed in lung cancer and the overexpression correlates with aggressive biological behaviors and poor clinical outcomes. We developed anti-HDGF monoclonal antibodies and tested their antitumor activity in lung cancer xenograft models. We also determined biological effects in tumors treated with the antibody alone or in combination with bevacizumab/avastin (an anti-vascular endothelial growth factor antibody) and/or gemcitabine (a chemotherapeutic agent). We found the anti-HDGF was effective to inhibit tumor growth in non-small cell lung cancer xenograft models. In the A549 model, compared with control IgG, tumor growth was substantially inhibited in animals treated with anti-HDGF antibodies, particularly HDGF-C1 (P = 0.002) and HDGF-H3 (P = 0.005). When HDGF-H3 was combined with either bevacizumab or gemcitabine, we observed enhanced tumor growth inhibition, particularly when the three agents were used together. HDGF-H3-treated tumors exhibited significant reduction of microvessel density with a pattern distinctive from the microvessel reduction pattern observed in bevacizumab-treated tumors. HDGF-H3-treated but not bevacizumab-treated tumors also showed a significant increase of apoptosis. Interestingly, many of the apoptotic cells in HDGF-H3-treated tumors are stroma cells, suggesting that the mechanism of the antitumor activity is, at least in part, through disrupting formation of tumor-stroma structures. Our results show that HDGF is a novel therapeutic target for lung cancer and can be effectively targeted by an antibody-based approach.

Impact of a stress coping strategy on perceived stress levels and performance during a simulated cardiopulmonary resuscitation: a randomized controlled trial

Background Cardiopulmonary resuscitation (CPR) causes significant stress, which may cause deficiencies in attention and increase distractibility. This may lead to misjudgements of priorities and delays in CPR performance, which may further increase mental stress (vicious cycle). This study assessed the impact of a task-focusing strategy on perceived stress levels and performance during a simulated CPR scenario. Methods This prospective, randomized-controlled trial was conducted at the simulator-center of the University Hospital Basel, Switzerland. A total of 124 volunteer medical students were randomized to receive a 10 minute instruction to cope with stress by loudly posing two taskfocusing questions (“what is the patient’s condition?”, “what immediate action is needed?”) when feeling overwhelmed by stress (intervention group) or a control group. The primary outcome was the perceived levels of stress and feeling overwhelmed (stress/overload); secondary outcomes were hands-on time, time to start CPR and number of leadership statements. Results Participants in the intervention group reported significantly less stress/overload levels compared to the control group (mean difference: -0.6 (95%CI −1.3, -0.1), p=0.04). Higher stress/overload was associated with less hands-on time. Leadership statements did not differ between groups, but the number of leadership statements did relate to performance. Hands-on time was longer in the intervention- group, but the difference was not statistically different (difference 5.5 (95%CI −3.1, 14.2), p=0.2); there were no differences in time to start CPR (difference −1.4 (95%CI −8.4, 5.7), p=0.71). Conclusions A brief stress-coping strategy moderately decreased perceived stress without significantly affecting performance in a simulated CPR. Further studies should investigate more intense interventions for reducing stress.