Self-healing concrete in aggressive enironments

Although certain crack widths are allowed in reinforced concrete structures, without having immediate effects on the structural stability, they may impair the durability and service life of the structure in the long term. Cracks wider than 10 μm will result, for instance, in a faster penetration of chlorides into the crack and from there onwards into the concrete matrix. Fortunately, the autogenous healing ability of concrete may close cracks of up to 100 μm completely. The further hydration of binder particles, will be supplemented by the deposition of calcium carbonate crystals in case of wet/dry cycles. In case of marine infrastructures in tidal zones, the presence of magnesium sulfates may enhance the crack sealing by means of brucite precipitation. These processes will result in reduced chloride penetration rates. If the cracks are larger than 100 μm or the conditions are not favourable for autogenous healing, autonomous healing mechanisms can be incorporated. In this case, healing is obtained through encapsulated polymeric healing agents, superabsorbent polymers, microbial agents, expansive additives, etc. With encapsulated polyurethane based healing agents, a reduction of the chloride concentration by 75% or more was obtained in a zone with a 300 μm wide crack after chloride diffusion tests, relative to the case in which cracks were not healed. As a result, the service life of reinforced concrete elements in marine environments could be increased with a factor of about 10. Neutron radiography images obtained during a capillary sorption test indicated that release of encapsulated polyurethane in wet conditions was favourable for the polyurethane reaction. As an alternative to the autonomous healing with encapsulated polyurethane, also the incorporation of encapsulated water repellent agents and corrosion inhibitors, has proven to effectively delay reinforcement corrosion during electrochemical measurement campaigns. Accelerated corrosion tests on cracked, manually treated mortar samples, allowed to rapidly screen different agents for their efficiency

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies

Implementation and evaluation of different eradication strategies for Brachyspira hyodysenteriae

Background: Brachyspira infections are causing major losses to the pig industry and lead to high antimicrobial use. Treatment of Brachyspira (B.) hyodysenteriae infections may be problematic due to the high level of antimicrobial resistance. The present study implemented and evaluated farm-specific eradication programmes for B. hyodysenteriae in 10 different infected pig farms in Belgium. Results: Ten pig farms clinically infected with B. hyodysenteriae volunteered to implement a farm-specific eradication programme. The programme depended on the farm and management characteristics, antimicrobial susceptibility of the B. hyodysenteriae strain and the motivation of the farmer. Two farms practiced total depopulation, six farms partial depopulation and two farms antimicrobial medication without depopulation. In addition, all farms implemented biosecurity measures, and faeces samples were tested for the presence of B. hyodysenteriae at 6, 9 and 12 months after the start of the program. Single Brachyspira isolates from before and after the programme were typed using multilocus sequence typing (MLST). Eradication was successful in four farms. Two of them (farrow-to-finish and finishing herd) had applied total depopulation and respected a vacancy period of at least 3 weeks. A third farm (gilt farm) practised partial depopulation, the rooms remained empty for 28 days and changed the source of breeding gilts. The fourth farm practised partial depopulation, the stables remained empty for 3 weeks, and used antimicrobial medication. The eradication programme was not successful in six farms. Two of the latter farms only used medication without partial depopulation. Four farms practiced partial depopulation, one of them combined it with antimicrobial medication. The cleaning and disinfection procedures, rodent control, stand-empty period and/or other biosecurity measures in the six farms were not always implemented properly. In two of three farms, isolates belonging to the same MLST type were found before and after eradication. Conclusions: Total depopulation or partial depopulation combined with implementing strict biosecurity measures allowed eradication of B. hyodysenteriae from clinically infected pig farms. Programmes based on antimicrobials without depopulation or partial depopulation without strictly adhering to all suggested biosecurity measures were not successful. Stockmanship and motivation of the farmer to permanently maintain high biosecurity standards are essential for success

BAY 81‐8973 prophylaxis and pharmacokinetics in haemophilia A: Interim results from the TAURUS study

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The anaphase-promoting complex/cyclosome : a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL. METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot. RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax. CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL

G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor-mediated cell death

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G 1 -phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of STGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels

Artificial Insemination in Pigs

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Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy:An Individual Participant Meta-analysis

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a metaanalysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. Study Design: Individual patient-level metaanalysis. Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials. Selection Criteria for Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R-2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R-2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN

Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis

Background The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated. Study Design Individual patient–level meta-analysis. Setting & Population Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels. Selection Criteria for Studies Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome. Predictor 9-month change in proteinuria. Outcome Doubling of serum creatinine level, end-stage renal disease, or death. Results Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, −19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32). Limitations Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events. Conclusions Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings