Immunosuppressive treatment is reported to improve cytopenia in some patients with myelodysplastic syndrome (MDS). Combined antithymocyte globulin (ATG) and cyclosporine (CSA) is most effective in ...patients with immune-mediated marrow failure.
This trial was designed to assess the impact of immunosuppression on hematopoiesis, transfusion requirements, transformation, and survival in patients with MDS randomly assigned to 15 mg/kg of horse ATG for 5 days and oral CSA for 180 days (ATG+CSA) or best supportive care (BSC), stratified by treatment center and International Prognostic Scoring System (IPSS) risk score. Primary end point was best hematologic response at 6 months. Eligible patients had an Eastern Cooperative Oncology Group performance status of ≤ 2 and transfusion dependency of less than 2 years in duration.
Between 2000 and 2006, 45 patients received ATG+CSA (median age, 62 years; range, 23 to 75 years; 56% men) and 43 patients received BSC (median age, 65 years; range, 24 to 76 years; 81% men). IPSS score was low, intermediate-1, intermediate-2, high, and not evaluable in eight, 24, seven, one, and five patients on ATG+CSA, respectively, and eight, 25, five, zero, and five patients on BSC, respectively. Refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess of blasts (RAEB) -I, RAEB-II, and hypoplastic disease were present in 21, six, nine, zero, and nine patients on ATG+CSA, respectively, and 18, eight, 11, two, and four patients on BSC, respectively. By month 6, 13 of 45 patients on ATG+CSA had a hematologic response compared with four of 43 patients on BSC (P = .0156). Two-year transformation-free survival (TFS) rates were 46% (95% CI, 28% to 62%) and 55% (95% CI, 34% to 70%) for ATG+CSA and BSC patients, respectively (P = .730), whereas overall survival (OS) estimates were 49% (95% CI, 31% to 66%) and 63% (95% CI, 42% to 78%), respectively (P = .828).
This open-label randomized phase III trial demonstrates that ATG+CSA treatment seems to be associated with hematologic response in a subset of patients without apparent impact on TFS and OS.
Background. Despite increasing evidence of the development of Plasmodium vivax chloroquine (CQ) resistance, there have been no trials comparing its efficacy with that of artemisinin-based combination ...therapies (ACTs) in Latin America. Methods. This randomized controlled trial compared the antischizontocidal efficacy and safety of a 3-day supervised treatment of the fixed-dose combination artesunate-amodiaquine Winthrop® (ASAQ) versus CQ for treatment of uncomplicated P. vivax infection in Manaus, Brazil. Patients were followed for 42 days. Primary endpoints were adequate clinical and parasitological responses (ACPR) rates at day 28. Genotype-adjustment was performed. Results. From 2012 to 2013, 380 patients were enrolled. In the per-protocol (PP) analysis, adjusted-ACPR was achieved in 100% (165/165) and 93.6% (161/172) of patients in the ASAQ and CQ arm (difference 6.4%, 95% CI 2.7%; 10.1%) at day 28 and in 97.4% (151/155) and 77.7% (129/166), respectively (difference 19.7%, 95% CI 12.9%; 26.5%), at day 42. Apart from ITT D28 assessment, superiority of ASAQ on ACPR was demonstrated. ASAQ presented faster clearance of parasitaemia and fever. Based on CQ blood level measurements, CQ resistance prevalence was estimated at 11.5% (95% CI: 7.5-17.3) up to day 42. At least one emergent adverse event (AE) was recorded for 79/190 (41×6%) in the ASAQ group and for 85/190 (44×7%) in the CQ group. Both treatments had similar safety profiles. Conclusions. ASAQ exhibited high efficacy against CQ resistant P. vivax and is an adequate alternative in the study area. Studies with an efficacious comparator, longer follow-up and genotype-adjustment can improve CQR characterization. Clinical Trials Registration. NCT01378286.
We have generated a large, unique database that includes morphologic, clinical, cytogenetic, and follow-up data from 2124 patients with myelodysplastic syndromes (MDSs) at 4 institutions in Austria ...and 4 in Germany. Cytogenetic analyses were successfully performed in 2072 (97.6%) patients, revealing clonal abnormalities in 1084 (52.3%) patients. Numeric and structural chromosomal abnormalities were documented for each patient and subdivided further according to the number of additional abnormalities. Thus, 684 different cytogenetic categories were identified. The impact of the karyotype on the natural course of the disease was studied in 1286 patients treated with supportive care only. Median survival was 53.4 months for patients with normal karyotypes (n = 612) and 8.7 months for those with complex anomalies (n = 166). A total of 13 rare abnormalities were identified with good (+1/+1q, t(1q), t(7q), del(9q), del(12p), chromosome 15 anomalies, t(17q), monosomy 21, trisomy 21, and −X), intermediate (del(11q), chromosome 19 anomalies), or poor (t(5q)) prognostic impact, respectively. The prognostic relevance of additional abnormalities varied considerably depending on the chromosomes affected. For all World Health Organization (WHO) and French-American-British (FAB) classification system subtypes, the karyotype provided additional prognostic information. Our analyses offer new insights into the prognostic significance of rare chromosomal abnormalities and specific karyotypic combinations in MDS.
•Novel fragility models for scoured-critical bridges exposed to multiple hazards were generated•Rigorous FEM included the water-soil-bridge interaction under flooding and earthquakes•Failure modes ...for bridge components exposed to floods were described•Insights on the flood vulnerability of integral and bridges with bearings are provided•Consideration of uncertainties in scour formation enhance the reliability of risk assessment
Building resilient bridges, that are able to withstand multiple natural stressors with minimal damage and quickly restore their functionality is paramount to delivering climate-resilient transport infrastructure. Nevertheless, bridges are proven to be vulnerable to natural hazards, with floods and earthquakes being the main causes of failure. The available research and practice for assessing the vulnerability of river-crossing bridges is predominantly qualitative and therefore relies heavily on visual inspections, while ignoring important characteristics of the complex water-soil-bridge interaction. This is a knowledge gap that this paper aims to fill. This work provides novel fragility models for hydraulically induced stressors and/or combinations of hydraulic and seismic hazards. To achieve this, unique detailed two- and three- dimensional numerical models are employed, for a typical three-span prestressed box-girder river-crossing bridge. This paper is a primer on the vulnerability of flood-critical bridges as it models the entire water-soil-bridge system, taking into account critical hydraulic stressors (scour, debris accumulation, hydraulic forces), the uncertainty in scour hole formation, and all components of integral and isolated bridges: deck, bearings, piers and abutments, backfill, and the foundation soil. A detailed description of the damage modes for each component is given and sets of fragility curves for floods and combinations of hydraulic stressors and earthquakes are developed. The study concludes that integral bridges are in most cases more vulnerable to local scour than bridges with bearings, since the latter are more flexible and can therefore adapt to changes in their geometry. The opposite is true for global scour and/or seismic earthquake excitations. The generated fragility models are useful tools for quantitative risk assessment of transport systems and provide practical means in resilience-based asset management by owners and operators of transport infrastructure.
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•Description of cocoa production chain and residual biomass generation.•Cocoa by-products as a source of high-value-added molecules.•Biotechnology as an alternative for the ...biotransformation of cocoa by-products.•Relevance of sustainability, innovation and technology in cocoa industry.
Cocoa beans provide raw materials for global food industries valued in excess of $47 billion in world exportations. Through on-farm processing, about 80% of cocoa fruit is discarded as residual biomass, including cocoa pod husks, cocoa bean shells and cocoa sweatings. Farmers routinely discard these residues/by-products during the initial cocoa bean processing steps, occupying vast areas and raising social and environmental concerns. Alternatively, this residual biomass is used as cocoa tree fertilizer. However, its disposal is performed without proper treatment, resulting in putrid odors and plant diseases. Recently, some studies have reported the use of cocoa by-products in the production of high-value-adding molecules with potential applications in the food, pharmaceutical and cosmetic industries. In this aspect, biotechnological approaches have been shown to be a viable alternative for the transformation of this residual biomass into fine products. This article reviews the biotechnological approaches implemented for the management and exploitation of cocoa by-product. Related topics on cocoa production and residual biomass generation, sustainability and valorization of cocoa chain are addressed and discussed.
Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and ...oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease.
To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation.
Sixty-four BALBc mice, were divided into eight groups (
= 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28).
Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4
, CD8
, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (
< 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (
< 0.05).
Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.
The importance of evapotranspiration is well-established in different disciplines such as hydrology, agronomy, climatology, and other geosciences. Reliable estimates of evapotranspiration are also ...vital to develop criteria for in-season irrigation management, water resource allocation, long-term estimates of water supply, demand and use, design and management of water resources infrastructure, and evaluation of the effect of land use and management changes on the water balance. The objective of this Special Issue is to define and discuss several ET terms, including potential, reference, and actual (crop) ET, and present a wide spectrum of innovative research papers and case studies.
Carbonate concretions hosted within organic carbon‐rich shale sequences represent unique archives of often exceptionally preserved fossil biota. Besides providing high‐fidelity preservation, their ...geochemical signatures can provide insight into the physical and chemical processes during early and later‐stage concretion growth. Here, two fossiliferous carbonate concretions of the late Early Cretaceous Santana Formation (Araripe Basin, north‐east Brazil) are analysed with an integrative geochemical approach including μ‐XRF scanning, δ13C, δ18O, 87Sr/86Sr and Δ47 (clumped isotope thermometry). Individual concretions show a concentric internal zonation with the outermost layer being composed of millimetre thick cone‐in‐cone calcite. A strong covariance of δ13C and δ18O values of the fine‐crystalline concretion body indicates mixing of two different carbonate phases and supports a scenario of temporally separated pervasive growth stages. Microbially‐mediated formation of an early porous calcite framework was controlled by the combined processes of fermentation and methanogenesis around the decaying carcass, forming localized environments within a zone of sulphate reduction. Microbial sulphate reduction is indicated by the concentric enrichment of pyrite in the outer part of the concretion body and by high pyrite abundance in the surrounding shale. Information on the later‐stage diagenetic processes affecting the Santana concretions can be derived from the outermost fringing cone‐in‐cone calcite. The carbonate precipitating fluid was characterized by a more or less marine δ18O composition (calculated δ18Oporewater = −1·0 to −1·8‰) and by radiogenic Sr‐isotope ratios (up to 0·713331 ± 7·0*10−6), the latter probably reflecting modification due to interaction with the surrounding shale or, alternatively, with underlying evaporitic sulphate deposits influenced by strong continental inflow or with crystalline basement rocks. The Δ47‐derived temperature estimates range between 37°C and 42°C ± 5, indicating precipitation of the cone‐in‐cone calcite at a depth of 650 to 850 m, which is only half as much as the maximum burial depth derived from existing fission‐track data. Overall, the study of fossiliferous carbonate concretions in organic carbon‐rich sedimentary sequences can reveal a complex growth history spanning incipient microbially‐influenced precipitates as well as later‐stage burial diagenetic phases.
Mucositis is an inflammatory condition of the gut, caused by an adverse effect of chemotherapy drugs, such as 5-fluorouracil (5-FU). In an attempt to develop alternative treatments for the disease, ...several research groups have proposed the use of probiotics, in particular, Lactic Acid Bacteria (LAB). In this context, the use of recombinant LAB, for delivering anti-inflammatory compounds has also been explored. In previous work, we demonstrated that either Lactococcus lactis NZ9000 or a recombinant strain expressing an antimicrobial peptide involved in human gut homeostasis, the Pancreatitis-associated Protein (PAP), could ameliorate 5-FU-induced mucositis in mice. However, the impact of these strains on the gut microbiota still needs to be elucidated. Therefore, in the present study, we aimed to characterize the effects of both Lactococci strains in the gut microbiome of mice through a 16 S rRNA gene sequencing metagenomic approach. Our data show 5-FU caused a significant decrease in protective bacteria and increase of several bacteria associated with pro-inflammatory traits. The Lactococci strains were shown to reduce several potential opportunistic microbes, while PAP delivery was able to suppress the growth of Enterobacteriaceae during inflammation. We conclude the strain secreting antimicrobial PAP was more effective in the control of 5-FU-dysbiosis.
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