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Background and objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. Methods: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. Results: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. Conclusion: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Additional file 7: Supplementary Table S2. List of used reagents including A, QuantiTect primer assays, B, siRNA and shRNA oligos, and C, antibodies.

Additional file 5: Supplemental Figure S5. Inducibly silencing EDI3 inhibits colony formation and cell viability. A, Representative images (top) and corresponding quantification (bottom) of colony number (left) and size (right) formed by HCC1954 shNEG and HCC1954 shEDI3 (oligos shEDI3 #1, #2, #3) cells treated with 0 or 0.1 µg/ml doxycycline. B, Viability (RFU) after treating HCC1954 shNEG and HCC1954 shEDI3 (oligos shEDI3 #1, #2) with 0.1 or 1 µg/ml doxycycline. All in vitro data are mean ± SD of three independent experiments. (*, P < 0.05; **, P < 0.01; ***, P < 0.001). RFU, relative fluorescence units.

Additional file 4: Supplementary Figure S4. Inhibiting EDI3 with dipyridamole, alone or in combination with HER2-targeting therapy, in ER-HER2+ tumors in mice. A-D EDI3 activity in percent after treatment with dipyridamole at different concentrations in A, HCC1954 B, SKBR3, C, BT474 and D, EFM192 cells. E, Cell viability in percent of vehicle control after treatment with different concentrations of dipyridamole in SKBR3, HCC1954, BT474 and EFM192A cells (upper panel) and EC50-values with corresponding 95% confidence intervals (CI) (lower panel). F, Concentration of dipyridamole in plasma after a single oral dose of 120 mg/kg dipyridamole in mice over time. G, Mouse weight (grams) after treatment with dipyridamole, lapatinib and the combination for up to 4 weeks. H, Images of CD1 nude mice with tumors encircled, after 4-week treatment of vehicle, dipyridamole, lapatinib and the combination of both. I, Plasma and tumor concentrations (µM) of dipyridamole (upper panel) and lapatinib (lower panel) after treatment with each compound alone or in combination (D+L). Data (A-E) are mean ± SD of three independent experiments; mean ± SD of three CD1 mice (F); mean ± SD 5 to 6 mice (G); and representative images of 4 mice per condition H. D+L (combined dipyridamole and lapatinib treatment); BQL (below quantification limit); EC50 (half maximal effective concentration).

Cacao agroforestry systems offer a wide range of ecosystem services beside food and timber production, such as biodiversity, carbon sequestration, microclimate regulation, water infiltration etc. which makes them interesting for farmers as well as for society. In many cases the mid to long-term benefit for farmers from the shade trees is not known. To assess the added value of timber and fruit trees, 16 smallholder cacao agroforestry fields in Alto Beni, Bolivia were selected in 2017 with the criteria of having dynamic agroforestry or diverse agroforestry systems implemented. Fields were georeferenced and tree inventories established. Quantitative and qualitative data of the timber trees were taken. The farmers were interviewed concerning the fruit tree productivity and use of the harvest. The regulative governmental entity for timber tree management was interviewed for assessment of the timber value chain. The cacao agroforestry plantations have an average age of 18 years. For the total of 2’941 timber trees the species were identified (72), 20% of it were Swietenia macrophylla, which makes it the most popular timber species. Followed by Myroxylon balsamum, Amburana cearensis and Centrolobium ochroxylum. The average timber tree density was 154 trees/ha and the standing timber volume was 38.8 m³/ha. The value of the standing timber was evaluated in average of 12’947 USD/ha. This value needs to be reduced due to lack of professional timber processing. Most numerous fruit are banana, followed by the fruit trees of Bactris gasipaes, Oenocarpus bataua, citrics and Garcinia gardneriana.There is a marked difference in fruit tree density according the agroforestry system, dynamic agroforestry systems harbor much more fruit trees compared to the simpler agroforestry systems which have the focus on timber. With the aim to increase farmer’s income from timber as well from fruit trees the value chains need to be strengthened.

Data de publicació electrònica: 23-03-2022 Background and purpose: The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods: We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results: Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions: We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients. Funding: H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon;#21466) to A.R. The work of B.W. is supported by the German Research Foundation (Wi945/17-1, SFB 1451 [project-ID 431549029–A01] and GRK1960 [project ID 233886668]), the European Research Council under the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 956185 (SMABEYOND), and the Center for Molecular Medicine Cologne (project No C18)