Calcinosis in Alpaca Crias (Vicugna pacos) Due to Vitamin D Intoxication—Clinical, Laboratory and Pathological Findings with a Focus on Kidney Function

Alpacas kept in Central Europe are often deficient in vitamin D3, which is supplemented orally or by injection by the owners or veterinarians. Vitamin D3 can be specified in two different units (IU and µg), which differ by a factor of 40. By mixing up these units, an overdosage can be induced. In this study, three alpaca crias were examined after vitamin D3 intoxication, with particular reference to kidney function. All three animals developed non-specific clinical alterations 1–2 weeks after a vitamin D3 overdose of approximately 40 times. Plasma of the animals revealed several alterations. The main findings were severe azotemia, hypercalcemia and hyperphosphatemia, 15 days after treatment. Kidney function analysis (endogenous creatinine clearance) in two of the crias revealed severe glomerular damage. All crias died despite intensive treatment within 23 days after vitamin D3 treatment. Necropsy revealed calcification in different organs, mainly the kidneys, lungs and liver. Since nine other crias in the same group were treated with comparable doses of vitamin D3 and no clinical signs were observed in these animals, it is concluded that individual animals show different levels of sensitivity to vitamin D3

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN

Calcinosis in Alpaca Crias (Vicugna pacos) Due to Vitamin D Intoxication—Clinical, Laboratory and Pathological Findings with a Focus on Kidney Function

Alpacas kept in Central Europe are often deficient in vitamin D3, which is supplemented orally or by injection by the owners or veterinarians. Vitamin D3 can be specified in two different units (IU and µg), which differ by a factor of 40. By mixing up these units, an overdosage can be induced. In this study, three alpaca crias were examined after vitamin D3 intoxication, with particular reference to kidney function. All three animals developed non-specific clinical alterations 1–2 weeks after a vitamin D3 overdose of approximately 40 times. Plasma of the animals revealed several alterations. The main findings were severe azotemia, hypercalcemia and hyperphosphatemia, 15 days after treatment. Kidney function analysis (endogenous creatinine clearance) in two of the crias revealed severe glomerular damage. All crias died despite intensive treatment within 23 days after vitamin D3 treatment. Necropsy revealed calcification in different organs, mainly the kidneys, lungs and liver. Since nine other crias in the same group were treated with comparable doses of vitamin D3 and no clinical signs were observed in these animals, it is concluded that individual animals show different levels of sensitivity to vitamin D3

Calcinosis in Alpaca Crias (Vicugna pacos) Due to Vitamin D Intoxication—Clinical, Laboratory and Pathological Findings with a Focus on Kidney Function

Alpacas kept in Central Europe are often deficient in vitamin D3, which is supplemented orally or by injection by the owners or veterinarians. Vitamin D3 can be specified in two different units (IU and µg), which differ by a factor of 40. By mixing up these units, an overdosage can be induced. In this study, three alpaca crias were examined after vitamin D3 intoxication, with particular reference to kidney function. All three animals developed non-specific clinical alterations 1–2 weeks after a vitamin D3 overdose of approximately 40 times. Plasma of the animals revealed several alterations. The main findings were severe azotemia, hypercalcemia and hyperphosphatemia, 15 days after treatment. Kidney function analysis (endogenous creatinine clearance) in two of the crias revealed severe glomerular damage. All crias died despite intensive treatment within 23 days after vitamin D3 treatment. Necropsy revealed calcification in different organs, mainly the kidneys, lungs and liver. Since nine other crias in the same group were treated with comparable doses of vitamin D3 and no clinical signs were observed in these animals, it is concluded that individual animals show different levels of sensitivity to vitamin D3

Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient-individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients' clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials