Progesterone Concentrations during Canine Pregnancy

Pregnancy and lactation are amongst the most challenging times of a bitch’s life. Most studies focusing on the endocrinological aspect of pregnancy consider only a small number of animals. The aim of this study was to evaluate progesterone (P4) concentrations in a large number of bitches during early, mid and late pregnancy. In total, 126 bitches of various breeds were recruited following a thorough clinical and gynecological examination during estrus. Blood samples were collected three times (T1–T3) during pregnancy or from non-pregnant dogs in diestrus, and P4 was measured via chemiluminescence. At T1 (11–19 days post-ovulation (dpo)), serum P4 concentrations were 30.23 ± 6.65 ng/mL and 28.45 ± 6.26 ng/mL, at T2 (23–32 dpo) they were 22.73 ± 6.27 ng/mL and 22.59 ± 5.77 ng/mL and at T3 (52–60 dpo) they were 6.68 ± 2.18 ng/mL and 3.17 ± 2.26 ng/mL, in pregnant (n = 98) and non-pregnant (n = 23) dogs respectively. The P4 concentrations differed significantly between pregnant and non-pregnant animals at the last examination (p ≤ 0.001). In the context of hypoluteoidism, the gathered data yielded interesting results. Overall, 28 out of 98 pregnant bitches showed a greater decline (>15 ng/mL) in P4 concentrations from early to mid-pregnancy, and 56 bitches showed P4 concentrations lower than deemed adequate (>20 ng/mL at T1 and T2, >5 ng/mL at T3) according to existing recommendations. Despite not being supplemented with P4, none of those animals suffered from abortion or preterm delivery. Considering that supplementation of P4 can entail considerable risks for the bitch and the puppies, more research on P4 concentration patterns, diagnosis of hypoluteoidism and treatment indications and options is indicated

Metabolomics during canine pregnancy and lactation

During pregnancy and parturition, female dogs have to cope with various challenges such as providing nutrients for the growth of the fetuses, hormonal changes, whelping, nursing, milk production, and uterine involution. Metabolomic research has been used to characterize the influence of several factors on metabolism such as inter- and intra-individual factors, feeding, aging, inter-breed differences, drug action, behavior, exercise, genetic factors, neuter status, and pathologic processes. Aim of this study was to identify metabolites showing specific changes in blood serum at the different phases of pregnancy and lactation. In total, 27 privately owned female dogs of 21 different breeds were sampled at six time points: during heat, in early, mid and late pregnancy, at the suspected peak of lactation and after weaning. A validated and highly automated canine-specific NMR metabolomics technology was utilized to quantitate 123 measurands. It was evaluated which metabolite concentrations showed significant changes between the different time points. Metabolites were then grouped into five clusters based on concentration patterns and biochemical relationships between the metabolites: high in mid-pregnancy, low in mid-pregnancy, high in late pregnancy, high in lactation, and low in lactation. Several metabolites such as albumin, glycoprotein acetyls, fatty acids, lipoproteins, glucose, and some amino acids show similar patterns during pregnancy and lactation as shown in humans. The patterns of some other parameters such as branched-chain amino acids, alanine and histidine seem to differ between these species. For most metabolites, it is yet unstudied whether the observed changes arise from modified resorption from the intestines, modified production, or metabolism in the maternal or fetal tissues. Hence, further species-specific metabolomic research may support a broader understanding of the physiological changes caused by pregnancy that are likely to be key for the normal fetal growth and development. Our findings provide a baseline of normal metabolic changes during healthy canine pregnancy and parturition. Combined with future metabolomics findings, they may help monitor vital functions of pre-, intra-, and post-partum bitches and may allow early detection of illness

Progesterone Concentrations during Canine Pregnancy

Pregnancy and lactation are amongst the most challenging times of a bitch’s life. Most studies focusing on the endocrinological aspect of pregnancy consider only a small number of animals. The aim of this study was to evaluate progesterone (P4) concentrations in a large number of bitches during early, mid and late pregnancy. In total, 126 bitches of various breeds were recruited following a thorough clinical and gynecological examination during estrus. Blood samples were collected three times (T1–T3) during pregnancy or from non-pregnant dogs in diestrus, and P4 was measured via chemiluminescence. At T1 (11–19 days post-ovulation (dpo)), serum P4 concentrations were 30.23 ± 6.65 ng/mL and 28.45 ± 6.26 ng/mL, at T2 (23–32 dpo) they were 22.73 ± 6.27 ng/mL and 22.59 ± 5.77 ng/mL and at T3 (52–60 dpo) they were 6.68 ± 2.18 ng/mL and 3.17 ± 2.26 ng/mL, in pregnant (n = 98) and non-pregnant (n = 23) dogs respectively. The P4 concentrations differed significantly between pregnant and non-pregnant animals at the last examination (p ≤ 0.001). In the context of hypoluteoidism, the gathered data yielded interesting results. Overall, 28 out of 98 pregnant bitches showed a greater decline (>15 ng/mL) in P4 concentrations from early to mid-pregnancy, and 56 bitches showed P4 concentrations lower than deemed adequate (>20 ng/mL at T1 and T2, >5 ng/mL at T3) according to existing recommendations. Despite not being supplemented with P4, none of those animals suffered from abortion or preterm delivery. Considering that supplementation of P4 can entail considerable risks for the bitch and the puppies, more research on P4 concentration patterns, diagnosis of hypoluteoidism and treatment indications and options is indicated

Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response

Heat shock protein 90 (HSP90) stabilizes many client proteins including BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of CML in which treatment-free remission (TFR) is limited with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics, which synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain (NTD) of HSP90 are under investigation; however, side effects such as induction of heat shock response (HSR) and toxicity have so far precluded their FDA approval. We have developed a novel inhibitor (referred to as aminoxyrone) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain (CTD). This was achieved by structure-based molecular design, chemical synthesis, and functional pre-clinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. Aminoxyrone (AX) is a promising potential candidate, which induces apoptosis in leukemic stem cells (LSCs) fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in TKI-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated and targeting HSP90 C-terminus by AX does not induce HSR in vitro and in vivo. We also probed the potential of AX in other therapy refractory leukemia such as BCR-ABL1+ BCP-ALL, FLT3-ITD+ AML and Ph-like BCP-ALL. Therefore, AX is the first peptidometic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other therapy-refractory leukemia, due to its low toxicity profile and lack of HSR