Search

We hypothesized that feeding 25-hydroxyvitamin D3 [25-(OH)D3] during lactation and prepartum in conjunction with negative dietary cation-anion difference diets would improve milk production, increase the probability of pregnancy, and reduce the incidence of postcalving diseases. Cows from 4 dairies with prepartum transition diets negative in dietary cation-anion difference were used in 2 randomized cohort experiments. In Experiment 1 (Exp. 1), cows were assigned to control [CON; n = 645; no 25-(OH)D3] or treatment [TRT; n = 537; 2 mg/d of 25-(OH)D3 from ∼21 d prepartum to parturition and 1 mg/d in lactation] groups at ∼21 d prepartum. Cows were monitored for weekly milk yield, milk composition every 60 d, and health and reproductive measures. In Experiment 2 (Exp. 2), cows (n = 2,064; median 147 d in milk) were assigned to 4 groups and monitored for the same measures as in Exp. 1 to the end of that lactation (L1), the subsequent transition (∼21 d prepartum to parturition), and the next lactation (L2). Groups were as follows, with the amount of 25-(OH)D3 fed (mg/d) indicated in parentheses for L1, transition, and L2, respectively: (A) control-control (CON-CON; 0-0-0), (B) treatment-treatment (TRT-TRT; 1-2-1), (C) control-treatment (CON-TRT; 0-2-1), and (D) treatment-control (TRT-CON; 1-0-0). For L1, a total of 1,032 cows entered the control groups A or C and a total of 1,032 cows in groups B or D. The number of cows in groups A to D that entered L2 was 521, 523, 273, and 248, respectively. Blood calcium, phosphorus, and 25-(OH)D3 concentrations were measured from 17 cows/group at 5 times. In Exp. 1, TRT cows had 0.2 lower log somatic cell count than CON cows (4.21 ± 0.045 vs. 4.01 ± 0.050, respectively) and multiparous TRT cows had 41 ± 23% higher probability of pregnancy/day than multiparous CON cows, resulting in a 22-d median decrease in time to pregnancy. Primiparous TRT cows had 1.67 ± 0.40 times greater odds of mastitis/day than primiparous CON cows. In Exp. 2 TRT-TRT cows had between 16 and 29% lower probability to be bred/day than other groups. Multiparous CON-CON and TRT-CON cows had 20 ± 8% and 30 ± 17% greater probability of pregnancy, respectively, than multiparous TRT-TRT cows. Serum calcium concentrations were not affected by group, but phosphorus and 25-(OH)D3 concentrations were highest in the TRT-TRT cows. The study provides further insights into the use of 25(OH)D3 in transition and lactation.

This review examines the role of nutritional strategies to improve lifetime performance in ruminants. Strategies to increase ruminants' productive longevity by means of nutritional interventions provide the opportunity not only to increase their lifetime performances and their welfare, but also to decrease their environmental impact. This paper will also address how such nutritional interventions can increase herd efficiency and farm profitability. The key competencies reviewed in this article are redox balance, skeletal development and health, nutrient utilization and sustainability, which includes rearing ruminants without antibiotics and methane mitigation. While the relationships between these areas are extremely complex, a multidisciplinary approach is needed to develop nutritional strategies that would allow ruminants to become more resilient to the environmental and physiological challenges that they will have to endure during their productive career. As the demand of ruminant products from the rapidly growing human world population is ever-increasing, the aim of this review is to present animal and veterinary scientists as well as nutritionists a multidisciplinary approach towards a sustainable ruminant production, while improving their nutrient utilization, health and welfare, and mitigation of their carbon footprint at the same time.

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.

The study of vitamin D in cattle has often focussed on its role in calcium and mineral metabolism. However, there is evidence of a wider role for vitamin D in bone and energy metabolism. Two studies were conducted to explore relationships between calcidiol supplementation, blood minerals and metabolites in mid-lactation dairy cows. In Experiment 1, a dose-response study was conducted in which 25 mid-lactation cows were fed one of five supplementary calcidiol doses (0, 0.5, 1, 2 or 4 mg calcidiol/day) for 30 days, with blood samples taken every 10 days. Increasing calcidiol dose increased plasma calcidiol (P = 0.001), 24,25-(OH)2-D3 (P = 0.001) and serum phosphate (P = 0.003) in a curvilinear manner, increased and then decreased plasma 25-OH-D2 (P = 0.004) and linearly increased 3-epi 25-OH-D3 (P = 0.001) and milk calcidiol concentrations (P = 0.001). Calcidiol supplementation did not affect milk yield or composition, bodyweight or condition score. In Experiment 2, relationships between blood calcidiol and mineral and metabolite concentrations over time were explored using time-series analysis. Ten mid-lactation cows were fed either 0 or 0.5 mg calcidiol/day for 27 days, with blood samples taken every 3 days. Feeding calcidiol increased plasma calcidiol (P = 0.001), 24,25-OH-D3 (P = 0.038), and insulin (P = 0.046), but decreased 25-OH-D2 (P = 0.008) concentrations. Positive associations were identified between blood calcidiol and concentrations of other metabolites, including cholecalciferol, calcium, osteocalcin, glucose, insulin, non-esterified fatty acids, β-hydroxybutyrate, cholesterol, magnesium, phosphorus and total protein at varying lags (±0, 3 or 6 days), while negative relationships were identified between calcidiol and 24,25-(OH)2-D3, and phosphorus 3 days later. Importantly, strong positive associations between calcidiol and indicators of energy metabolism were identified. Overall, these experiments provide support for a positive effect of calcidiol treatment on dairy cow metabolism.

Presenilins are components of the gamma-secretase protein complex that mediates intramembranous cleavage of betaAPP and Notch proteins. A C. elegans genetic screen revealed two genes, aph-1 and pen-2, encoding multipass transmembrane proteins, that interact strongly with sel-12/presenilin and aph-2/nicastrin. Human aph-1 and pen-2 partially rescue the C. elegans mutant phenotypes, demonstrating conserved functions. The human genes must be provided together to rescue the mutant phenotypes, and the inclusion of presenilin-1 improves rescue, suggesting that they interact closely with each other and with presenilin. RNAi-mediated inactivation of aph-1, pen-2, or nicastrin in cultured Drosophila cells reduces gamma-secretase cleavage of betaAPP and Notch substrates and reduces the levels of processed presenilin. aph-1 and pen-2, like nicastrin, are required for the activity and accumulation of gamma-secretase.

BackgroundMany proteins that are dysregulated or mutated in cancer cells rely on the molecular chaperone HSP90 for their proper folding and activity, which has led to considerable interest in HSP90 as a cancer drug target. The diverse array of HSP90 client proteins encompasses oncogenic drivers, cell cycle components, and a variety of regulatory factors, so inhibition of HSP90 perturbs multiple cellular processes, including mitogenic signaling and cell cycle control. Although many reports have investigated HSP90 inhibition in the context of the cell cycle, no large-scale studies have examined potential correlations between cell genotype and the cell cycle phenotypes of HSP90 inhibition.Methodology/principal findingsTo address this question, we developed a novel high-content, high-throughput cell cycle assay and profiled the effects of two distinct small molecule HSP90 inhibitors (XL888 and 17-AAG [17-allylamino-17-demethoxygeldanamycin]) in a large, genetically diverse panel of cancer cell lines. The cell cycle phenotypes of both inhibitors were strikingly similar and fell into three classes: accumulation in M-phase, G2-phase, or G1-phase. Accumulation in M-phase was the most prominent phenotype and notably, was also correlated with TP53 mutant status. We additionally observed unexpected complexity in the response of the cell cycle-associated client PLK1 to HSP90 inhibition, and we suggest that inhibitor-induced PLK1 depletion may contribute to the striking metaphase arrest phenotype seen in many of the M-arrested cell lines.Conclusions/significanceOur analysis of the cell cycle phenotypes induced by HSP90 inhibition in 25 cancer cell lines revealed that the phenotypic response was highly dependent on cellular genotype as well as on the concentration of HSP90 inhibitor and the time of treatment. M-phase arrest correlated with the presence of TP53 mutations, while G2 or G1 arrest was more commonly seen in cells bearing wt TP53. We draw upon previous literature to suggest an integrated model that accounts for these varying observations.

This paper covers the first developments of the SCREAMER from its beginning when we dropped 250 lbs under a 14 square foot ram-air canopy, this (manned!) flight, with a wing loading of 16 lbs per sq. ft. of canopy proved the concept. A contract was then obtained in early 2001 from Natick Soldier Center (NSC) to develop and demonstrate the concept with 500 lbs. A demonstration drop with 750 lbs was accomplished in December 2001 at Yuma Proving Grounds, AZ. A follow-on contract received from NSC to further develop the SCREAMER system to a payload weight of 2,000 lbs. included utilizing radio control for the small ram-air canopy. This paper describes the four years of subsequent development of the SCREAMER system being commanded by a “control box” utilizing GPS for navigation and round recovery parachutes for the final descent to a target area. Throughout this development, design refinements and unique solutions needed to be found to solve the problems of dropping from larger aircraft with air speed in access of 130 knots and altitudes up to 25,000 feet MLS.

The US Army Natick Soldier Center (NSC) is currently engaged in the development of a family of modified high altitude low opening (HALO) autonomously guided precision cargo aerial delivery systems. In alliance with the US Joint Forces Command and the US Air Force Air Mobility Command, DUSD-AS&C, the NSC including PM-FSS and Strong Enterprises, has engaged in the design and development of an autonomously guided 2000 lbs. and 10,000 lbs capable high glide delivery system, which has been successfully demonstrated in weight ranges 500 lbs. through 10,000 lbs. GRW. This platform known as SCREAMER is currently being tested at system design weight of 10,000 lbs GRW from military C-130/C-17 aircraft at the US Army Yuma Proving Ground, Arizona.

Long-term, declining fertility is a reported trend in high-production dairy herds. Nutrition management is identified as a key area where improvement is required. Most published literature relating to nutrition management of dairy cow fertility examines energy and protein status and peri-parturient calcium (Ca) homeostasis availability. This paper examines the current understanding of Ca homeostasis relevant to improving performance in the high-production dairy herd. In particular, this article reviews Ca and vitamin D nutrition during lactation, for achieving health and productivity improvements in subsequent lactations, with specific reference to pasture-based dairy herds. Vitamin D metabolites are essential for increasing the proportion of absorbed Ca when dietary Ca concentration is low or when the requirement for Ca is high. Vitamin D metabolites stimulate the synthesis of the proteins that control active intestinal Ca absorption. This has particular relevance to cows that may not be able to replenish Ca reserves before parturition, which may be a common occurrence in current pasture-based dairy systems. It is possible that due to reductions in Ca reserves, the effectiveness of the cow to liberate sufficient Ca into plasma at parturition will be compromised as she faces subsequent lactations. This has significant implications for the ability of the cow to progress through transition in a healthy state, maintain an optimum energy balance during early lactation and subsequently conceive. Suboptimal nutritional management of Ca status through successive lactations may be shortening the productive life of the high-producing dairy cow.

Introduction: XL184 (BMS-907351) produces balanced pharmacodynamic inhibition of MET, VEGFR2, and RET, as well as robust antiangiogenic and anti-tumor effects with oral dosing in preclinical models. Based on the encouraging preclinical activity, XL184 is being studied in multiple Phase 1 to 3 clinical studies of various tumor types. Methods: Biomarker studies from a Phase 1 trial (XL184-001, n=85) of XL184 in solid tumors enriched for a medullary thyroid carcinoma (MTC) population and from a Phase 2 trial (XL184-201, n=46) in recurrent or progressive glioblastoma multiforme (GBM) are reported here. Plasma samples were analyzed for pharmacodynamic, on-target effects of XL184 and biomarkers known to change in response to anti-angiogenic treatment. Surrogate tissue sections of skin or hair were analyzed for biomarkers of ontarget activity of XL184 using immunofluorescence. Genomic DNA isolated from archival tumor and/or fresh blood samples was analyzed for alterations in genes relevant to either GBM or MTC and/or the target profile of XL184, such as RET, MET, KIT, PTEN, and MGMT. Plasma and genotypic biomarkers were investigated for potential correlation with clinical benefit (durable stable disease or partial response). Results: Plasma biomarker data from patients (pts) in both groups receiving 175 mg oral XL184 once daily demonstrated statistically significant changes from baseline in sVEGFR2, PlGF, VEGF-A, EPO, and sKIT levels (XL184-001 n=28; XL184-201 n=22; all p Conclusion: Biomarker analyses in plasma and surrogate tissues confirm pharmacodynamic activity of XL184. Changes in plasma HGF may be a predictive biomarker of clinical benefit and will be further evaluated. The clinical benefit rates produced in GBM and MTC coupled with clear evidence of XL184 on-target activity, independent of tumor genotypes, suggests that the clinical benefits produced by this compound may be a result of its multitargeted profile which includes inhibition of MET, VEGFR2 and RET activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B269.