Watsonmichelsen3189

The use of portable X-ray fluorescence (PXRF) spectrometry to detect external markers on processed or unprocessed cattle and sheep fecal specimens to estimate apparent total tract digestibility (ATTD) was evaluated. Exp. 1 ruminally cannulated Angus-crossbred steers (n = 7; BW = 520 ± 30 kg) were individually fed ad libitum for 21 d in a completely randomized design (CRD). Markers (Cr2O3 and TiO2) were placed inside the rumen twice daily (7.5 g of each marker). Fecal samples were collected twice daily from day 14 to 21. Exp. 2 crossbred wethers (n = 8; BW = 68 ± 3 kg) were individually fed ad libitum for 21 d in a CRD. During this period, 2 g of Cr2O3 and TiO2 were top-dressed onto the feed twice daily. Sheep were housed in metabolism crates for 5 d for total fecal collection. Concentration of markers was determined on diets, refusals, and fecal specimens (fresh, dry-only, and dried/ground) using atomic absorption to detect Cr and spectrophotometry for Ti. Concentration of both markers was also determined viaetection method. The Cr fecal recovery tended (P = 0.10) to be the lowest for dry-only, the greatest for wet chemistry, intermediate for fresh and dry/ground sheep-fecal specimens; while not affected (P = 0.40) for Ti. The PXRF is an accurate technology to detect Cr and Ti in fresh cattle fecal samples to estimate ATTD. For fresh and dry/ground, the technology was effective for determining the concentration of Cr, or dry-only fecal specimens when detecting Ti in sheep specimens. © The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.The recent Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) publication calculated the attributable risk of breast cancer from use of estrogen alone and estrogen plus a synthetic progestogen for less then 5 to ≥15 years of use. This CGHFB report calculated attributable risk based on their findings of relative risk from pooled data from 58 studies. Notably, neither the CGHFBC nor other previous studies have examined the effect of underlying risk of breast cancer on attributable risk. This omission prompted us to determine the magnitude of the effect of underlying risk on attributable risk in this Perspective. Meaningful communication of the potential risk of menopausal hormonal therapy requires providing women with the estimated risk above their existing underlying risk (i.e. attributable risk). Therefore we have estimated attributable risks from the data published by the CGHFBC, taking into account varying degrees of underlying risk. Based on the Endocrine Society Guideline on Menopausal Hormone Therapy (MHT), we divided groups into three categories of risk low (1.5%), intermediate (3.0%), and high (6.0%) underlying risk of breast cancer over 5 years. In women taking estrogen plus a synthetic progestogen (E+SP) for 5-9 years, the attributable risks of MHT increased from 12, to 42, to 85 additional women per 1000 in the low, intermediate, and high risk groups respectively. The attributable risks for estrogen alone were lower but also increased based on underlying risk. Notably, the attributable risks were amplified with duration of MHT use which increased both relative risk and breast cancer incidence. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Clustered regularly interspaced short palindromic repeats (CRISPR) is described as RNA mediated adaptive immune system defense, which is naturally found in bacteria and archaea. CRISPR-Cas9 has shown great promise for cancer treatment in cancer immunotherapy, manipulation of cancer genome and epigenome and elimination or inactivation of carcinogenic viral infections. However, many challenges remain to be addressed to increase its efficacy, including off-target effects, editing efficiency, fitness of edited cells, immune response and delivery methods. Here, we explain CRISPR-Cas classification and its general function mechanism for gene editing. Then, we summarize these preclinical CRISPR-Cas9-based therapeutic strategies against cancer. ZD1839 Moreover, the challenges and improvements of CRISPR-Cas9 clinical applications will be discussed. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.OBJECTIVES Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy. This study aimed to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of cortisol using 17-OHP as a biomarker in pediatric patients with CAH and to assess different hydrocortisone dosing regimens. METHODS Cortisol and 17-OHP concentrations from 30 CAH patients (7-17 years of age) receiving standard hydrocortisone replacement therapy (5-20 mg) twice (n = 17) or 3 times (n = 13) daily were used to develop a PK/PD model. Sequentially, simulated cortisol concentrations for clinically relevant 3- and 4-times daily dosing regimens were compared with cortisol and 17-OHP target ranges and to concentrations in healthy children. RESULTS Cortisol concentration-time profiles were accurately described by a 2-compartment model with first-order absorption and expected high bioavailability (82.6%). A time-delayed model with cortisol-mediated inhibition of 17-OHP synthesis accurately described 17-OHP concentrations. The cortisol concentration inhibiting 50% of 17-OHP synthesis was 48.6 nmol/L. A 4-times-daily dosing better attained the target ranges and mimicked the cortisol concentrations throughout the 24-hour period than 3-times-daily. CONCLUSIONS A PK/PD model following hydrocortisone administration has been established. An improved dosing regimen of 38% at 0600, 22% at 1200, 17% at 1800, and 22% at 2400 of the daily hydrocortisone dose was suggested. The 4-times-daily dosing regimen was superior, avoiding subtherapeutic cortisol concentrations and better resembling the circadian rhythm of cortisol. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.