Greater blood concentrations of nonesterified fatty acids (NEFA) and lesser blood concentrations of glucose are indicative of the normal process of nutrient partitioning that occurs in early postpartum dairy cows. The objective was to determine the relationship between blood NEFA and glucose concentrations and subsequent conception at first insemination in postpartum dairy cows. Holstein (n=148) and Guernsey (n=8) dairy cows were blood sampled at approximately d 10, 7, and 3 prepartum, on the day of calving and 3, 7, 14, and 21 d postpartum for measurement of NEFA and glucose concentrations. Serum and plasma were harvested and used for measurement of NEFA and glucose concentrations, respectively. Cows were given a presynchronization treatment (2 injections of PGF(2α) 14 d apart) with the second PGF(2α) injection occurring 14 d before the initiation of the timed AI (TAI) protocol. Blood for determination of progesterone concentrations was collected at each presynchronization injection and at the initiation of the TAI protocol that was used for first insemination (74±7 d postpartum). Cows were considered noncycling if serum progesterone concentrations at the 2 presynchronization PGF(2α) injections (d 37 and 51±7 postpartum) and at the initiation of the TAI protocol (d 65±7 postpartum) were ≤1 ng/mL, and there was no indication of ovulation or presence of a corpus luteum by ultrasound examination at the initiation of the TAI protocol. Pregnancy was determined at 33 d and again at 61 d after first insemination by using ultrasound. Across all days, serum NEFA and plasma glucose concentrations were not different between cows that ovulated before the initiation of the TAI program (cycling) compared with those that did not ovulate (noncycling). Serum NEFA concentrations, however, were less and plasma glucose concentrations were greater during the early postpartum period for cows that subsequently became pregnant at first insemination compared with those that failed to become pregnant. Logistic regressions were used to predict the probability of pregnancy based on NEFA and glucose concentrations from individual days. The prediction with the greatest likelihood ratio was for d 3 postpartum NEFA and glucose concentrations. Nutritional status during the early postpartum period (within 1 wk after calving), as indicated by blood NEFA and glucose concentrations, may affect subsequent fertility by a mechanism that is independent from interval to first ovulation.
Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRAS G12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRAS G12D , the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.
The COSynch protocol has been used to synchronize ovulation and facilitate fixed-time AI in beef cattle. Establishment and maintenance of pregnancy was negatively affected, in previous studies, by GnRH-induced ovulation of small dominant follicles (=11 mm). The reason for the presence of small follicles at the second GnRH (GnRH 2) is not clear. The objectives of this study were 1) to determine the effect of ovulatory response at the first GnRH (GnRH 1) on diameter and variation in diameter of the largest follicle at GnRH 2, and 2) to determine the effect of day of the cycle (stage of a follicular wave) on GnRH-induced luteinizing hormone (LH) release, and the resulting ovulatory response after GnRH 1 and 2. Two experiments used pubertal beef heifers synchronized to be on different days of the estrous cycle (d 2, 5, 10, 15, and 18 after estrus) in which a dominant follicle would or would not respond to GnRH 1. Ovulatory response to GnRH 1 did not affect size or variation in diameter of the largest follicle at GnRH 2 in Exp. 1 or 2. In Exp. 1, ovulatory response after GnRH 1 (0/14(a), 12/13(b), 4/13(ac), 9/13(bc), and 2/10(a) in the d 2, 5, 10, 15, and 18 groups; (a-c)P < 0.05) and GnRH 2 (13/14(a), 12/13(a), 12/13(a), 2/13(b), and 2/10(b) in the d 2, 5, 10, 15, and 18 groups, respectively; (a,b)P < 0.05) was affected by day of the cycle. In Exp. 2, day of the cycle also affected the proportion of heifers ovulating after GnRH 1 (0/7(a), 8/8(b), 0/6(a) 5/8(ab), and 5/8(ab) of the d 2, 5, 10, 15, and 18 heifers, respectively; (a-c)P < 0.05) and GnRH 2 (3/7(ab), 8/8(b), 5/6(b), 1/8(a), and 2/8(a) of the d 2, 5, 10, 15, and 18 heifers, respectively; (a,b)P < 0.05). In both experiments, heifers receiving GnRH 1 on d 15 and 18 had a greater (P < 0.05) occurrence of luteolysis before PGF(2alpha) injection and expression of estrus than heifers treated on d 2, 5, and 10. The GnRH-induced LH surge was of greatest magnitude in heifers receiving GnRH 1 on d 18 of the cycle followed by d 5, 15, 10, and 2 (9,054(b), 5,774(bc), 4,672(c), 2,548(c), and 915(d) arbitrary units; respectively; (a-d)P < 0.05). In summary, ovulatory response to GnRH 1 did not affect size of the dominant follicle at GnRH 2. Day of the cycle when GnRH 1 was delivered affected dominant follicle size at GnRH 2. Treatment with GnRH 1 in the earlier part of the estrous cycle (on or before d 10) increased the proportion of dominant follicles that were large enough to respond to GnRH 2 (>/=10 mm) and increased ovulatory response after GnRH 2.
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