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Pancreatic cancer is an aggressive disease with a 5 year survival rate of 13%. This poor survival is attributed, in part, to limited and ineffective treatments for patients with metastatic disease, highlighting a need to identify molecular drivers of pancreatic cancer to target for more effective treatment. CD200 is a glycoprotein that interacts with the receptor CD200R and elicits an immunosuppressive response. Overexpression of CD200 has been associated with differential outcomes, depending on the tumor type. In the context of pancreatic cancer, we have previously reported that CD200 is expressed in the pancreatic tumor microenvironment (TME), and that targeting CD200 in murine tumor models reduces tumor burden. We hypothesized that CD200 is overexpressed on tumor and stromal populations in the pancreatic TME and that circulating levels of soluble CD200 (sCD200) have prognostic value for overall survival. We discovered that CD200 was overexpressed on immune, stromal, and tumor populations in the pancreatic TME. Particularly, single-cell RNA-sequencing indicated that CD200 was upregulated on inflammatory cancer-associated fibroblasts. Cytometry by time of flight analysis of PBMCs indicated that CD200 was overexpressed on innate immune populations, including monocytes, dendritic cells, and monocytic myeloid-derived suppressor cells. High sCD200 levels in plasma correlated with significantly worse overall and progression-free survival. Additionally, sCD200 correlated with the ratio of circulating matrix metalloproteinase (MMP) 3: tissue inhibitor of metalloproteinase (TIMP) 3 and MMP11/TIMP3. This study highlights the importance of CD200 expression in pancreatic cancer and provides the rationale for designing novel therapeutic strategies that target this protein., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastasis and therapeutic resistance. Activating transcription factor 4 (ATF4), a master regulator of cellular stress, is exploited by cancer cells to survive. Prior research and data reported provide evidence that high ATF4 expression correlates with worse overall survival in PDAC. Tomatidine, a natural steroidal alkaloid, is associated with inhibition of ATF4 signaling in multiple diseases. Here, we discovered that in vitro and in vivo tomatidine treatment of PDAC cells inhibits tumor growth. Tomatidine inhibited nuclear translocation of ATF4 and reduced the transcriptional binding of ATF4 with downstream promoters. Tomatidine enhanced gemcitabine chemosensitivity in 3D ECM-hydrogels and in vivo . Tomatidine treatment was associated with induction of ferroptosis signaling validated by increased lipid peroxidation, mitochondrial biogenesis, and decreased GPX4 expression in PDAC cells. This study highlights a possible therapeutic approach utilizing a plant-derived metabolite, tomatidine, to target ATF4 activity in PDAC., Competing Interests: Authors declare that they have no potential conflicts of interest., (© 2023 The Author(s).)

The subchronic (90-day) toxicity of esterified propoxylated glycerol (EPG) was assessed in micropigs. Animals (5/sex/group) received feed containing 5%, 10%, and 17% EPG, mixed accordingly throughout the study to deliver 1.5, 3, and 5 g/kg bw/day of EPG, respectively. Corn oil served as the vehicle control (0 g/kg bw/day). Subsets of animals were evaluated at Week 6; the remainder between Weeks 12 and 14. With the exception of liver and serum vitamin levels, statistically significant difference between control and EPG groups were seen sporadically, and with no apparent connection to treatment and/or no consistency across time intervals. EPG intakes of 3 and 5 g/kg bw/day, but not at 1.5 g/kg bw/day were associated with significantly lower serum 25-OH vitamin D levels. Serum total vitamin D levels were significantly lower across all EPG groups. There were also trends toward lower levels of liver vitamins A and E among EPG-treated animals, but the effects were less consistent. The effects on vitamin levels observed in EPG-treated animals were not accompanied by any signs of vitamin deficiency (e.g., effects on growth, clinical signs, or clinical pathology), and might have been related to the larger mass of EPG acting as a lipid "sink" during transit in the gastrointestinal tract., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pediatric evaluations are useful only when the animal model and human neonate have similar timing in system development. The objective of this study was to compare the growth of 24-hour-old swine provided 3 different feeding regimens of a simulated sow milk formula for 3 weeks. Three groups of three swine per sex were used. Group 1 was fed every 4 hours for weeks 1 through 3. Group 2 was fed every 3 hours during week 1 and every 4 hours during weeks 2 and 3. Group 3 (as close to ad libitum as possible) was fed every 2 hours for the first 2 days; every 2.5 hours for the next 2 days; every 3 hours for the next 3 days; and every 4 hours during weeks 2 and 3. No mortality occurred. Body weights were within normal limits. Organ weights, physical and ophthalmologic examinations, hematology and serum chemistry parameters, gross necropsy observations, and microscopic evaluation of the brain, liver, and kidneys were not affected by the three feeding regimens. Day 21 body weight gain of group 3 was greater than that for groups 1 or 2. Mean formula consumption (ounces/day) over 21 days was significantly increased (p < .01) for group 3 (males and combined sexes) compared to the two other groups, supporting the greater weight gain of group 3 versus groups 1 and 2 over the 21-day feeding period. Body weights of the piglets fed simulated sow milk and historical control 21-day-old suckling pigs were within the same range. Only the labor-intensive feeding of simulated sow milk in a regimen close to ad libitum produced maximal weight gain in 24-hour-old piglets during the initial 3 weeks postpartum.

The goal for humanistic end-of-life care is to maintain quality of life and personal dignity. The nursing outcome called "dignified dying" is defined as maintaining personal control and comfort with the approaching end of life and lists indicators for measuring this. These criteria enable nurses to measure the effectiveness of their nursing interventions, monitor patient progress over time, and summarize research data. This article describes the development of this outcome and illustrates its use with a case study.

Reproductive toxicology studies with Omadine MDS were conducted using rats and rabbits, and plasma levels of the metabolite, 2-methylsulfonylpyridine (2-MSP), were assayed. In phase I (treated males, untreated females) of the fertility study, the no-effect level, for oral dosing, was 3.0 mg/kg; 7.5 mg/kg caused a decrease in male weight gain. In phase II (treated females, untreated males), the no-effect oral dose level was 1.0 mg/kg. At 3.0 mg/kg, decreases were seen in maternal body weight gain, the fertility index, and in total implantations and viable embryos at the 13-day uterine examination. Severe maternal toxicity including impaired motor function of limbs, decrease in weight gain, and mortality occurred at 7.5 mg/kg. In the perinatal/postnatal study, the no-effect level was 3.0 mg/kg. At 7.5 mg/kg, mortality was high, with a majority of animals dying during mid lactation. In the rat teratology study, the high dosage level, 30 mg/kg, dermally administered on Gestation Days 6 through 15 caused slight maternal toxicity, whereas 10 mg/kg produced none. These dosage levels corresponded to peak plasma levels on Gestation Day 10 of 470 and 1950 ng/ml 2-MSP at the 10- and 30-mg/kg dosage levels, respectively. In the rabbit, 5 mg/kg topically applied on Gestation Days 6 through 18 produced slight maternal toxicity while 1.5 mg/kg produced no maternal effects. The plasma levels of 2-MSP peaked on Days 12 and 15 of gestation. At 1.5 mg/kg these levels were 155 and 148 ng/ml; at 5.0 mg/kg, levels were 513 and 573 ng/ml. There was no teratogenic response seen in either species.

Teratogenesis studies were performed in rats and rabbits given N-cyclohexyl-2-pyrrolidone, an aprotic solvent used in chemical processing. Dosages of 0, 15, 50, 150, or 500 mg N-cyclohexyl-2-pyrrolidone/kg body wt/day were administered by gavage to groups of 25 pregnant Sprague-Dawley rats on Days 6 through 15 of gestation. Dosages of 0, 10, 30, 100, or 300 mg/kg/day were administered by gavage to groups of at least 15 pregnant Dutch-Belted rabbits on Days 6 through 18 of gestation. Animals were killed and subjected to uterine examination on Day 20 of gestation for rats and on Day 29 for rabbits. There were no significant differences between the vehicle control and N-cyclohexyl-2-pyrrolidone-treated groups for implantation numbers or live or dead fetuses, resorptions, and fetal body weight in rats and rabbits. Dam body weight gain during gestation was comparable among groups. External gross visual examination of the fetus as well as examination of skeletal and soft tissues revealed no effects related to treatment with N-cyclohexyl-2-pyrrolidone.

A single chemical dose of dipyrithione (2,2'-dithiobispyridine-1,1'-dioxide), 4 or 12 micrograms/cm(2) (containing 1 micro Ci of 2-6-14C material), was applied to the ventral forearm (intact skin, methyl alcohol vehicle [MeOH]), forehead (intact and stripped skin; cosmetic cream and MeOH vehicle), and scalp (intact and stripped skin; shampoo and MeOH vehicle) of human (white and black) volunteers. The urinary excretion of 14C was measured over the 7-day study period. Percutaneous penetration data were corrected for incomplete urinary recovery using data from intravenous studies (Wedig et al). The results obtained in this study suggested: (1) means from the complete analysis indicated 34% less (p less than 0.02) absorbed by blacks; (2) less was absorbed by blacks than whites when seven out of seven means were compared within groups (p less than 0.02); (3) a difference (p less than 0.03) in penetration, blacks 47% lower than whites, between a cosmetic cream vehicle vs MeOH on the forehead; (4) on the scalp (MeOH vs shampoo vehicle) more was absorbed using MeOH (p less than 0.02); (5) no evidence of a significant difference in penetration was noted when (a) the various anatomic sites were compared or (b) intact skin was compared with stripped skin.

o-Toluenediamine in corn oil was administered po to Sprague-Dawley rats at dosages of 10, 30, 100, or 300 mg/kg body wt/day during Days 6 through 15 of gestation. All animals were killed on Day 20 of gestation. A similar study was conducted with Dutch-Belted rabbits dosed po daily at 3, 10, 30, or 100 mg of o-toluenediamine/kg body wt/day from Days 6 through 18 of gestation. Rabbits were killed on Day 29 of gestation. Maternal toxicity was indicated at 300 mg/kg in rats and 100 mg/kg in rabbits by reduced body weight gain during gestation. Fetal body weight was reduced at the highest dosage in both rats and rabbits. In addition, at the high dosage, an increase in the number of resorption sites in rabbits were noted. Skeletal examination of rats showed increased incidence of missing sternebrae at 300 mg/kg and incompletely ossified vertebrae at 100 and 300 mg/kg in comparison to control fetuses. The effects on the fetus could be the result of maternal toxicity. There was no evidence of teratogenic effects or effects on the dams at dosages through 30 mg/kg body wt.