A mouse model of prenatal exposure to Interleukin-6 to study the developmental origin of health and disease.

Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult progeny is not known. Since IL-6 crosses the placental barrier, we administered recombinant IL-6 (10 pg/g) to pregnant mice starting at mid-gestation yielded newborns with lower body (p < 0.001) and kidney (p < 0.001) weights. Histomorphometry indicated decreased nephrogenic zone width (p = 0.039) with increased numbers of mature glomeruli (p = 0.002) and pre-tubular aggregates (p = 0.041). Accelerated maturation in IL-6 newborns was suggested by early expression of podocyte-specific protein podocin in glomeruli, increased 5-methyl-cytosine (LC-MS analysis for CpG DNA methylation) and altered expression of certain genes of cell-cycle and apoptosis (RT-qPCR array-analysis). Western blotting showed upregulated pJAK2/pSTAT3. Thus, treating dams with IL-6 as a surrogate provides newborns to study effects of maternal systemic inflammation on future susceptibility to CKD in adulthood.

Application of pharmacogenomics for trauma and critical care patients: A case report.

BACKGROUND: Pharmacogenomics is increasingly becoming a valuable tool for improving health outcomes, reducing health care costs and avoiding adverse drug reactions. While application of pharmacogenomics is quite common in oncology and cardiology, routine use of this technology is rare in certain other fields including Trauma and Critical Care Surgery. We are testing feasibility of applying pharmacogenomic testing to improve therapeutic outcomes of trauma and acute care patients at MercyOne Medical Center in Des Moines, IA. METHODS: Trauma patients admitted to the hospital with projected stay of >5 days, or with admission extended due to failed multiple trials of medication volunteered to participate in this IRB-approved study. Effectiveness of medical therapy was evaluated using standard pain scores recorded prior to admission of any pain medication to conscious and competent patients. Pharmacogenomic results were obtained from commercial providers within 3-5 days and used to alter medical therapy as needed. RESULTS: An 18-year-old African American male, admitted for gunshot wounds to the neck, exhibited an ASIA A spinal cord injury, with no sensation or movement of his extremities, persistent nausea with emesis and a history of depression. He also developed gastritis with hematemesis. In addition to all standard trauma procedures, he received standard doses of tramadol, oxycodone or hydrocodone, ondansetron, citalopram, and intravenous protonix daily. He reported no pain relief. The patient's pharmacogenomic analysis revealed his ultrarapid and rapid genotype for CYP2D6 and CYP2C19 respectively, allowing us to choose dilaudid resulting in immediate improvement of his pain scores. Additionally, using metoclopramide, duloxetine and famotidine led to immediate improvement or complete resolution of symptoms. CONCLUSION: Pharmacogenomics testing is a useful tool for selecting appropriate pain management of trauma patients with expected hospital stay ≥5 days. Additionally, standard pharmacogenomic panels allow tailoring medical therapy to common conditions associated with traumatic injury.

Addition of Allopurinol for Altering Thiopurine Metabolism to Optimize Therapy in Patients with Inflammatory Bowel Disease.

Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.

Clinical Trials of Poly(ADP-Ribose) Polymerase Inhibitors for Cancer Therapy: A Review.

Poly(ADP-Ribose) Polymerase (PARP) is a family of enzymes involved in DNA repair, genome stability, cellular energy metabolism and cell division. Inhibition of PARP-1, the well characterized member of this family, has been explored as a strategy for enhancing anti-cancer activity of existing drugs and for developing new drugs. Recently unique enzymatic properties and biological functions of PARP-2 and PARP-3 have been discovered, further expanding the utility of PARP as a target for cancer pharmacotherapy. We compare and contrast the structural and enzymatic properties of these three members of the PARP family. Interactions of these enzymes with proteins specific to different DNA repair pathways are summarized. Further, we evaluate progress on development of PARP inhibitors as anticancer agents. Results of Phase I and Phase II clinical trials of seven PARP inhibitors, used alone or in combination with known anticancer agents are reviewed highlighting common observations regarding the maximum tolerable dose, adverse reactions profile, PARP inhibition and anticancer effects. While further clinical studies are warranted, based on current data, Olaparib (Ola), Veliparib (Veli) and Rucaparib (Ruca) offer considerable potential. Prolonged exposure to Ola and Veli leads to resistant cancer cells, primarily through restoration of the HR pathway, overexpression of the P-glycoprotein efflux pump or modulation of PARP expression. Some resistant cancer cells continue to respond to platinum based drugs, encouraging further development of PARP inhibitors for cancer treatment. Future course of this research, specifically focusing on use of PARP inhibition as a strategy for personalized cancer therapy, is discussed.

Impact of mixtures of different fresh-cut fruits on respiration and ethylene production rates.

UNLABELLED: Packaging and storage of fresh-cut fruits and vegetables are a challenging task, since fresh produce continue to respire and senesce after harvest and processing accelerates the physiological processes. The response on respiration and ethylene production rates of fresh produce to changes in O2 and CO2 concentrations and temperature has been extensively studied for whole fruits but literature is limited on processed and mixed fresh-cut fruits. This study aimed to investigate the effects of mixing various proportions of fresh-cut fruits (melon chunks, apple slices, and pineapples cubes) on respiration and ethylene production rates and to develop predictive models for modified atmosphere packaging. The experiment was designed according to a simplex lattice method and respiration and ethylene production rates were measured at 10 °C. Results showed that single component pineapple cubes, apple slices, and melon chunks, in this order, had significant constant coefficients (P = 0.05) and the greatest impact on respiration rate while the interactive binary and tertiary coefficients were insignificant. For ethylene production rates, single component apple slices, melon chunks, and pineapple cubes, and their 3-component mixtures, in this order, had significant constant coefficients (P = 0.05) while binary coefficients were insignificant. Mathematical models were developed and validated; the cubical model was the best to describe the influence of proportion of fruit on respiration and ethylene production rates, however, considering simplicity the linear part of the model is recommended to quantify respiration and ethylene production rates of mixed fresh-cut fruits. PRACTICAL APPLICATION: This research helps to quantify the ethylene production and respiration rates of multicomponent mixed fresh-cut fruit, which then can be used for packaging design of fresh-cut produce.