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John J Byrnes

Publications and source records attributed to John J Byrnes.

5 recordsLinked to original sources
PubMed2026

Selective Inhibition of DNA Polymerase Proofreading: A Metabolic-Fidelity Mechanism Explains Agent Orange-Associated Myelodysplasia.

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint-selective inhibition of the proofreading exonuclease-thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell.

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PubMed2006

Sensorimotor gating and dopamine function in postpartum rats.

There is much speculation regarding the effects of estrogen withdrawal at the end of pregnancy on forebrain dopamine, however, few studies have directly examine changes in this system postpartum. The present work sought to determine what changes in forebrain dopamine function occur in the postpartum rat. Specifically, prepulse inhibition of the acoustic startle response (PPI) was measured in primiparous female rats on postpartum day 2 (PPD2) or 14 (PPD14) following treatment with saline or the dopamine D2 agonist, quinpirole. Diestrus (DI) females served as controls. Dopamine content and turnover as well as cyclic AMP (cAMP) accumulation were determined within the nucleus accumbens and dorsal striatum in these same females. In addition, circulating levels of plasma corticosterone, estradiol and progesterone were measured. PPI was significantly disrupted in both postpartum groups. This effect was associated with decreased cAMP content within the nucleus accumbens. Quinpirole treatment (0.1 and 0.5 mg/kg) dose-dependently disrupted PPI in DI controls while PPD2 and PPD14 animals demonstrated reduced sensitivity to the D2 agonist. PPD14 animals demonstrated increased startle amplitude, an effect that was attenuated by quinpirole treatment. PPD14 females were also less sensitive to quinpirole-mediated reductions in DA turnover within the nucleus accumbens and both PPD2 and PPD14 females had an attenuated response to the stimulatory effects of quinpirole on corticosterone secretion. Collectively these findings suggest that the postpartum period is associated with reduced sensorimotor gating and altered forebrain DA systems, which may be related to shifts in circulating hormones.

Animals↗
PubMed2006

Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity.

BACKGROUND & AIMS: Fatty Acid Transport Protein 5 (FATP5) is a liver-specific member of the FATP/Slc27 family, which has been shown to exhibit both fatty acid transport and bile acid-CoA ligase activity in vitro. Here, we investigate its role in bile acid metabolism and body weight homeostasis in vivo by using a novel FATP5 knockout mouse model. METHODS: Bile acid composition was analyzed by mass spectroscopy. Body weight, food intake, energy expenditure, and fat absorption were determined in animals fed either a low- or a high-fat diet. RESULTS: Although total bile acid concentrations were unchanged in bile, liver, urine, and feces of FATP5 knockout mice, the majority of gallbladder bile acids was unconjugated, and only a small percentage was conjugated. Primary, but not secondary, bile acids were detected among the remaining conjugated forms in FATP5 deletion mice, suggesting a specific requirement for FATP5 in reconjugation of bile acids during the enterohepatic recirculation. Fat absorption in FATP5 deletion mice was largely normal, and only a small increase in fecal fat was observed on a high-fat diet. Despite normal fat absorption, FATP5 deletion mice failed to gain weight on a high-fat diet because of both decreased food intake and increased energy expenditure. CONCLUSIONS: Our findings reveal an important role for FATP5 in bile acid conjugation in vivo and an unexpected function in body weight homeostasis, which will require further analysis. FATP5 deletion mice provide a new model to study the intersection of bile acid metabolism, lipid metabolism, and body weight regulation.

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PubMed2004

Thalidomide effects in the post-transplantation setting in patients with multiple myeloma.

UNLABELLED: Thalidomide recently has been proven to have an impact on plasma cell dyscrasia through multiple mechanisms. Its effects on hematopoietic stem cells both in harvesting and in the immediate post-transplant setting are still unknown. We report on 12 cases (9 males and 3 females), median age 56 years old (range 41-65 years old) who underwent autologous peripheral stem cell transplantation for multiple myeloma and received thalidomide as maintenance therapy post-transplantation. Patients received various cytoreductive therapies prior to stem cell harvest. Eleven patients were in partial remission (PR) and one in complete remission (CR) on entry into the transplant phase of therapy. The median CD34+/kg harvested was 4.7 x 10(6) (range 1.9-55.4 x 10(6) CD34+/kg). All patients received intravenous melphalan 200 mg/m2 as their conditioning regimen. Six of twelve patients attained a CR post-transplant, and six a PR. Thalidomide was started after all patients engrafted post-transplant (absolute neutrophil count >0.5 x 10(9)/l and self-sustained platelet count >20 x 10(9)/l) and following satisfactory resolution of transplant toxicity including mucositis and diarrhea. Thalidomide was initiated at a median of 43 days post-transplant (range 23-138 days). The median leukocyte and platelet counts at the moment of thalidomide initiation were 5.8 x 10(9)/l (range 2.9-8.6 x 10(9)/l) and 196 x 10(9)/l (range 30-351 x 10(9)/l), respectively. Thalidomide was started at 100 mg daily, increasing 100 mg/day/month until reaching a dose of 400 mg/day. One patient failed to tolerate thalidomide due to CNS symptoms and stopped therapy at 12 days. Another patient stopped thalidomide therapy after 71 days, because of severe fatigue secondary to hypothyroidism. The most common adverse effects were constipation (5), rash (4), dry skin (3) and dizziness (3). No grade 3-4 adverse effects were documented. Neutropenia, previously reported as an adverse effect in this setting, was not seen to date in our cohort. All patients attained a CR or PR after transplant and thalidomide maintenance. We have had two relapses during a median follow-up of 68 weeks (range 42-172 weeks). CONCLUSION: Thalidomide appears to be a safe drug in the post-transplant setting, perhaps adding to the response achieved post-transplant without major toxicity. Longer follow up and future randomized trials will be needed to validate the role of thalidomide and its long-term effect when used as maintenance therapy in the post-transplant setting.

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