Browsing by Subject "Toxicity"
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Item Antineuroinflammatory Activities and Neurotoxicological Assessment of Curcumin Loaded Solid Lipid Nanoparticles on LPS-Stimulated BV-2 Microglia Cell Models(MDPI, 2019-03-25) Ganesan, Palanivel; Kim, Byungwook; Ramalaingam, Prakash; Karthivashan, Govindarajan; Revuri, Vishnu; Park, Shinyoung; Kim, Joon Soo; Ko, Young Tag; Choi, Dong-Kug; Medical and Molecular Genetics, School of MedicineCurcumin, which is a potential antineuroinflammatory and neuroprotective compound, exhibits poor bioavailability in brain cells due to its difficulty in crossing the blood⁻brain barrier and its rapid metabolism during circulation, which decreases its efficacy in treating chronic neuroinflammatory diseases in the central nervous system. The bioavailability and potential of curcumin can be improved by using a nanodelivery system, which includes solid lipid nanoparticles. Curcumin-loaded solid lipid nanoparticles (SLCN) were efficiently developed to have a particle size of about 86 nm and do not exhibit any toxicity in the endothelial brain cells. Furthermore, the curcumin-loaded solid lipid nanoparticles (SLCN) were studied to assess their efficacy in BV-2 microglial cells against LPS-induced neuroinflammation. The SLCN showed a higher inhibition of nitric oxide (NO) production compared to conventional curcumin in a dose-dependent manner. Similarly, the mRNA and proinflammatory cytokine levels were also reduced in a dose-dependent manner when compared to those with free curcumin. Thus, SLCN could be a potential delivery system for curcumin to treat microglia-mediated neuroinflammation.Item Clinical outcomes of FOLFIRINOX in locally advanced pancreatic cancer: A single center experience(Wolters Kluwer, 2018-12) Lee, Jongchan; Lee, Jong-chan; Gromski, Mark A.; Kim, Hyoung Woo; Kim, Jinwon; Kim, Jaihwan; Hwang, Jin-Hyeok; Medicine, School of MedicineSystemic chemotherapy or chemoradiotherapy is the initial primary option for patients with locally advanced pancreatic cancer (LAPC). This study analyzed the effect of FOLFIRINOX and assessed the factors influencing conversion to surgical resectability for LAPC.Sixty-four patients with LAPC who received FOLFIRINOX as initial chemotherapy were enrolled retrospectively. Demographic characteristics, tumor status, interval/dosage/cumulative relative dose intensity (cRDI) of FOLFIRINOX, conversion to resection, and clinical outcomes were reviewed and factors associated with conversion to resectability after FOLFIRINOX were analyzed.After administration of FOLFIRINOX (median 9 cycles, 70% of cRDI), the median patient overall survival (OS) was 17.0 months. Fifteen of 64 patients underwent surgery and R0 resection was achieved in 11 patients. During a median follow-up time of 9.4 months after resection, cumulative recurrence rate was 28.5% at 18 months after resection. The estimated median OS was significantly longer for the resected group (>40 months vs 13 months). There were no statistical differences between the resected and non-resected groups in terms of baseline characteristics, tumor status and hematologic adverse effects. The patients who received standard dose of FOLFIRINOX had higher probability of subsequent resection compared with patients who received reduced dose, although cRDIs did not differ between groups.FOLFIRINOX is an active regimen in patients with LAPC, given acceptable resection rates and promising R0 resection rates. Additionally, our data demonstrate it is advantageous for obtaining resectability to administer FOLFIRINOX without dose reduction.Item Correction to: The Potential Proconvulsant Effects of Cannabis: a Scoping Review(Springer, 2022) Kaczor, Eric E.; Greene, Kevin; Zacharia, Jennifer; Tormoehlen, Laura; Neavyn, Mark; Carreiro, Stephanie; Neurology, School of MedicineCorrection to: Journal of Medical Toxicology 10.1007/s13181-022-00886-3 The surname of coauthor Stephanie Carreiro was spelled incorrectly (as “Carriero”) in this article as originally published. The original article has been corrected.Item Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used?(Springer, 2021) Baum, Regan A.; Woolum, Jordan A.; Bailey, Abby M.; Howell, Molly M.; Weant, Kyle A.; Geraghty, LeeAnn; Mohan, Sanjay; Webb, Ashley N.; Su, Mark K.; Akpunonu, Peter; Medicine, School of MedicineIntroduction: Acetaminophen is a commonly used analgesic and antipyretic, with the potential to cause significant injury when ingested in toxic amounts. Although the antidote n-acetylcysteine (NAC) is available, evidence supporting dose recommendations for patients weighing over 100 kg are lacking. We performed a retrospective, multi-center analysis to determine if a capped NAC dosing scheme is similar to a non-capped dosing scheme in patients weighing over 100 kg. Methods: Between January 2009 and January 2016, we identified patients presenting to 12 different centers who were evaluated for acetaminophen poisoning treatment. Patients must have weighed greater than 100 kg and were evaluated and identified as needing treatment for acetaminophen-related poisoning with NAC. The primary outcome was occurrence of hepatic injury, defined as an AST or ALT ≥ 100 IU/L. Secondary endpoints included number of drug-related adverse events, occurrence of hepatotoxicity, cumulative NAC dose, regimen cost, length of hospital and intensive care unit stays, and in-hospital mortality. Results: There were 83 patients identified as meeting the pre-specified inclusion and exclusion criteria. A capped NAC dosing scheme resulted in no difference in hepatic injury when compared to a non-capped regimen (49.4% vs 50%, p = 1.000). The capped dosage regimen was associated with a lower cumulative dose (285.2 mg/kg vs 304.6 mg/kg, p < 0.001) and cost. No other statistically significant differences were identified among the secondary endpoints. Conclusion: A capped NAC dosing scheme was not associated with higher rates of hepatic injury or hepatotoxicity in obese patients in the setting of acetaminophen poisoning when compared to a non-capped regimen. Further research is needed to verify these results.Item Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury(Elsevier, 2017-01) de Boer, Ynto S.; Kosinski, Andrzej S.; Urban, Thomas J.; Zhao, Zhen; Long, Nanye; Chalasani, Naga; Kleiner, David E.; Hoofnagle, Jay H.; Drug-Induced Liver Injury Network.; Medicine, School of MedicineBACKGROUND & AIMS: Drug-induced liver injury (DILI) has features similar to those of other liver diseases including autoimmune hepatitis (AIH). We aimed to characterize the clinical and autoimmune features of liver injury caused by nitrofurantoin, minocycline, methyldopa, or hydralazine. METHODS: We analyzed data from 88 cases of DILI attributed to nitrofurantoin, minocycline, methyldopa, or hydralazine included in the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. Sera were collected from patients at baseline and follow-up examination and tested for levels of immunoglobulin G (IgG), antibodies to nuclear antigen (ANA), smooth muscle (SMA), and soluble liver antigen (SLA). An autoimmune score was derived on the basis of increases in levels of IgG, ANA, SMA, and SLA (assigned values of 0, 1+, or 2+). AIH-associated HLA-DRB1*03:01 and HLA-DRB1*04:01 allele frequencies were compared with those of the general population (controls). RESULTS: Of the 88 cases, 80 were women (91%), 74% had hepatocellular injury, and 25% had severe injury. At the onset of DILI, 39% of cases had increased levels of IgG, 72% had increased levels of ANA, 60% had increased levels of SMA, and none had increases in SLA. A phenotype of autoimmunity (autoimmune score ≥2) was observed in 82% of cases attributed to nitrofurantoin and 73% of cases attributed to minocycline (73%) but only 55% of cases attributed to methyldopa and 43% of cases attributed to hydralazine (P = .16 for nitrofurantoin and minocycline vs methyldopa and hydralazine). We observed a decrease in numbers of serum samples positive for ANA (P = .01) or SMA (P < .001) and in autoimmune scores (P < .001) between DILI onset and follow-up. Similar percentages of patients with DILI had HLA-DRB1*03:01 (15%) and HLA-DRB1*04:01 (9%) as controls (12% and 9%, respectively). CONCLUSIONS: In analysis of data from the DILIN prospective study, we found that most cases of DILI attributed to nitrofurantoin or minocycline and about half of cases that were due to methyldopa and hydralazine have a phenotype of autoimmunity similar to AIH. These features decrease with recovery of the injury and are not associated with the typical HLA alleles found in patients with idiopathic AIH.Item Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors(Elsevier, 2018-10-23) Ellsworth, Susannah G.; Radiation Oncology, School of MedicinePurpose: Radiation-induced lymphopenia (RIL) is the result of direct toxicity to circulating lymphocytes as they traverse the irradiated field, occurs in 40% to 70% of patients who undergo conventional external beam radiation therapy, and is associated with worse outcomes in multiple solid tumors. As immunotherapy strategies evolve, a better understanding of radiation's effects on the immune system is needed in order to develop rational methods of combining RT with immunotherapy. Methods and materials: This paper is a review of the available literature on the clinical significance and dosimetric predictors of radiation-induced toxicity to the immune system. Results: An association between severe RIL and inferior survival has been described in multiple solid tumors, including glioma, lung cancer, and pancreatic cancer. RIL risk is correlated with field size, dose per fraction, and fraction number. SBRT and proton therapy techniques are associated with lower RIL risk. Conclusions: The immune system should be considered an organ at risk during RT, and absolute lymphocyte count is an important biomarker of RT-induced immunotoxicity. Radiation dose and technique affect the risk and severity of RIL. Further research is needed to accurately characterize RT-induced immunotoxicity and develop strategies to prevent or mitigate this clinically significant side effect.Item Genetic Associations With Toxicity-related Discontinuation of Aromatase Inhibitor Therapy for Breast Cancer(Breast Cancer Research and Treatment, 2013-04-02) Henry, N. Lynn; Skaar, Todd C.; Dantzer, Jessica; Li, Lang; Kidwell, Kelley; Gersch, Christina; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Oesterreich, Steffi; Philips, Santosh; Carpenter, Janet S.; Storniolo, Anna M.; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor-positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.Item Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103(American Society of Clinical Oncology, 2017) Schneider, Bryan P.; Shen, Fei; Jiang, Guanglong; O'Neill, Anne; Radovich, Milan; Li, Lang; Gardner, Laura; Lai, Dongbing; Foroud, Tatiana; Sparano, Joseph A.; Sledge, George W., Jr.; Miller, Kathy D.; Medicine, School of MedicinePurpose: Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. Patients and Methods: This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results: Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). Conclusion: AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.Item Local Anesthetic Systemic Toxicity: A Pediatric Simulation Case for Anesthesiology Residents(2022-09-17) Hunter, Isaac; Egan, Brian; Abbasi, Rania; Cossu, Anne; Acquaviva, Michael; Boyer, Tanna J.INTRODUCTION: Local anesthetic systemic toxicity (LAST) is a rare but potentially lethal complication of anesthesia. It is therefore crucial for providers to be prepared when cases arise. Simulations allow providers and trainees to practice rare events with potentially severe consequences with a narrow margin for error in a controlled environment. OBJECTIVE: The objective for this article is to describe the successful implementation of a LAST simulation scenario in order to assist other institutions in organizing similar simulations, as well as to describe the importance of this particular simulation. METHODS: This simulation requires access to a simulation mannequin and OR setup. It involves a 2-year-old male undergoing a hypospadias repair who experiences LAST. Residents are expected to diagnose LAST and manage the patient using pediatric advanced life support (PALS) and intralipid. We conducted the simulation yearly for CA1 residents in 1-hour sessions with three to five learners at a time. Evaluation was done using the Anesthetists’ Non-Technical Skills (ANTS) assessment tool, as well as direct observation during the simulation and debriefing session and a follow-up survey sent to participants. RESULTS: Five cohorts of 25-28 anesthesiology residents have completed this simulation. Common areas for improvement include delayed recognition of LAST and not using the ASRA LAST checklist. Most participants were knowledgeable about the treatment of LAST and knew the pediatric dosing, but still reported finding the simulation valuable for both their skills and confidence. CONCUSIONS: Teaching about LAST is critical for all anesthesiology residents, as this is a rare but can’t-miss diagnosis. This simulation scenario is a useful and broadly applicable resource to allow residents to practice this critical learning, and residents consistently provide positive feedback about their experience.Item Lysine acetylation regulates the activity of nuclear Pif1(Elsevier, 2020) Ononye, Onyekachi E.; Sausen, Christopher W.; Balakrishnan, Lata; Bochman, Matthew L.; Biology, School of ScienceIn Saccharomyces cerevisiae, the Pif1 helicase functions in both nuclear and mitochondrial DNA replication and repair processes, preferentially unwinding RNA:DNA hybrids and resolving G-quadruplex structures. We sought to determine how the various activities of Pif1 are regulated in vivo Here, we report lysine acetylation of nuclear Pif1 and demonstrate that it influences both Pif1's cellular roles and core biochemical activities. Using Pif1 overexpression toxicity assays, we determined that the acetyltransferase NuA4 and deacetylase Rpd3 are primarily responsible for the dynamic acetylation of nuclear Pif1. MS analysis revealed that Pif1 was modified in several domains throughout the protein's sequence on the N terminus (Lys-118 and Lys-129), helicase domain (Lys-525, Lys-639, and Lys-725), and C terminus (Lys-800). Acetylation of Pif1 exacerbated its overexpression toxicity phenotype, which was alleviated upon deletion of its N terminus. Biochemical assays demonstrated that acetylation of Pif1 stimulated its helicase, ATPase, and DNA-binding activities, whereas maintaining its substrate preferences. Limited proteolysis assays indicate that acetylation of Pif1 induces a conformational change that may account for its altered enzymatic properties. We propose that acetylation is involved in regulating of Pif1 activities, influencing a multitude of DNA transactions vital to the maintenance of genome integrity.