scholarly journals 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

2018 ◽  
Vol 37 (12) ◽  
pp. 1310-1322 ◽  
Author(s):  
JY Akakpo ◽  
A Ramachandran ◽  
SE Kandel ◽  
HM Ni ◽  
SC Kumer ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nuclear Dna ◽  
Standard Of Care ◽  
The United States ◽  
Human Hepatocytes ◽  
Current Standard ◽  
Apap Overdose ◽  
Primary Human Hepatocytes ◽  
Nuclear Dna Fragmentation ◽  
Acetaminophen Hepatotoxicity

Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the United States. While treatment with N-acetylcysteine is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300 mg/kg of APAP and 50 mg/kg of 4MP. The severe liver injury induced by APAP at 6 h as indicated by elevated plasma alanine aminotransferase activities, centrilobular necrosis, and nuclear DNA fragmentation was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-Jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial intermembrane proteins. Importantly, 4MP inhibited the generation of APAP protein adducts and formation of APAP-glutathione (GSH) conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.

scholarly journals Late Protective Effect of Netrin-1 in the Murine Acetaminophen Hepatotoxicity Model

2020 ◽  
Vol 175 (2) ◽  
pp. 168-181 ◽  
Author(s):  
Luqi Duan ◽  
Benjamin L Woolbright ◽  
Hartmut Jaeschke ◽  
Anup Ramachandran
Keyword(s):  
Liver Injury ◽  
Alanine Aminotransferase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Clinical Problem ◽  
The United States ◽  
Therapeutic Window ◽  
Protective Effects ◽  
Apap Overdose ◽  
Important Clinical Problem

Abstract Acetaminophen (APAP) overdose-induced acute liver failure is an important clinical problem in the United States and the current antidote N-acetylcysteine, has a short early therapeutic window. Since most patients present late to the clinic, there is need for novel late-acting therapeutic options. Though the neuronal guidance cue netrin-1, has been shown to promote hepatic repair and regeneration during liver ischemia/reperfusion injury, its effect in APAP-induced hepatotoxicity is unknown. In the quest for a late-acting therapeutic intervention in APAP-induced liver injury, we examined the role of netrin-1 in a mouse model of APAP overdose. Male C57BL/6J mice were cotreated with exogenous netrin-1 or vehicle control, along with 300 mg/kg APAP and euthanized at 6, 12, and 24 h. Significant elevations in alanine aminotransferase indicative of liver injury were seen in control mice at 6 h and this was not affected by netrin-1 administration. Also, netrin-1 treatment did not influence mitochondrial translocation of phospho-JNK, or peroxynitrite formation indicating that there was no interference with APAP-induced injury processes. Interestingly however, netrin-1 administration attenuated liver injury at 24 h, as seen by alanine aminotransferase levels and histology, at which time significant elevations in the netrin-1 receptor, adenosine A2B receptor (A2BAR) as well as macrophage infiltration was evident. Removal of resident macrophages with clodronate liposomes or treatment with the A2BAR antagonist PSB1115 blocked the protective effects of netrin-1. Thus, our data indicate a previously unrecognized role for netrin-1 in attenuation of APAP hepatotoxicity by enhancing recovery and regeneration, which is mediated through the A2BAR and involves resident liver macrophages.

A decision-analytic model of idelalisib in relapsed or refractory patients with follicular lymphoma in the United States.

2014 ◽  
Vol 32 (30_suppl) ◽  
pp. 30-30 ◽  
Author(s):  
Nathaniel Smith ◽  
Alexander Xenakis ◽  
Rachel Beckerman ◽  
Jagpreet Chhatwal ◽  
Stephanie A. Gregory ◽  
...  
Keyword(s):  
Health Outcomes ◽  
Follicular Lymphoma ◽  
Survival Data ◽  
Treatment Options ◽  
Standard Of Care ◽  
The United States ◽  
Sensitivity Analyses ◽  
Decision Analytic Model ◽  
Current Standard ◽  
Utilization Data

30 Background: There are currently few treatment options for relapsed/refractory (RR) indolent non-Hodgkin’s lymphoma (iNHL) patients. Idelalisib (IDELA) is a first-in class PI3Kδ inhibitor with substantial clinical efficacy in iNHL patients refractory to rituximab and an alkylating agent. A single-arm clinical trial (Study 101-09) showed RR iNHL patients treated with IDELA have a median of 11 and 20.3 months of progression-free and overall survival (PFS and OS), respectively. Efficacy was also demonstrated in patients with iNHL subtypes such as follicular lymphoma (FL). The objective of this study was to project the health outcomes of IDELA versus the current standard of care for US FL patients. Methods: A partitioned survival model simulated a cohort of RR FL patients over 10 year time horizon. Patients first received IDELA or an aggregate comparator of current RR iNHL chemotherapy regimens in a progression-free state before transitioning to a progressive-disease state where they received palliative care until death. Survival data was fit and extrapolated from Study 101-09 (IDELA) for FL patients. A real-world database claims analysis provided survival, disease- and treatment-related adverse event (AEs) profiles, and medical resource utilization data for RR iNHL patients for the comparator. All outcomes were discounted at 3%. Results: Claims data predicted a median of 6.16 and 13.04 months of PFS and OS, respectively, for the comparator. Our model suggests that IDELA treatment improved health outcomes over 10 years versus the comparator, increasing life-months (LMs) and progression-free life-months (PFLMs) by 9.94 and 4.63 mos, respectively. Over 1 year, IDELA reduced both AEs and hospitalisations in FL patients by 40.3% and 49.8%, respectively. Deterministic and probabilistic sensitivity analyses demonstrated the model results are robust across different methods of survival extrapolation. Conclusions: IDELA was projected to improve health outcomes in RR FL patients compared to current treatments, largely driven by improved PFS and OS; short-term reductions in AEs and hospitalisation were specifically related to a delayed disease progression.

Locally Advanced Rectal Cancer: Time for Precision Therapeutics

2015 ◽  
pp. e192-e196 ◽  
Author(s):  
Martin R. Weiser ◽  
Zhen Zhang ◽  
Deborah Schrag
Keyword(s):  
Rectal Cancer ◽  
Local Recurrence ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Advanced Rectal Cancer ◽  
The United States ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Chemoradiation ◽  
Current Standard ◽  
Trimodality Therapy

The year 2015 marks the 30th anniversary of the publication of NSABP-R01, a landmark trial demonstrating the benefit of adding pelvic radiation to the treatment regimen for locally advanced rectal cancer with a resultant decrease in local recurrence from 25% to 16%. These results ushered in the era of multimodal therapy for rectal cancer, heralding modern treatment and changing the standard of care in the United States. We have seen many advances over the past 3 decades, including optimization of the administration and timing of radiation, widespread adoption of total mesorectal excision (TME), and the implementation of more effective systemic chemotherapy. The current standard is neoadjuvant chemoradiation with 5-fluorouracil (5-FU) and a radiosensitizer, TME, and adjuvant chemotherapy including 5-FU and oxaliplatin. The results of this regimen have been impressive, with a reported local recurrence rate of less than 10%. However, the rates of distant relapse remain 30% to 40%, indicating room for improvement. In addition, trimodality therapy is arduous and many patients are unable to complete the full course of treatment. In this article we discuss the current standard of care and alternative strategies that have evolved in an attempt to individualize therapy according to risk of recurrence.

scholarly journals Transfer learning from simulations improves the classification of OCT images of glandular epithelia

2020 ◽  
Author(s):  
Sassan Ostvar ◽  
Han Truong ◽  
Elisabeth R. Silver ◽  
Charles J. Lightdale ◽  
Chin Hur ◽  
...  
Keyword(s):  
Deep Learning ◽  
Transfer Learning ◽  
Preventive Intervention ◽  
Synthetic Data ◽  
Standard Of Care ◽  
The United States ◽  
Tissue Imaging ◽  
Current Standard ◽  
Cad Systems

AbstractEsophageal adenocarcinoma (EAC) is a rare but lethal cancer with rising incidence in several global hotspots including the United States. The five-year survival rate for patients diagnosed with advanced disease can be as low as 5% in EAC, making early detection and preventive intervention crucial. The current standard of care for EAC targets patients with Barrett’s esophagus (BE), the main precursor to EAC and a relatively common condition in adults with chronic acid reflux disease. Preventive care for EAC requires repeated surveillance endoscopies of BE patients with biopsy sampling, and can be intrusive, error-prone, and costly. The integration of minimally-invasive subsurface tissue imaging in the current standard of care can reduce the need for exhaustive tissue sampling and improve the quality of life in BE patients. Effective adoption of subsurface imaging in EAC care can be facilitated by computer-aided detection (CAD) systems based on deep learning. Despite their recent successes in lung and breast cancer imaging, the development of deep neural networks for rare conditions like EAC remains challenging due to data scarcity, heavy bias in existing datasets toward non-cases, and uncertainty in image labels. Here we explore the use of synthetic datasets–specifically data derived from simulations of optical back-scattering during imaging– in the development of CAD systems based on deep learning. As a proof of concept, we studied the binary classification of esophageal OCT into normal squamous and glandular mucosae, typical of BE. We found that deep convolutional networks trained on synthetic data had improved performance over models trained on clinical datasets with uncertain labels. Model performance also improved with dataset size during training on synthetic data. Our findings demonstrate the utility of transfer from simulations to real data in the context of medical imaging, especially in the severely data-poor regime and when significant uncertainty in labels are present, and motivate further development of transfer learning from simulations to aid the development of CAD for rare malignancies.

scholarly journals Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis

Toxicon ◽  
2017 ◽  
Vol 125 ◽  
pp. 99-109 ◽  
Author(s):  
Benjamin L. Woolbright ◽  
C. David Williams ◽  
Hongmin Ni ◽  
Sean C. Kumer ◽  
Timothy Schmitt ◽  
...  
Keyword(s):  
Liver Injury ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes

scholarly journals Incidence of Cerebral Palsy, Seizure Disorder and Developmental Delay in Newborns with Hypoxic Ischemic Encephalopathy Following Treatment with Hypothermia

2020 ◽  
Vol 3 ◽  
Author(s):  
Kazeerat Adedokun ◽  
Heather Wolfe
Keyword(s):  
Cerebral Palsy ◽  
Developmental Delay ◽  
Oxygen Deficiency ◽  
Standard Of Care ◽  
The United States ◽  
Seizure Disorder ◽  
Hypoxic Ischemic Encephalopathy ◽  
Current Standard ◽  
Data Set ◽  
Ischemic Encephalopathy

Neonatal Hypoxic ischemic encephalopathy (HIE) is a serious condition that can lead to significant neurological problems, developmental delay, and mortality. Fetal oxygen deficiency decreases cardiac output, leading to reduced cerebral blood flow and brain injury. In 2006 the United States spent over 300 billion dollars in disability related health care expenditure. HIE if left untreated leads to poor quality of life, and survivors end up with lifelong disabilities. Therapeutic hypothermia became standard of care in 2002, and evidence has shown it has neuroprotective benefit. We hypothesize that neonates treated with hypothermia will have lower incidence of cerebral palsy (CP), seizure disorder (SD) and developmental delay (DD), compared to neonates diagnosed with HIE prior to the current standard of care. Compared to healthy neonates, neonates treated with hypothermia will have higher incidence of CP, SD, and DD    Project Methods: A retrospective chart review will be performed using 200 participants with medical records from Lutheran health network neonate intensive care unit. Historical data from prior to the current standard of care (January 2007 to 2011) will be used for newborns with HIE. Another data set from January 2015 to December 2019 will be used for newborns treated with hypothermia and healthy patients as well. The TIMP test will be used to assess motor performance in early infancy. The Bayley Scales of Infant and Toddler Development third edition will be used to measure cognitive, language and motor development. Cerebral palsy will be assessed using the Gross Motor Function Classification System.    Results: We expect that the results of this study will match previous research, which found that neonates treated with hypothermia had better outcomes compared to neonates not treated with hypothermia.    Potential Impact: If found to be effective, this intervention may improve the quality and quantity of a patient’s life and reduce the cost of healthcare spending on disability. 

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