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Introduction: This study aimed to describe the patterns of palliative intent treatment and/or palliative care (PC) delivery among a population-based sample of individuals diagnosed with advanced nonsmall cell lung cancer (NSCLC) or advanced melanoma. Methods: Data from 655 advanced-stage melanoma patients and 2688 advanced-stage NSCLC patients included in the National Cancer Institute's 2017/2018 Patterns of Care study were analyzed. Bivariate and multivariate logistic regression analyses examined factors associated with (1) receipt of PC (including palliative surgery, radiation, and/or systemic therapy after cancer diagnosis, and PC consultations); and (2) timing from diagnosis to receipt of PC. Proportional hazards models also examined factors associated with timing of receipt of PC after diagnosis. Results: A total of 23.5% of those with melanoma and 52.6% of those with NSCLC received some type of PC. For melanoma, stage 4 (vs. stage 3) was associated with higher receipt of PC and receipt within three months of diagnosis. For NSCLC, stage 4 (vs. stage 3) and a diagnosis of depression or psychosocial distress within three months of diagnosis were significantly associated with receipt of PC and receipt within three months of diagnosis. Conclusion: Study findings indicate that those with advanced-stage cancer or who report distress are more likely to receive palliative intent treatment and/or PC. Given that individuals with advanced cancers are living longer and often experience long-lasting symptoms, it is critical to identify and overcome barriers for broadly delivering comprehensive palliative and supportive care.

Throughput needs, costs of time and resources, and concerns about the use of animals in hazard and safety assessment studies are fueling a growing interest in adopting new approach methodologies for use in product development and risk assessment. However, current efforts to define "next-generation risk assessment" vary considerably across commercial and regulatory sectors, and an a priori definition of the biological scope of data needed to assess hazards is generally lacking. We propose that the absence of clearly defined questions that can be answered during hazard assessment is the primary barrier to the generation of a paradigm flexible enough to be used across varying product development and approval decision contexts. Herein, we propose a biological questions-based approach (BQBA) for hazard and safety assessment to facilitate fit-for-purpose method selection and more efficient evidence-based decision-making. The key pillars of this novel approach are bioavailability, bioactivity, adversity, and susceptibility. This BQBA is compared with current hazard approaches and is applied in scenarios of varying pathobiological understanding and/or regulatory testing requirements. To further define the paradigm and key questions that allow better prediction and characterization of human health hazard, a multidisciplinary collaboration among stakeholder groups should be initiated., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

Drug-induced liver injury (DILI) remains the main reason for drug development attritions largely due to poor mechanistic understanding. Toxicogenomic to interrogate the mechanism of DILI has been broadly performed. Gene coregulation network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improve mechanistic interpretation of toxicogenomic data. Here we performed an extensive concentration time course response-toxicogenomic study in the HepG2 cell line exposed to 20 DILI compounds, 7 reference compounds for stress response pathways, and 10 agonists for cytokines and growth factor receptors. We performed whole transcriptome targeted RNA sequencing to more than 500 conditions and applied weighted gene coregulated network analysis to the transcriptomics data followed by the identification of gene coregulated networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress response gene coregulated networks. We correlated gene coregulated networks with cell death onset and causal relationships of 67 critical target genes of these modules with the onset of cell death was evaluated using RNA interference screening. We identified GTPBP2, HSPA1B, IRF1, SIRT1, and TSC22D3 as essential modulators of DILI compound-induced cell death. These genes were also induced by DILI compounds in PHH. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: Cancer is becoming more of a chronic disease due to improvements in treatment and early detection for multiple cancer sites. To gain insight on increased life expectancy due to these improvements, we quantified trends in the loss in expectation of life (LEL) due to a cancer diagnosis for six cancer sites from 1975 through 2018., Methods: We focused on patients diagnosed with female breast cancer, chronic myeloid leukemia (CML), colon and rectum cancer, diffuse large B-cell lymphoma (DLBCL), lung cancer, or melanoma between 1975 and 2018 from nine Surveillance, Epidemiology, and End Results cancer registries. Life expectancies for patients with cancer ages 50+ were modeled using flexible parametric survival models. LEL was calculated as the difference between general population life expectancy and life expectancy for patients with cancer., Results: Over 2 million patients were diagnosed with one of the six cancers between 1975 and 2018. Large increases in life expectancy were observed between 1990 and 2010 for female breast, DLBCL, and CML. Patients with colon and rectum cancer and melanoma had more gradual improvements in life expectancy. Lung cancer LEL only began decreasing after 2005. Increases in life expectancy corresponded with decreases in LEL for patients with cancer., Conclusions: The reported gains in life expectancy largely correspond to progress in the screening, management, and treatment of these six cancers since 1975., Impact: LEL provides an important public health perspective on how improvements in treatment and early detection and their impacts on survival translate into changes in cancer patients' life expectancy., (©2023 American Association for Cancer Research.)

To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical species and humans. Species differences in sensitivity to acetaminophen (APAP) liver injury have been related to differences in the fraction of the drug that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically based pharmacokinetic modeling to identify oral doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats, indicative of a more robust transcriptional adaptation to the equivalent insult. Components of these pathways were also found to be expressed at a higher basal level in the livers of rats compared with both mice and humans. Our findings exemplify a systems approach to understanding differential species sensitivity to hepatotoxicity. Multiomics analysis indicated that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans, with important implications for species selection and human translation in the safety testing of new drug candidates associated with reactive metabolite formation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

Toxicogenomic technologies query the genome, transcriptome, proteome, and the epigenome in a variety of toxicological conditions. Due to practical considerations related to the dynamic range of the assays, sensitivity, cost, and technological limitations, transcriptomic approaches are predominantly used in toxicogenomics. Toxicogenomics is being used to understand the mechanisms of toxicity and carcinogenicity, evaluate the translational relevance of toxicological responses from in vivo and in vitro models, and identify predictive biomarkers of disease and exposure. In this session, a brief overview of various transcriptomic technologies and practical considerations related to experimental design was provided. The advantages of gene network analyses to define mechanisms were also discussed. An assessment of the utility of toxicogenomic technologies in the environmental and pharmaceutical space showed that these technologies are being increasingly used to gain mechanistic insights and determining the translational relevance of adverse findings. Within the environmental toxicology area, there is a broader regulatory consideration of benchmark doses derived from toxicogenomics data. In contrast, these approaches are mainly used for internal decision-making in pharmaceutical development. Finally, the development and application of toxicogenomic signatures for prediction of apical endpoints of regulatory concern continues to be area of intense research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer., Methods: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy., Results: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84)., Conclusions: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Tissue injury induces inflammation and the surgical stress response, which are thought to be central to the orchestration of recovery or deterioration after surgery. Enhanced formation of reactive oxygen and nitrogen species accompanies the inflammatory response and triggers separate but integrated reduction/oxidation (redox) pathways that lead to oxidative and/or nitrosative stress (ONS). Quantitative information on ONS in the perioperative period is scarce. This single-centre exploratory study investigated the effects of major surgery on ONS and systemic redox status and their potential associations with postoperative morbidity., Methods: Blood was collected from 56 patients at baseline, end of surgery (EoS) and the first postoperative day (day-1). Postoperative morbidity was recorded using the Clavien-Dindo classification and further categorised into minor, moderate and severe. Plasma/serum measures included markers of lipid oxidation (thiobarbituric acid-reactive substances; TBARS, 4-hydroxynonenal; 4-HNE, 8-iso-prostaglandin F 2⍺ ; 8-isoprostanes). Total reducing capacity was measured using total free thiols (TFTs) and ferric-reducing ability of plasma (FRAP). Nitric oxide (NO) formation/metabolism was measured using cyclic guanosine monophosphate (cGMP), nitrite, nitrate and total nitroso-species (RxNO). Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-⍺) were measured to evaluate inflammation., Results: Both oxidative stress (TBARS) and nitrosative stress (total nitroso-species) increased from baseline to EoS (+14%, P = 0.003 and +138%, P < 0.001, respectively), along with an increase in overall reducing capacity (+9%, P = 0.03) at EoS and protein-adjusted total free thiols (+12%, P = 0.001) at day-1 after surgery. Nitrite, nitrate and cGMP concentrations declined concomitantly from baseline to day-1. Baseline nitrate was 60% higher in the minor morbidity group compared to severe (P = 0.003). The increase in intraoperative TBARS was greater in severe compared to minor morbidity (P = 0.01). The decline in intraoperative nitrate was more marked in the minor morbidity group compared to severe (P < 0.001), whereas the cGMP decline was greatest in the severe morbidity group (P = 0.006)., Conclusion: In patients undergoing major HPB surgery, intraoperative oxidative and nitrosative stress increased, with a concomitant increase in reductive capacity. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism., (© 2023. The Author(s).)

Purpose: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level., Methods: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling., Results: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients., Conclusion: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.

Animal testing is the current standard for drug and chemicals safety assessment, but hazards translation to human is uncertain. Human in vitro models can address the species translation but might not replicate in vivo complexity. Herein, we propose a network-based method addressing these translational multiscale problems that derives in vivo liver injury biomarkers applicable to in vitro human early safety screening. We applied weighted correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset to obtain co-regulated gene clusters (modules). We identified modules statistically associated with liver pathologies, including a module enriched for ATF4-regulated genes as associated with the occurrence of hepatocellular single-cell necrosis, and as preserved in human liver in vitro models. Within the module, we identified TRIB3 and MTHFD2 as a novel candidate stress biomarkers, and developed and used BAC-eGFPHepG2 reporters in a compound screening, identifying compounds showing ATF4-dependent stress response and potential early safety signals., Competing Interests: L.I.F. and J.P.G. are employees and shareholders of MedBioInformatics Solutions SL., (© 2023 The Author(s).)

T-cell engager (TCE) molecules provide a targeted immunotherapy approach to treat hematologic malignancies and solid tumors. Since the approval of the CD19-targeted BiTE® (bispecific T-cell engager) molecule blinatumomab, multiple TCE molecules against different targets have been developed in several tumor types, with the approval of three additional TCE molecules in 2022. Some of the initial challenges, such as the need for continuous intravenous administration and low productivity, have been addressed in subsequent iterations of the platform by advancing half-life extended, Fc-based molecules. As clinical data from these molecules emerge, additional optimization of formats and manufacturability will be necessary. Ongoing efforts are focused on further improving TCE efficacy, safety, and convenience of administration., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program is continuously exploring opportunities to augment its already extensive collection of data, enhance the quality of reported cancer information, and contribute to more comprehensive analyses of cancer burden. This manuscript describes a recent linkage of the LexisNexis longitudinal residential history data with 11 SEER registries and provides estimates of the inter-state mobility of SEER cancer patients. To identify mobility from one state to another, we used state postal abbreviations to generate state-level residential histories. From this, we determined how often cancer patients moved from state-to-state. The results in this paper provide information on the linkage with LexisNexis data and useful information on state-to-state residential mobility patterns of a large portion of US cancer patients for the most recent 1-, 2-, 3-, 4-, and 5-year periods. We show that mobility patterns vary by geographic area, race/ethnicity and age, and cancer patients tend to move less than the general population., (© 2022 National Cancer Registrars Association.)

Sodium-glucose co-transporter-2 inhibitors are increasingly prescribed for patients with type 2 diabetes. Their use has been associated with life-threatening diabetic ketoacidosis. The risk is increased during times of fasting and intercurrent medical illness, which are common in the perioperative period. Diagnosis can be difficult, so perioperative clinicians must be familiar with preventing and recognising such complications.

Background: This study examines the association between Medicaid enrollment, including through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), and distant stage for three screening-amenable cancers: breast, cervical, and colorectal., Methods: We use the Surveillance, Epidemiology, and End Results Cancer Registry linked with Medicaid enrollment data to compare patients who were Medicaid insured with patients who were not Medicaid insured. We estimate the likelihood of distant stage at diagnosis using logistic regression., Results: Medicaid enrollment following diagnosis was associated with the highest likelihood of distant stage. Medicaid enrollment through NBCCEDP did not mitigate the likelihood of distant stage disease relative to Medicaid enrollment prior to diagnosis. Non-Hispanic Black patients had a greater likelihood of distant stage breast and colorectal cancer. Residing in higher socioeconomic areas was associated with a lower likelihood of distant stage breast cancer., Conclusions: Medicaid enrollment prior to diagnosis is associated with a lower likelihood of distant stage in screen amenable cancers but does not fully ameliorate disparities., Impact: Our study highlights the importance of health insurance coverage prior to diagnosis and demonstrates that while targeted programs such as the NBCCEDP provide critical access to screening, they are not a substitute for comprehensive insurance coverage., (©2022 American Association for Cancer Research.)

Mechanism-based risk assessment is urged to advance and fully permeate into current safety assessment practices, possibly at early phases of drug safety testing. Toxicogenomics is a promising source of mechanisms-revealing data, but interpretative analysis tools specific for the testing systems (e.g. hepatocytes) are lacking. In this study, we present the TXG-MAPr webtool (available at https://txg-mapr.eu/WGCNA&#95;PHH/TGGATEs&#95;PHH/ ), an R-Shiny-based implementation of weighted gene co-expression network analysis (WGCNA) obtained from the Primary Human Hepatocytes (PHH) TG-GATEs dataset. The 398 gene co-expression networks (modules) were annotated with functional information (pathway enrichment, transcription factor) to reveal their mechanistic interpretation. Several well-known stress response pathways were captured in the modules, were perturbed by specific stressors and showed preservation in rat systems (rat primary hepatocytes and rat in vivo liver), with the exception of DNA damage and oxidative stress responses. A subset of 87 well-annotated and preserved modules was used to evaluate mechanisms of toxicity of endoplasmic reticulum (ER) stress and oxidative stress inducers, including cyclosporine A, tunicamycin and acetaminophen. In addition, module responses can be calculated from external datasets obtained with different hepatocyte cells and platforms, including targeted RNA-seq data, therefore, imputing biological responses from a limited gene set. As another application, donors' sensitivity towards tunicamycin was investigated with the TXG-MAPr, identifying higher basal level of intrinsic immune response in donors with pre-existing liver pathology. In conclusion, we demonstrated that gene co-expression analysis coupled to an interactive visualization environment, the TXG-MAPr, is a promising approach to achieve mechanistic relevant, cross-species and cross-platform evaluation of toxicogenomic data., (© 2021. The Author(s).)

Background: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO 2 ) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients., Methods: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO 2 88-92%) or usual care (control - SpO 2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed., Results: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO 2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group., Conclusion: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DSM and MGM are in part funded by the UCLH/UCL NIHR Biomedical Research Centre. MPWG is in part funded by the Southampton NIHR Biomedical Research Centre., (© The Intensive Care Society 2021.)

Background: Little is known about the real-world care of young adult (YA) females (aged 20-39 years) with breast cancer. This study describes factors associated with the receipt of guideline-concordant care (GCC) among YAs., Methods: The authors identified 1259 YA women with invasive breast cancer diagnosed in 2013 in the National Cancer Institute's Patterns of Care study. Hospital records were re-abstracted, and treatment was verified. Using the National Comprehensive Cancer Network's 2013 breast cancer guidelines, the authors assessed the receipt of GCC by cancer subtype among a subset of YAs (n = 952). Associations between sociodemographic and clinical factors and GCC receipt were examined., Results: Most YAs were 35 to 39 years old (51.2%) and partnered (56.4%); half had hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) tumors. GCC was found for 81.7% of YAs. Relationships between sociodemographic and clinical factors and GCC receipt differed by subtype. Stage was the only significant predictor of GCC receipt for all subtypes (stage II vs III: odds ratio [OR] for HR+/HER2+, 0.20; 95% confidence interval [CI], 0.08-0.50; OR for HR-/HER2+, 0.13; 95% CI, 0.07-0.25; OR for HR-/HER2-, 3.86; 95% CI, 1.55-9.62; OR for HR+/HER2-, 2.81; 95% CI, 1.63-5.80)., Conclusions: GCC is high among YAs with breast cancer. The effects of sociodemographic factors and treatment facility size on GCC differ by subtype. Consistent with recommendations, tumor biology, not age, is associated with GCC for all subtypes. Future studies should assess the effect of GCC on survival among YAs., (© 2021 American Cancer Society. This article is a U.S. Government work and is in the public domain in the USA.)

Drug-induced liver injury (DILI) is the most prevalent adversity encountered in drug development and clinical settings leading to urgent needs to understand the underlying mechanisms. In this study, we have systematically investigated the dynamics of the activation of cellular stress response pathways and cell death outcomes upon exposure of a panel of liver toxicants using live cell imaging of fluorescent reporter cell lines. We established a comprehensive temporal dynamic response profile of a large set of BAC-GFP HepG2 cell lines representing the following components of stress signaling: i) unfolded protein response (UPR) [ATF4, XBP1, BIP and CHOP]; ii) oxidative stress [NRF2, SRXN1, HMOX1]; iii) DNA damage [P53, P21, BTG2, MDM2]; and iv) NF-κB pathway [A20, ICAM1]. We quantified the single cell GFP expression as a surrogate for endogenous protein expression using live cell imaging over > 60 h upon exposure to 14 DILI compounds at multiple concentrations. Using logic-based ordinary differential equation (Logic-ODE), we modelled the dynamic profiles of the different stress responses and extracted specific descriptors potentially predicting the progressive outcomes. We identified the activation of ATF4-CHOP axis of the UPR as the key pathway showing the highest correlation with cell death upon DILI compound perturbation. Knocking down main components of the UPR provided partial protection from compound-induced cytotoxicity, indicating a complex interplay among UPR components as well as other stress pathways. Our results suggest that a systematic analysis of the temporal dynamics of ATF4-CHOP axis activation can support the identification of DILI risk for new candidate drugs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Key Message: Novel disease resistance gene paralogues are generated by targeted chromosome cleavage of tandem duplicated NBS-LRR gene complexes and subsequent DNA repair in soybean. This study demonstrates accelerated diversification of innate immunity of plants using CRISPR. Nucleotide-binding-site-leucine-rich-repeat (NBS-LRR) gene families are key components of effector-triggered immunity. They are often arranged in tandem duplicated arrays in the genome, a configuration that is conducive to recombinations that will lead to new, chimeric genes. These rearrangements have been recognized as major sources of novel disease resistance phenotypes. Targeted chromosome cleavage by CRISPR/Cas9 can conceivably induce rearrangements and thus emergence of new resistance gene paralogues. Two NBS-LRR families of soy have been selected to demonstrate this concept: a four-copy family in the Rpp1 region (Rpp1L) and a large, complex locus, Rps1 with 22 copies. Copy-number variations suggesting large-scale, CRISPR/Cas9-mediated chromosome rearrangements in the Rpp1L and Rps1 complexes were detected in up to 58.8% of progenies of primary transformants using droplet-digital PCR. Sequencing confirmed development of novel, chimeric paralogs with intact open reading frames. These novel paralogs may confer new disease resistance specificities. This method to diversify innate immunity of plants by genome editing is readily applicable to other disease resistance genes or other repetitive loci.

Background: A national data source for identifying patients with cancer enrolled in Medicaid is needed to evaluate cancer care for low-income, publicly insured patients. In this study, a population-based data set of patients diagnosed with cancer and enrolled in Medicaid was created and evaluated. The objective was to compare the characteristics of patients with cancer identified in Surveillance, Epidemiology, and End Results (SEER) data and linked to the Medicaid Analytic eXtract (MAX) Personal Summary files with the characteristics of patients who were not linked to the MAX file., Methods: All persons in 14 SEER registries diagnosed with cancer from 2006 to 2013 who were or were not linked to the 2006-2013 nationwide MAX files were selected, and patient demographic characteristics were compared for 3 age groups. Common cancer sites and the timing of Medicaid enrollment with respect to patients' cancer diagnoses were reported, and the stage at diagnosis and 4-year mortality were compared by 3 categories of Medicaid enrollment., Results: Approximately 18% of the sample was enrolled in Medicaid within 25 months of diagnosis. Enrollees had a greater proportion of racial/ethnic minorities in comparison with patients who were not enrolled. A late-stage diagnosis was more common among Medicaid patients and particularly among those who enrolled after their diagnosis. For every common cancer site, mortality was highest in the sample of Medicaid patients who enrolled after their diagnosis., Conclusions: The Medicaid enrollment data newly added to SEER records enhance researchers' ability to investigate research questions related to Medicaid policies and care delivery. For patients enrolled before their diagnosis, Medicaid appears to offer protection against late-stage disease and mortality., (© 2020 American Cancer Society.)

Hereditary hemolytic anemias (HHA) are a heterogeneous group of anemias associated with decreased red cell survival. While there can be clinical benefit of splenectomy in many cases, splenectomy is not appropriate for all types of HHA. Additionally, there are significant risks during and following splenectomy including surgical risks, postsplenectomy sepsis, and thrombotic complications. This review discusses the diagnostic approach to HHA as well as the role of splenectomy in the management. Surgical approaches and outcomes for total and partial splenectomy are discussed., (© 2020 Wiley Periodicals, Inc.)

Jellybones and NHagos are bacteriophages that were identified in the host bacterium Gordonia rubripertincta NRRL B-16540. Jellybones has a direct terminal repeat and was assigned to the CS2 subcluster with a length of 77,514 bp. NHagos is circularly permuted and was assigned to the DR cluster with a length of 59,580 bp., (Copyright © 2020 Harrington et al.)

Chemical-induced liver cancer occurs in rodents through well-characterized adverse outcome pathways. We hypothesized that measurement of the 6 most common molecular initiating events (MIEs) in liver cancer adverse outcome pathways in short-term assays using only gene expression will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in 2-year bioassays. We tested this hypothesis using transcript data from a rat liver microarray compendium consisting of 2013 comparisons of 146 chemicals administered at doses with previously established effects on rat liver tumor induction. Five MIEs were measured using previously characterized gene expression biomarkers composed of gene sets predictive for genotoxicity and activation of 1 or more xenobiotic receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Because chronic injury can be important in tumorigenesis, we also developed a biomarker for cytotoxicity that had a 96% balanced accuracy. Characterization of the genes in each biomarker set using the unsupervised TXG-MAP network model demonstrated that the genes were associated with distinct functional coexpression modules. Using the Toxicological Priority Index to rank chemicals based on their ability to activate the MIEs showed that chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Balanced accuracies using thresholds derived from either TG-GATES or DrugMatrix data sets to predict tumorigenicity in independent sets of chemicals were up to 93%. These results show that a MIE-directed approach using only gene expression biomarkers could be used in short-term assays to identify chemicals and their doses that cause tumors., (Published by Oxford University Press on behalf of the Society of Toxicology 2020. This work is written by US Government employees and is in the public domain in the US.)

Background: Visual estimation of blood loss following delivery often under-reports actual bleed volume. To improve accuracy, quantitative blood loss measurement was introduced for all births in the 12 hospitals providing maternity care in Wales. This intervention was incorporated into a quality improvement programme (Obstetric Bleeding Strategy for Wales, OBS Cymru). We report the incidence of postpartum haemorrhage in Wales over a 1-year period using quantitative measurement., Methods: This prospective, consecutive cohort included all 31,341 women giving birth in Wales in 2017. Standardised training was cascaded to maternity staff in all 12 hospitals in Wales. The training comprised mock-scenarios, a video and team drills. Uptake of quantitative blood loss measurement was audited at each centre. Data on postpartum haemorrhage of > 1000 mL were collected and analysed according to mode of delivery. Data on blood loss for all maternities was from the NHS Wales Informatics Service., Results: Biannual audit data demonstrated an increase in quantitative measurement from 52.1 to 87.8% (P < 0.001). The incidence (95% confidence intervals, CI) of postpartum haemorrhage of > 1000 mL, > 1500 mL and > 2000 mL was 8.6% (8.3 to 8.9), 3.3% (3.1 to 3.5) and 1.3% (1.2 to 1.4), respectively compared to 5%, 2% and 0.8% in the year before OBS Cymru. The incidence (95% CI) of bleeds of > 1000 mL was similar across the 12 hospitals despite widely varied size, staffing levels and case mix, median (25th to 75th centile) 8.6% (7.8-9.6). The incidence of PPH varied with mode of delivery and was mean (95% CI) 4.9% (4.6-5.2) for unassisted vaginal deliveries, 18.4 (17.1-19.8) for instrumental vaginal deliveries, 8.5 (7.7-9.4) for elective caesarean section and 19.8 (18.6-21.0) for non-elective caesarean sections., Conclusions: Quantitative measurement of blood loss is feasible in all hospitals providing maternity care and is associated with detection of higher rates of postpartum haemorrhage. These results have implications for the definition of abnormal blood loss after childbirth and for management and research of postpartum haemorrhage.

Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl 4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl 4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl 4 -induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.

Reactive oxygen species (ROS) are essential for cellular signaling and physiological function. An imbalance between ROS production and antioxidant protection results in a state of oxidative stress (OS), which is associated with perturbations in reduction/oxidation (redox) regulation, cellular dysfunction, organ failure, and disease. The pathophysiology of OS is closely interlinked with inflammation, mitochondrial dysfunction, and, in the case of surgery, ischemia/reperfusion injury (IRI). Perioperative OS is a complex response that involves patient, surgical, and anesthetic factors. The magnitude of tissue injury inflicted by the surgery affects the degree of OS, and both duration and nature of the anesthetic procedure applied can modify this. Moreover, the interindividual susceptibility to the impact of OS is likely to be highly variable and potentially linked to underlying comorbidities. The pathological link between OS and postoperative complications remains unclear, in part due to the complexities of measuring ROS- and OS-mediated damage. Exogenous antioxidant use and exercise have been shown to modulate OS and may have potential as countermeasures to improve postoperative recovery. A better understanding of the underlying mechanisms of OS, redox signaling, and regulation can provide an opportunity for patient-specific phenotyping and development of targeted interventions to reduce the disruption that surgery can cause to our physiology. Anesthesiologists are in a unique position to deliver countermeasures to OS and improve physiological resilience. To shy away from a process so fundamental to the welfare of these patients would be foolhardy and negligent, thus calling for an improved understanding of this complex facet of human biology.

The microbiome of built structures has considerable influence over an inhabitant's well-being, yet the vast majority of research has focused on human-built structures. Ants are well-known architects, capable of constructing elaborate dwellings, the microbiome of which is underexplored. Here, we explore the bacterial and fungal microbiomes in functionally distinct chambers within and outside the nests of Azteca alfari ants in Cecropia peltata trees. We predicted that A. alfari colonies (1) maintain distinct microbiomes within their nests compared to the surrounding environment, (2) maintain distinct microbiomes among nest chambers used for different functions, and (3) limit both ant and plant pathogens inside their nests. In support of these predictions, we found that internal and external nest sampling locations had distinct microbial communities, and A. alfari maintained lower bacterial richness in their 'nurseries'. While putative animal pathogens were suppressed in chambers that ants actively inhabited, putative plant pathogens were not, which does not support our hypothesis that A. alfari defends its host trees against microbial antagonists. Our results show that ants influence microbial communities inside their nests similar to studies of human homes. Unlike humans, ants limit the bacteria in their nurseries and potentially prevent the build-up of insect-infecting pathogens. These results highlight the importance of documenting how indoor microbiomes differ among species, which might improve our understanding of how to promote indoor health in human dwellings.

Applying toxicogenomics to improving the safety profile of drug candidates and crop protection molecules is most useful when it identifies relevant biological and mechanistic information that highlights risks and informs risk mitigation strategies. Pathway-based approaches, such as gene set enrichment analysis, integrate toxicogenomic data with known biological process and pathways. Network methods help define unknown biological processes and offer data reduction advantages. Integrating the 2 approaches would improve interpretation of toxicogenomic information. Barriers to the routine application of these methods in genome-wide transcriptomic studies include a need for "hands-on" computer programming experience, the selection of 1 or more analysis methods (eg pathway analysis methods), the sensitivity of results to algorithm parameters, and challenges in linking differential gene expression to variation in safety outcomes. To facilitate adoption and reproducibility of gene expression analysis in safety studies, we have developed Collaborative Toxicogeomics, an open-access integrated web portal using the Django web framework. The software, developed with the Python programming language, is modular, extensible and implements "best-practice" methods in computational biology. New study results are compared with over 4000 rodent liver experiments from Drug Matrix and open TG-GATEs. A unique feature of the software is the ability to integrate clinical chemistry and histopathology-derived outcomes with results from gene expression studies, leading to relevant mechanistic conclusions. We describe its application by analyzing the effects of several toxicants on liver gene expression and exemplify application to predicting toxicity study outcomes upon chronic treatment from expression changes in acute-duration studies., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: Black women with ovarian cancer experience worse survival than white women. Receipt of guideline care improves survival, yet care may vary by race. We assessed rates of guideline care and role of guideline treatment on survival disparities., Methods: This retrospective cohort analysis used the NCI's Patterns of Care data for women diagnosed with ovarian cancer, 2002 and 2011 (weighted n = 3,999), with follow-up through December 12, 2014. Logistic regression included patient characteristics, insurance, and gynecologic oncologist (GO) consultation to produce adjusted standardized percentages of women receiving guideline treatment by race. Cox proportional hazards analysis assessed risk of ovarian cancer death., Results: Guideline care was significantly lower for black women compared with white women (adjusted 27.5% vs. 34.1%). Increased receipt of guideline care was associated with GO consultation, younger ages, stage, and insurance. Rates of GO consultation were comparable for black and white women, approximately 60%. Black women were more likely to receive no surgery or no chemotherapy if they did not consult a GO. The unadjusted death risk was significantly higher in black women (HR = 1.33). After adjusting for receipt of guideline care and other factors, black and white women had similar risk of death (HR = 1.05)., Conclusions: Race was not associated with risk of death when guideline care was included in multivariate survival models. However, black patients received less guideline care. GO consultation significantly increased receipt of guideline care., Impact: Research is needed to understand treatment perspectives for black patients and their providers to increase the receipt of guideline care and reduce survival disparities., (©2018 American Association for Cancer Research.)

The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulated by siRNA targeting NRF2 and upregulated by siRNA targeting KEAP1 in PHH. Applying weighted gene co-expression network analysis (WGCNA) to transcriptomic data from the Open TG-GATES toxicogenomics repository (representing PHH exposed to 158 compounds) revealed four co-expressed gene sets or 'modules' enriched for these and other NRF2-associated genes. By classifying the 158 TG-GATES compounds based on published evidence, and employing the four modules as network perturbation metrics, we found that the activation of NRF2 is a very good indicator of the intrinsic biochemical reactivity of a compound (i.e. its propensity to cause direct chemical stress), with relatively high sensitivity, specificity, accuracy and positive/negative predictive values. We also found that NRF2 activation has lower sensitivity for the prediction of clinical DILI risk, although relatively high specificity and positive predictive values indicate that false positive detection rates are likely to be low in this setting. Underpinned by our comprehensive analysis, activation of the NRF2 network is one of several mechanism-based components that can be incorporated into holistic systems toxicology models to improve mechanistic understanding and preclinical prediction of DILI in man.

Protein-based biotherapeutics are produced in engineered cells through complex processes and may contain a wide variety of variants and post-translational modifications that must be monitored or controlled to ensure product quality. Recently, a low level (~1-5%) impurity was observed in a number of proteins derived from stably transfected Chinese hamster ovary (CHO) cells using mass spectrometry. These molecules include antibodies and Fc fusion proteins where Fc is on the C-terminus of the construct. By liquid chromatography-mass spectrometry (LC-MS), the impurity was found to be ~1177 Da larger than the expected mass. After tryptic digestion and analysis by LC-MS/MS, the impurity was localized to the C-terminus of Fc in the form of an Fc sequence extension. Targeted higher-energy collision dissociation was performed using various normalized collision energies (NCE) on two charge states of the extended peptide, resulting in nearly complete fragment ion coverage. The amino acid sequence, SLSLSPEAEAASASELFQ, obtained by the de novo sequencing effort matches a portion of the vector sequence used in the transfection of the CHO cells, specifically in the promoter region of the selection cassette downstream of the protein coding sequence. The modification was the result of an unexpected splicing event, caused by the resemblance of the commonly used GGU codon of the C-terminal glycine to a consensus splicing donor. Three alternative codons for glycine were tested to alleviate the modification, and all were found to completely eliminate the undesirable C-terminal extension, thus improving product quality.

Introduction: Non-Hispanic black (NHB) women with breast cancer have poorer survival than non-Hispanic white (NHW) women. Although NHB women are more often diagnosed at later stages, it is less established whether racial disparities exist among women diagnosed with late-stage breast cancer, particularly when care is provided in the community setting., Methods: Treatment and survival were examined by race/ethnicity among women diagnosed in 2012 with stage IIIB-IV breast cancer using the National Cancer Institute's population-based Patterns of Care Study. Medical records were re-abstracted and treating physicians were contacted to verify therapy. Vital status was available through 2014., Results: A total of 533 women with stage IIIB-C and 625 with stage IV tumors were included; NHW women comprised about 70% of each group. Among women with stage IIIB-C disease, racial/ethnicity variations in systemic treatment were not observed but there was a borderline association indicating worse all-cause mortality among NHB women (hazard ratio 1.52; 95% confidence interval (CI) 0.96-2.41). In contrast, among women with stage IV disease, borderline associations indicating NHB women were more likely to receive chemotherapy (OR 1.44, 95% CI 0.90-2.30) and, among those with hormone receptor-positive tumors, less likely to receive endocrine therapy (OR 0.60, 95% CI 0.35-1.04). All-cause mortality did not vary by race/ethnicity for stage IV disease (hazard ratio 0.92; 95% CI 0.68-1.25)., Conclusions: More research is needed to identify additional factors associated with the potential survival disparities among women with stage IIIB-C disease and potential treatment disparities among women with stage IV disease.

Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

Objective: This study's objective was determine the incremental association of reasons for living to the lifetime number of suicide attempts in relation to other known risk and protective factors in a sample of psychiatric patients with extensive psychopathology in residential treatment., Methods: Participants (n = 131) completed a demographic questionnaire that also asked for information about lifetime suicide history, psychiatric history, trauma, and abuse history. Additional measures of resilience, reasons for living (RFL), and impulsiveness were completed., Results: A history of sexual abuse was associated with an increasing lifetime number of suicide attempts, while a history of physical abuse and trait impulsiveness were not associated with the lifetime number of suicide attempts. Survival and coping beliefs, a subscale of the Reasons for Living Inventory (RFLI), was found to add incremental predictive validity to the number of lifetime suicide attempts. A composite fear variable, combining fear of suicide and fear of social consequences of suicide, was negatively correlated with lifetime number of attempts but did not add incremental validity to the prediction of lifetime number of suicide attempts., Conclusion: In a sample of participants with significant psychiatric impairment, the protective factor of survival and coping beliefs may be an important barrier to repeated suicide attempts and may be considered a suicide-specific resilience measure. Understanding the psychological processes contributing to the development of such protective factors as resilience, meaning in life, and coping resources is an important area of study and a potential avenue for targeted therapeutic intervention in high-risk populations.

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Patients with a history of suicidal ideation or attempts, especially if they have serious psychopathology with repeated hospitalizations, are burdened by ongoing risk for suicide. We studied this high-risk group to assess their psychological status following their most recent suicide attempt, in contrast to equally ill patients without a suicide history. Further, among suicidal patients, we compared those with only ideation, with a non-medically serious suicide attempt and with medically serious suicide attempts. We also report on the development of a new measure of psychic pain., Methods: Patients in residential treatment (n=131) completed self-report questionnaires about suicide history, impulsiveness, psychic pain, resilience, and reasons for living. A series of univariate ordinal logistic regressions identified variables to include in a multivariable logistic regression to examine the odds associated with increasing levels of suicidality., Results: A history of suicidal ideation or suicide attempts is associated with proportionally more psychic pain and fewer current reasons for living. Prior history of abuse, impulsiveness, and general resilience were not significantly associated with suicidal severity., Conclusions: For patients who have suicidal ideation, or have attempted suicide, and also have additional risk factors including past hospitalization, treatments should include both understanding the sources of psychic pain and promoting individual discovery of reasons for living., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Childhood neuroblastoma describes a heterogeneous group of extracranial solid tumors, that are treated per risk profile. We sought to describe treatment patterns and survival using population-based data from throughout the United States., Materials and Methods: Using the National Cancer Institute (NCI)'s Patterns of Care data, we analyzed treatment provided to newly diagnosed, histologically confirmed neuroblastoma patients in 2010 and 2011, registered to one of 14 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Data were re-abstracted from hospital records and treating physicians contacted for verification. Application of the Children's Oncology Group (COG)'s 3-level (low, intermediate and high) neuroblastoma risk classification system for therapeutic decision-making provided insight to community-based treatment patterns. Kaplan-Meier survival analyses, based on 5-years of follow-up, were also performed., Results: 76% of the 250 patients were enrolled on an open/active clinical trial. All low-risk patients received surgery. Most intermediate-risk patients (81%) received a chemotherapy regimen that included carboplatin, etoposide, cyclophosphamide and doxorubicin. High-risk patients received extensive, multimodal treatment consisting of chemotherapy, surgery, myeloablative chemotherapy with stem cell rescue (transplant), radiation, immunotherapy (dinutuximab), and isotretinoin therapy. 21% patients had died at the end of the maximum 60-month follow-up period. The 5-year estimated survival rates were lower for patients diagnosed with stage 4 disease, unfavorable DNA ploidy, MYCN gene amplification or classified as high-risk., Conclusion: Most neuroblastoma patients are registered on a risk-based open/active clinical trial. Variation in modality, systemic agents and sequence of treatment reflects the heterogeneity of therapy received by these patients.

Introduction: The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

Background: The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. We examined sorafenib use since Food and Drug Administration (FDA) approval in 2007 and associated survival for individuals diagnosed with advanced HCC, conducting a population-based evaluation of treatment patterns and outcomes for this newly approved drug in the US over time., Methods: We identified individuals diagnosed with Barcelona Clinic Liver Cancer Stage C from the 2007 and 2012 National Cancer Institute Patterns of Care study. We examined trends in use as well as patient and clinical factors associated with receiving sorafenib using multivariate logistic regression analysis. We then evaluated the association between sorafenib use and overall hazard of death using multivariate Cox proportional hazards regression., Results: Among 550 individuals diagnosed with advanced HCC, we found no significant increase in the proportion of patients treated with sorafenib from 2007 to 2012 (26.3 vs. 30.4%). After adjusting for patient and clinical characteristics, non-Hispanic Blacks (compared to non-Hispanic Whites) and those with a lower Child-Pugh score remained more likely to receive sorafenib. Individuals receiving systemic chemotherapy only, radiation therapy only, or no treatment at all experienced a higher risk of death than those treated with sorafenib, while those receiving a transplant experienced a lower risk of death., Conclusions: Sorafenib has not been widely adopted into oncology practice since FDA approval for advanced HCC. Few factors apart from Child-Pugh score and race/ethnicity predict sorafenib use in clinical practice, although sorafenib treatment is associated with a lower risk of death.

Background: Researchers have used prostate-specific antigen (PSA) values collected by central cancer registries to evaluate tumors for potential aggressive clinical disease. An independent study collecting PSA values suggested a high error rate (18%) related to implied decimal points. To evaluate the error rate in the Surveillance, Epidemiology, and End Results (SEER) program, a comprehensive review of PSA values recorded across all SEER registries was performed., Methods: Consolidated PSA values for eligible prostate cancer cases in SEER registries were reviewed and compared with text documentation from abstracted records. Four types of classification errors were identified: implied decimal point errors, abstraction or coding implementation errors, nonsignificant errors, and changes related to "unknown" values., Results: A total of 50,277 prostate cancer cases diagnosed in 2012 were reviewed. Approximately 94.15% of cases did not have meaningful changes (85.85% correct, 5.58% with a nonsignificant change of <1 ng/mL, and 2.80% with no clinical change). Approximately 5.70% of cases had meaningful changes (1.93% due to implied decimal point errors, 1.54% due to abstract or coding errors, and 2.23% due to errors related to unknown categories). Only 419 of the original 50,277 cases (0.83%) resulted in a change in disease stage due to a corrected PSA value., Conclusions: The implied decimal error rate was only 1.93% of all cases in the current validation study, with a meaningful error rate of 5.81%. The reasons for the lower error rate in SEER are likely due to ongoing and rigorous quality control and visual editing processes by the central registries. The SEER program currently is reviewing and correcting PSA values back to 2004 and will re-release these data in the public use research file. Cancer 2017;123:697-703. © 2016 American Cancer Society., Competing Interests: Conflict/Interest disclosures: None, (© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Introduction: Lung cancer remains a common and deadly cancer in the United States. This study evaluated factors associated with stage-specific cancer therapy and survival focusing on temporal trends and sociodemographic disparities., Methods: A random sample (n=3,318) of non-small cell lung cancer (NSCLC) patients diagnosed in 1996, 2005 and 2010, and reported to the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program was analyzed. Logistic regression was utilized to identify factors associated with receipt of surgery among stage I/II patients and chemotherapy among stage IIIB/IV patients. Cox proportional hazard regression was utilized to assess factors associated with all-cause mortality, stratified by stage., Results: Surgery among stage I/II patients decreased non-significantly overtime (1996: 78.8%; 2010: 68.5%; p=0.18), whereas receipt of chemotherapy among stage IIIB/IV patients increased significantly overtime (1996: 36.1%; 2010: 51.2%; p<0.01). Receipt of surgery (70-79 and ≥80 vs. <70: Odds Ratio(OR):0.31; 95% Confidence Interval (CI): 0.16-0.63 and OR:0.04; 95% CI: 0.02-0.10, respectively) and chemotherapy (≥80 vs. <70: OR: 0.26; 95% CI:0.15-0.45) was less likely among older patients. Median survival improved non-significantly among stage I/II patients from 51 to 64 months (p=0.75) and significantly among IIIB/IV patients from 4 to 5 months (p<0.01)., Conclusion: Treatment disparities were observed in both stage groups, notably among older patients. Among stage I/II patients, survival did not change significantly possibly due to stable surgery utilization. Among stage IIIB/IV patients, although the use of chemotherapy increased and survival improved, the one-month increase in median survival highlights the need for addition research., Competing Interests: The authors declare that they have no conflict of interest., (Published by Elsevier Ireland Ltd.)

The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.