Check this out: treatment paradigms in immune-checkpoint inhibitor colitis.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) have become a pillar of cancer therapy for many people around the world. However, up to two-thirds of all patients undergoing ICI therapy will have immune-related adverse events (irAEs), including immune-checkpoint inhibitor colitis (ICIC). This review summarizes the most valuable and currently available information about the mechanism, diagnosis, and management of ICIC. RECENT FINDINGS: Recent findings include several developments on the leading theories for the mechanisms of ICIC such as the role of the gut microbiome. New emerging therapy strategies include tocilizumab, ustekinumab, mycophenolate mofetil, and calcineurin inhibitors. SUMMARY: The occurrence of irAEs remains a limiting factor for the use of immunotherapy in cancer treatment. Prompt diagnosis of ICIC with endoscopy and histologic confirmation can lead to early utilization of known effective treatments such as corticosteroids, infliximab, vedolizumab, and other emerging therapy strategies. We summarize the key points of this review article in our abstract video, Supplemental Digital Content 1, http://links.lww.com/COG/A44.

Ferumoxytol dynamic contrast enhanced magnetic resonance imaging identifies altered placental cotyledon perfusion in rhesus macaques†.

Identification of placental dysfunction in early pregnancy with noninvasive imaging could be a valuable tool for assessing maternal and fetal risk. Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) can be a powerful tool for interrogating placenta health. After inoculation with Zika virus or sham inoculation at gestation age (GA) 45 or 55 days, animals were imaged up to three times at GA65, GA100, and GA145. DCE MRI images were acquired at all imaging sessions using ferumoxytol, an iron nanoparticle-based contrast agent, and analyzed for placental intervillous blood flow, number of perfusion domains, and perfusion domain volume. Cesarean section was performed at GA155, and the placenta was photographed and dissected for histopathology. Photographs were used to align cotyledons with estimated perfusion domains from MRI, allowing comparison of estimated cotyledon volume to pathology. Monkeys were separated into high and low pathology groups based on the average number of pathologies present in the placenta. Perfusion domain flow, volume, and number increased through gestation, and total blood flow increased with gestation for both low pathology and high pathology groups. A statistically significant decrease in perfusion domain volume associated with pathology was detected at all gestational ages. Individual perfusion domain flow comparisons demonstrated a statistically significant decrease with pathology at GA100 and GA145, but not GA65. Since ferumoxytol is currently used to treat anemia during human pregnancy and as an off-label MRI contrast agent, future transition of this work to human pregnancy may be possible.

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques.

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in vitro and in vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titers and caused more-severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here, we infected four pregnant rhesus macaques with a low-passage-number strain of African-lineage ZIKV and compared its pathogenesis to those for a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. The viral replication kinetics for the two experimental groups were not significantly different, and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1 to 1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV viral RNA (vRNA) was found in the maternal-fetal interface tissues of the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015 to 2016. In its most recent update, the WHO stated that improved understanding of African-lineage ZIKV pathogenesis during pregnancy must be a priority. The recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here, we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational nonhuman primate model. We show that African-lineage isolates replicate with kinetics similar to those of Asian-lineage isolates and can infect the placenta. However, there was no evidence of more-severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for epidemiological and translational in vivo studies with African-lineage ZIKV.

Diagnosis and Monitoring of Ulcerative Colitis.

Ulcerative colitis is one of the two main subtypes of inflammatory bowel disease, along with Crohn's disease. Understanding the clinical and endoscopic features of ulcerative colitis is critical in achieving a timely diagnosis. An initial evaluation includes assessing clinical symptoms, inflammatory markers, endoscopic findings, and determination of the presence or absence of extraintestinal manifestations. Initial disease management should consider disease severity at the time of diagnosis as well as prognostication, or the determination of risk factors present with a high likelihood of severe disease in the future. Once appropriate therapy has been initiated, ongoing monitoring is crucial, which may include repeated clinical assessments over time, measuring noninvasive markers of inflammation, and endoscopic and histologic reevaluation. An important aspect of disease monitoring in ulcerative colitis is dysplasia surveillance; there are many patient-specific risk factors which influence surveillance strategies. Utilizing appropriate surveillance techniques is necessary for early detection of dysplasia and colorectal neoplasia.

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

COVID-19 and People Who Use Drugs - A Commentary.

OBJECTIVE: People who use drugs (PWUD) face increased risk of exposure to COVID-19, but also elevated risk associated from injection drug use. We describe factors underlying their increased risk and identify mechanisms for reducing or minimizing rates of COVID-19 transmission and other health outcomes. METHODS: Our commentary draws upon empirical data, governmental and other reports, and field-based unpublished data from our own studies to inform our conclusion and recommendations. RESULTS: Co-morbid health conditions (eg, diabetes), structural challenges (eg, homelessness, criminal justice involvement), stigma (eg, social devaluation, discrediting), and syndemic clustering of of overdose, HCV, and HIV among PWUD are exacerbated by COVID-19. CONCLUSIONS: Beyond the many challenges all people face to remain safe and healthy during the COVID-19 pandemic, PWUD face additional barriers to remaining safe not only from COVID-19 but from negative health outcomes associated with their living environments, socioeconomic positions, and injection drug use. Collaborative efforts among governmental agencies, health providers, SSPs, CBOs, and other agencies providing services to PWUD is essential to the development of programs and services to meet the many needs of PWUD, which have been particularly accentuated during the COVID-19 pandemic.

Effects of Cardiac Sympathetic Neurodegeneration and PPARγ Activation on Rhesus Macaque Whole Blood miRNA and mRNA Expression Profiles.

Degeneration of sympathetic innervation of the heart occurs in numerous diseases, including diabetes, idiopathic REM sleep disorder, and Parkinson's disease (PD). In PD, cardiac sympathetic denervation occurs in 80-90% of patients and can begin before the onset of motor symptoms. Today, there are no disease-modifying therapies for cardiac sympathetic neurodegeneration, and biomarkers are limited to radioimaging techniques. Analysis of expression levels of coding mRNA and noncoding RNAs, such as microRNAs (miRNAs), can uncover pathways involved in disease, leading to the discovery of biomarkers, pathological mechanisms, and potential drug targets. Whole blood in particular is a clinically relevant source of biomarkers, as blood sampling is inexpensive and simple to perform. Our research group has previously developed a nonhuman primate model of cardiac sympathetic denervation by intravenous administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA). In this rhesus macaque (Macaca mulatta) model, imaging with positron emission tomography showed that oral administration of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5 mg/kg daily) significantly decreased cardiac inflammation and oxidative stress compared to placebo (n = 5). Here, we report our analysis of miRNA and mRNA expression levels over time in the whole blood of these monkeys. Differential expression of three miRNAs was induced by 6-OHDA (mml-miR-16-2-3p, mml-miR-133d-3p, and mml-miR-1262-5p) and two miRNAs by pioglitazone (mml-miR-204-5p and mml-miR-146b-5p) at 12 weeks posttoxin, while expression of mRNAs involved in inflammatory cytokines and receptors was not significantly affected. Overall, this study contributes to the characterization of rhesus coding and noncoding RNA profiles in normal and disease-like conditions, which may facilitate the identification and clinical translation of biomarkers of cardiac neurodegeneration and neuroprotection.

In Vitro CRISPR/Cas9-Directed Gene Editing to Model LRRK2 G2019S Parkinson's Disease in Common Marmosets.

Leucine-rich repeat kinase 2 (LRRK2) G2019S is a relatively common mutation, associated with 1-3% of Parkinson's disease (PD) cases worldwide. G2019S is hypothesized to increase LRRK2 kinase activity. Dopaminergic neurons derived from induced pluripotent stem cells of PD patients carrying LRRK2 G2019S are reported to have several phenotypes compared to wild type controls, including increased activated caspase-3 and reactive oxygen species (ROS), autophagy dysfunction, and simplification of neurites. The common marmoset is envisioned as a candidate nonhuman primate species for comprehensive modeling of genetic mutations. Here, we report our successful use of CRISPR/Cas9 with repair template-mediated homology directed repair to introduce the LRRK2 G2019S mutation, as well as a truncation of the LRRK2 kinase domain, into marmoset embryonic and induced pluripotent stem cells. We found that, similar to humans, marmoset LRRK2 G2019S resulted in elevated kinase activity. Phenotypic evaluation after dopaminergic differentiation demonstrated LRRK2 G2019S-mediated increased intracellular ROS, decreased neuronal viability, and reduced neurite complexity. Importantly, these phenotypes were not observed in clones with LRRK2 truncation. These results demonstrate the feasibility of inducing monogenic mutations in common marmosets and support the use of this species for generating a novel genetic-based model of PD that expresses physiological levels of LRRK2 G2019S.

High Total Bilirubin as a Protective Factor for Diabetes Mellitus: An Analysis of NHANES Data From 1999 - 2006.

BACKGROUND: Diabetes Mellitus (DM) is a rampantly growing epidemic in the United States, affecting nearly 10% of the adult population. Studies have shown that higher levels of Total Bilirubin (TBili) convey a protective effect with regard to cardiovascular risk. In this study, we will examine the relationship between TBili level and prevalence of DM to discern whether a similar relationship exists. METHODS: The National Health and Nutrition Examination Survey (NHANES) is a comprehensive survey performed regularly to evaluate the overall health and nutrition status of the United States population. For the purpose of this study, we combined NHANES data collected between 1999 and 2006. Totally 15,876 eligible participants were selected after excluding all patients younger than twenty years, those with a history of abnormal liver function tests, or those who disclosed a history of liver disease. The data collected on these individuals was adjusted for demographic characteristics, as well as risk factors for DM, and was analyzed via multivariate logistic regression, using SAS proc survey methodology. RESULTS: After age adjustment, increased TBili was associated with 26% reduction in diabetes risk (OR 0.74, 95% CI 0.64 - 0.88). Multivariate analysis, adjusting for all diabetes risk factors assessed, confirmed this association (OR 0.80, 95% CI 0.67 - 0.95). CONCLUSIONS: Our results show that a higher level of serum TBili is associated with odds of having a lower incidence of DM. This finding supports the hypothesis that the antioxidant nature of TBili, demonstrating a protective effect with regard to the risk of stroke, atherosclerosis, and vasculitis in prior research, also extends to DM risk. Furthermore, research has shown that higher levels of TBili increase glucose mobilization into the cells, leading to more efficient, biologic glucose utilization. There is no doubt that the beneficial effect of TBili is multifactorial; thus further investigation is warranted. KEYWORDS: Bilirubin; Diabetes; Antioxidant; Protective.

Bilirubin as a Protective Factor for Rheumatoid Arthritis: An NHANES Study of 2003 - 2006 Data.

BACKGROUND: Rheumatoid arthritis(RA) is a chronic inflammatory, autoimmune polyarthritis, with a prevalence estimated at one percent of the United States(US) population. Serum bilirubin, because of its antioxidant nature, has been conjectured to exert an anti-inflammatory biologic effect. The objective of this study is to discern whether higher serum Total Bilirubin(TBili) levels are protective against RA. METHODS: This is a secondary analysis of National Health and Nutrition Examination Survey (NHANES) data collected between 2003-2006. Study participants completed a comprehensive questionnaire regarding their health history, underwent a physical examination, and had body fluids collected for laboratory studies. In NHANES, to assess for the presence of RA, the following questions were asked: Doctor ever said you had arthritis?" If so, Which type of arthritis. Statistical analysis was performed, using SAS version 9.1, proc survey methods. Participant data were adjusted for demographic characteristics as well as risk factors for RA. RESULTS: NHANES 2003-2006 included 20,470 individuals, chosen as a representative sampling of the entire US population. Exclusion criteria included age less than twenty years or liver dysfunction, defined as history of abnormal liver function tests or liver disease. 8,147 subjects did not have any exclusion criteria and were included in the data analysis. RA is inversely related to the serum level of TBili with an odds ratio of 0.679 (95% CI 0.533-0.865) and remained significant even after adjusting for age, gender, race, education, and tobacco history, with an odds ratio 0.749 (95% CI 0.575 - 0.976). CONCLUSIONS: Our study supports the hypothesis that higher TBili levels are protective against RA. A plausible mechanism for this association would be that the anti-oxidant effects of TBili exert a physiologic anti-inflammatory effect, which provides protection against RA. This explanation is supported by prior studies which show that higher TBili levels are protective against stroke, atherosclerosis, and vasculitis. Further studies are needed to delineate the exact nature of the protective properties of TBili. KEYWORDS: Bilirubin; Rheumatoid arthritis; Antioxidant; Protective.

Regulatory effects of iNOS on acute lung inflammatory responses in mice.

The role of endogenous NO in the regulation of acute lung injury is not well defined. We investigated the effects of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the acute inflammatory response in mouse lungs. Acute lung injury was induced by intratracheal instillation of bacterial lipopolysaccharide (LPS) into wild-type (WT) mice and mice deficient in iNOS (iNOS(-/-)) or eNOS (eNOS(-/-)). Endpoints of inflammatory injury were myeloperoxidase (MPO) content and leak of albumin into lung. Inflammatory injury was similar in WT and eNOS(-/-) mice but was substantially increased in iNOS(-/-) mice. Bronchoalveolar lavage (BAL) fluids of iNOS(-/-) and WT mice showed similar levels of CXC chemokines (MIP-2, KC) but enhanced levels of CC chemokines (MCP-1, MCP-3). Increased lung content of MPO in iNOS(-/-) mice was reduced by anti-MCP-1 to values found in WT mice. In vitro stimulation of microvascular endothelial cells with LPS and IFN gamma revealed elevated production of CXC and CC chemokines in cells from iNOS(-/-) mice when compared to endothelial cells from iNOS(+/+) mice. Peritoneal macrophages from iNOS(-/-) donors also revealed increased production of CC chemokines after stimulation with LPS and interferon (IFN gamma). These data indicate that absence of iNOS causes enhanced lung inflammatory responses in mice which may be related to enhanced production of MCP-1 by endothelial cells and macrophages. It appears that iNOS affects the lung inflammatory response by regulating chemokine production.