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This research aimed to characterize and compare the subchronic impacts of Cu to a Cu, Cd, and Zn mixture in early life stages of rainbow trout (Oncorhynchus mykiss) by examining uptake, survival, growth, development, and histopathology parameters. To accomplish this, rainbow trout were exposed for 31 days from eyed embryos to the swim-up fry life stage to waterborne Cu (31, 47, 70, and 104 μg/L) individually or as mixture containing Cd (4.1, 6.2, 9.3, and 14 μg/L) and Zn (385, 578, 867, and 1300 μg/L). Exposures elicited pronounced effects on survival when Cu was administered as a mixture (LC 25  = 32.9 μg/L Cu) versus individually (LC 25  = 46.3 μg/L Cu). Mixtures of Cu, Cd, and Zn also elicited more pronounced sublethal toxicity relative to equivalent Cu treatments with respect to reduced yolk sac resorption and increased incidence and/or severity of gill, liver, and kidney lesions. Our findings of reduced body weight (EC 10, Cu  = 55.0 μg/L Cu; EC 10, Cu+Cd+Zn  = 58.9 μg/L Cu), yolk sac resorption (LOEC Cu  = 70 μg/L Cu; LOEC Cu+Cd+Zn  = 70 μg/L Cu), coelomic fat (LOEC Cu  = 47 μg/L Cu; LOEC Cu+Cd+Zn  = 70 μg/L Cu), and increased hepatocellular cytoplasmic vacuolation (LOEC Cu  = 70 μg/L Cu; LOEC Cu+Cd+Zn  = 47 μg/L Cu) collectively indicate a complicated metabolic interference by metals in exposed fish. These lethal and sublethal effects observed in the laboratory could translate to reduced survival and fitness of wild salmonid populations inhabiting waterbodies receiving wastewater or runoff containing multiple metals at elevated concentrations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. Dicer is phosphorylated by the ERK-MAP kinase pathway and because this pathway is activated in human cancers, we asked whether phosphorylated Dicer1 contributed to tumor development. In human endometrioid cancers, we discovered that phosphorylated DICER1 is significantly associated with invasive disease. To test a direct involvement of Dicer1 phosphorylation in tumor development, we studied mice with phosphomimetic alterations at the two conserved serines phosphorylated by ERK and discovered that a phosphomimetic Dicer1 drives tumor development and dissemination in two independent murine cancer models ( KRas +/LA1 and p53 +/- ). Our findings demonstrate that phosphomimetic Dicer1 promotes tumor development and invasion. SIGNIFICANCE: This work highlights the relevance of Dicer1 phosphorylation in mammalian tumor development and dissemination., (©2019 American Association for Cancer Research.)

When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half ( P = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. SIGNIFICANCE: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2327/F1.large.jpg., (©2019 American Association for Cancer Research.)

DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1 S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals., Competing Interests: The authors declare no conflict of interest.

Lung adenocarcinoma is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma-promoting histone methylation reader protein show that heterochromatin protein 1γ (HP1γ; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human lung adenocarcinoma, and that high HP1γ mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. In vivo depletion of HP1γ reduced K-Ras G12D -driven lung adenocarcinoma and lengthened survival of mice bearing K-Ras G12D -induced lung adenocarcinoma. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma cells. HP1γ directly repressed expression of the transcription-repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1γ-depleted lung adenocarcinoma cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high HP1γ mRNA levels in lung adenocarcinoma samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1γ and its reader activity in lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma-promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes. Significance: Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1γ leads to activation of protumorigenic genes in lung adenocarcinoma. Cancer Res; 78(14); 3834-48. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions, but the source of the osteoblastic lesions remains unclear. We show that the tumor-induced bone derives partly from tumor-associated endothelial cells that have undergone endothelial-to-osteoblast (EC-to-OSB) conversion. The tumor-associated osteoblasts in PCa bone metastasis specimens and patient-derived xenografts (PDXs) were found to co-express endothelial marker Tie-2. BMP4, identified in PDX-conditioned medium, promoted EC-to-OSB conversion of 2H11 endothelial cells. BMP4 overexpression in non-osteogenic C4-2b PCa cells led to ectopic bone formation under subcutaneous implantation. Tumor-induced bone was reduced in trigenic mice (Tie2 cre /Osx f/f /SCID) with endothelial-specific deletion of osteoblast cell-fate determinant OSX compared with bigenic mice (Osx f/f /SCID). Thus, tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa., (Copyright © 2017 Elsevier Inc. All rights reserved.)

For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations.

Background: Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M) or Bangladesh (NiV-B)., Methodology/principal Findings: Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi). Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi., Conclusions/significance: Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central nervous system pathology., Competing Interests: The authors have declared that no competing interests exist.

Middle East respiratory syndrome coronavirus (MERS-CoV) was initially isolated from a Saudi Arabian man with fatal pneumonia. Since the original case in 2012, MERS-CoV infections have been reported in >1500 humans, and the case fatality rate is currently 35%. This lineage C betacoronavirus has been reported to cause a wide range of disease severity in humans, ranging from asymptomatic to progressive fatal pneumonia that may be accompanied by renal or multiorgan failure. Although the clinical presentation of human MERS-CoV infection has been documented, many facets of this emerging disease are still unknown and could be studied with animal models. Several animal models of MERS-CoV have been developed, including New Zealand white rabbits, transduced or transgenic mice that express human dipeptidyl peptidase 4, rhesus macaques, and common marmosets. This review provides an overview of the current state of knowledge on human MERS-CoV infections, the probable origin of MERS-CoV, and the available animal models of MERS-CoV infection. Evaluation of the benefits and limitations of these models will aid in appropriate model selection for studying viral pathogenesis and transmission, as well as for testing vaccines and antivirals against MERS-CoV., (© The Author(s) 2016.)

Nipah virus is a paramyxovirus in the genus Henipavirus, which has caused outbreaks in humans in Malaysia, India, Singapore, and Bangladesh. Whereas the human cases in Malaysia were characterized mainly by neurological symptoms and a case fatality rate of ∼40%, cases in Bangladesh also exhibited respiratory disease and had a case fatality rate of ∼70%. Here, we compared the histopathologic changes in the respiratory tract of Syrian hamsters, a well-established small animal disease model for Nipah virus, inoculated oronasally with Nipah virus isolates from human cases in Malaysia and Bangladesh. The Nipah virus isolate from Bangladesh caused slightly more severe rhinitis and bronchointerstitial pneumonia 2 days after inoculation in Syrian hamsters. By day 4, differences in lesion severity could no longer be detected. Immunohistochemistry demonstrated Nipah virus antigen in the nasal cavity and pulmonary lesions; the amount of Nipah virus antigen present correlated with lesion severity. Immunohistochemistry indicated that both Nipah virus isolates exhibited endotheliotropism in small- and medium-caliber arteries and arterioles, but not in veins, in the lung. This correlated with the location of ephrin B2, the main receptor for Nipah virus, in the vasculature. In conclusion, Nipah virus isolates from outbreaks in Malaysia and Bangladesh caused a similar type and severity of respiratory tract lesions in Syrian hamsters, suggesting that the differences in human disease reported in the outbreaks in Malaysia and Bangladesh are unlikely to have been caused by intrinsic differences in these 2 virus isolates., (© The Author(s) 2014.)

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease that recapitulates mild to moderate human MERS-CoV cases. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.

In 2012 a novel coronavirus, MERS-CoV, associated with severe respiratory disease emerged in the Arabian Peninsula. To date, 55 human cases have been reported, including 31 fatal cases. Several of the cases were likely a result of human-to-human transmission. The emergence of this novel coronavirus prompts the need for a small animal model to study the pathogenesis of this virus and to test the efficacy of potential intervention strategies. In this study we explored the use of Syrian hamsters as a small animal disease model, using intratracheal inoculation and inoculation via aerosol. Clinical signs of disease, virus replication, histological lesions, cytokine upregulation nor seroconversion were observed in any of the inoculated animals, indicating that MERS-CoV does not replicate in Syrian hamsters.