Background: There is little published evidence on the gastrointestinal features of COVID-19. Aims:To report on the gastrointestinal manifestations and pathological findings of patients with COVID-19, and to discuss the possibility of faecal transmission. Methods:We have reviewed gastrointestinal features of, and faecal test results in, COVID-19 from case reports and retrospective clinical studies relating to the digestive system published since the outbreak.

Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/ secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45 min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6-9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.direct-acting antiviral agents | mathematical modeling | viral dynamics H epatitis C virus (HCV) infection is a major health burden affecting about 150 million people worldwide (1) and ∼4.1 million in the United States (2), where it is the primary cause of liver cirrhosis and liver cancer (1). Until 2011, the most advanced antiviral therapy was pegylated interferon-α (IFN-α) plus ribavirin (Peg-IFN/RBV), with a cure rate of 50% or less in patients infected with HCV genotype 1, the most prevalent in the Western world.To obtain higher cure rates, drug development has focused mainly on inhibiting the function of nonstructural (NS) viral proteins with known enzymatic functions, such as the NS3-4A protease and the NS5B polymerase. Through the use of an innovative screening approach to search for nonenzymatic targets, daclatasvir (BMS-790052) was identified as a potent NS5A inhibitor (3). The functions of the NS5A protein are not fully elucidated, although in vitro studies suggest an essential role of NS5A in both viral replication (4-7) and assembly/release of infectious particles (8-11). The efficacy of daclatasvir as an antiviral agent was confirmed in a single ascending-dose study in which a mean 3.3-log 10 reduction in viral load 24 h after drug administration was observed in patients receiving a 1...

Approximately 170 million people worldwide are infected with hepatitis C virus (HCV). Current standard therapy leads to sustained viral elimination in only about 50% of patients treated. Telaprevir, a novel HCV protease inhibitor, has demonstrated substantial antiviral activity in patients with chronic HCV infection. However, drug-resistant variants emerge at frequencies of 5 to 20% of the total virus population as early as the second day after treatment initiation. Here, using probabilistic and viral dynamic models, we show that such rapid emergence of drug resistance is expected. We calculate that all possible single and double mutant viruses preexist before treatment, and that one additional mutation is expected to arise during therapy. Examining data from a clinical trial of telaprevir therapy for HCV infection in detail, we show that our model fits the observed dynamics of both drug-sensitive and -resistant viruses, and argue that combination therapy of direct antivirals will require drug combinations that have a genetic barrier of four or more mutations.