Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

Background:Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.Methodology/Principal Findings:Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.Conclusions/Significance:Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug. © 2014 Caroline et al

MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells

Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem cells

The effects of endogenous and exogenous androgens on cardiovascular disease risk factors and progression

Cardiovascular disease incidence rates have long been known to significantly differ between the two sexes. Estrogens alone fail to explain this phenomenon, bringing an increasing amount of attention to the role of androgens. Contrary to what was initially hypothesized, androgens seem to have an overall cardioprotective effect, especially in men. Recent studies and published data continue to support this notion displaying a consistent inverse correlation with atherosclerosis progression and cardiovascular disease both in regressive and prospective study models. Clinical studies have also revealed what seems to be a differential androgenic effect on various cardiovascular risk factors between men and women. Further insight indicates that in order to avoid confusion it may be also preferable to separately examine the effects of endogenous androgen levels from exogenous testosterone administration, as well as discern the differential results of low to normal and supraphysiological administration doses. This review summarizes old and recent data according to the above distinctions, in an attempt to further our understanding of the role of androgens in cardiovascular disease

Sharing a Polluted River Network

A polluted river network is populated with agents (e.g., firms, villages, municipalities, or countries) located upstream and downstream. This river network must be cleaned, the costs of which must be shared among the agents. We model this problem as a cost sharing problem on a tree network. Based on the two theories in international disputes, namely the Absolute Territorial Sovereignty (ATS) and the Unlimitted Territorial Integrity (UTI), we propose three different cost sharing methods for the problem. They are the Local Responsibility Sharing (LRS), the Upstream Equal Sharing (UES), and the Downstream Equal Sharing (DES), respectively. The LRS and the UES generalize Ni and Wang ("Sharing a polluted river", Games Econ. Behav., 60 (2007), 176-186) but the DES is new. The DES is based on a new interpretation of the UTI. We provide axiomatic characterizations for the three methods. We also show that they coincide with the Shapley values of the three different games that can be defined for the problem. Moreover, we show that they are in the cores of the three games, respectively. Our methods can shed light on pollution abatement of a river network with multiple sovereignties

Update on hepatitis E virology: Implications for clinical practice.

Hepatitis E virus (HEV) is a positive-strand RNA virus transmitted by the fecal-oral route. The 7.2kb genome encodes three open reading frames (ORF) which are translated into (i) the ORF1 polyprotein, representing the viral replicase, (ii) the ORF2 protein, corresponding to the viral capsid, and (iii) the ORF3 protein, a small protein involved in particle secretion. Although HEV is a non-enveloped virus in bile and feces, it circulates in the bloodstream wrapped in cellular membranes. HEV genotypes 1 and 2 infect only humans and cause mainly waterborne outbreaks. HEV genotypes 3 and 4 are widely represented in the animal kingdom and are transmitted as a zoonosis mainly via contaminated meat. HEV infection is usually self-limited but may persist and cause chronic hepatitis in immunocompromised patients. Reduction of immunosuppressive treatment or antiviral therapy with ribavirin have proven effective in most patients with chronic hepatitis E but therapy failures have been reported. Alternative treatment options are needed, therefore. Infection with HEV may also cause a number of extrahepatic manifestations, especially neurologic complications. Progress in the understanding of the biology of HEV should contribute to improved control and treatment of HEV infection

Ribavirin Inhibits In Vitro Hepatitis E Virus Replication through Depletion of Cellular GTP Pools and Is Moderately Synergistic with Alpha Interferon

Hepatitis E virus (HEV) is a common cause of acute hepatitis that results in high mortality in pregnant women and may establish chronic infections in immunocompromised patients. We demonstrate for the first time that alpha interferon (IFN-alpha) and ribavirin inhibit in vitro HEV replication in both a subgenomic replicon and an infectious culture system based on a genotype 3 strain. IFN-alpha showed a moderate but significant synergism with ribavirin. These findings corroborate the reported clinical effectiveness of both drugs. In addition, the antiviral activity of ribavirin against wild-type genotype 1, 2, and 3 strains was confirmed by immunofluorescence staining. Furthermore, the in vitro activity of ribavirin depends on depletion of intracellular GTP pools, which is evident from the facts that (i) other GTP-depleting agents (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide [EICAR] and mycophenolic acid) inhibit viral replication, (ii) exogenously added guanosine reverses the antiviral effects, and (iii) a strong correlation (R-2 = 0.9998) exists between the antiviral activity and GTP depletion of ribavirin and other GTP-depleting agents