Identification of hepatic microvascular adhesion-related genes of human colon cancer cells using random homozygous gene perturbation.

Random homozygous gene perturbation (RHGP), in combination with liver sinusoidal endothelial cell (LSEC) adhesion screening of clonal colon cancer cells with perturbed genes, was used to identify genes contributing to the hepatic microvascular adhesion of colon cancer cells. Plasmid vector encoding transactivator and gene search vector were transfected into HT-29 human colorectal cancer cells to create a HT-29 RHGP cell library; the adhesion of these library cells to primary cultured mouse LSEC significantly decreased in the presence of RSL1 ligand (inducer), indicating that most of the genes contributing to HT-29 adhesion to LSEC were altered. Next, HT-29 RHGP cell library fractions with upregulated or silenced LSEC adhesion-related genes were isolated.

Aerobiology and its role in the transmission of infectious diseases.

Aerobiology plays a fundamental role in the transmission of infectious diseases. As infectious disease and infection control practitioners continue employing contemporary techniques (e.g.

TSG101 exposure on the surface of HIV-1 infected cells: implications for monoclonal antibody therapy for HIV/AIDS.

HIV infection remains a major global public health problem, in part because of the ability of the virus to elude antiretroviral therapies. Most conventional drugs were designed to directly target virus-encoded mechanisms. However, there is increasing appreciation that certain host-encoded molecules are comparably important for the viral life cycle and could therefore represent potential antiviral targets.

Identification of annexin A13 as a regulator of chemotherapy resistance using random homozygous gene perturbation.

Objective: To utilize a powerful new technology for target discovery, Random Homozygous Gene Perturbation (RHGP), and to identify novel targets that cause tumor cells to become chemoresistant.

Study Design: RHGP was used to identify and validate genetic changes that cause chemoresistance of tumor cells to Rapamycin.

Results: A series of targets was identified that allowed tumor cells to survive treatment with Rapamycin.

FGI-104: a broad-spectrum small molecule inhibitor of viral infection.

The treatment of viral diseases remains an intractable problem facing the medical community. Conventional antivirals focus upon selective targeting of virus-encoded targets. However, the plasticity of viral nucleic acid mutation, coupled with the large number of progeny that can emerge from a single infected cells, often conspire to render conventional antivirals ineffective as resistant variants emerge.

Identification of PTCH1 requirement for influenza virus using random homozygous gene perturbation.

Influenza infection remains a leading cause of infectious disease-mediated morbidity and mortality. Accumulating evidence indicates that most variants of seasonal and pandemic influenza have developed resistance to conventional therapies. Such information has spawned new interest in identifying novel approaches to target influenza.

Identification of novel host-oriented targets for Human Immunodeficiency Virus type 1 using Random Homozygous Gene Perturbation.

Background: Human Immunodeficiency Virus (HIV) is a global threat to public health. Current therapies that directly target the virus often are rendered ineffective due to the emergence of drug-resistant viral variants. An emerging concept to combat drug resistance is the idea of targeting host mechanisms that are essential for the propagation of the virus, but have a minimal cellular effect.

Development of a broad-spectrum antiviral with activity against Ebola virus.

We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge.

Function-first approaches to improve target identification in cancer.

Target discovery for cancer is undergoing a sort of revival with an increasing need for improved therapeutics. Likewise, the strategies to discover new and better therapeutic targets have come full circle, with greater emphasis placed upon targets that are functionally relevant to the disease process. In this article, we review the evolution of cancer target discovery and discuss random homozygous gene perturbation, an emerging technology that combines the practicality of screening for new targets by emphasizing function as the primary criterion, with cutting-edge advances in gene-based screening of all potential targets in a cell.

The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza.

Conventional approaches for therapeutic targeting of viral pathogens have consistently faced obstacles arising from the development of resistant strains and a lack of broad-spectrum application. Influenza represents a particularly problematic therapeutic challenge since high viral mutation rates have often confounded many conventional antivirals. Newly emerging or engineered strains of influenza represent an even greater threat as typified by recent interest in avian subtypes of influenza.