After the systemic administration of adenoviral vectors, most of the virus ends up in the liver. When adenoviral replication is not strictly restricted to certain cell types or tissues, severe liver damage might occur due to adenoviral replication and consequential lysis of the liver cells. Because of this importance to restrict adenoviral replication, solutions have to be found for the observed aspecific replication of CRAds. One solution is a double-controlled conditionally replicating adenovirus (dcCRAd). In a dcCRAd not one but two replication essential genes are controlled by two tumor-specific promoters. For example, both the adenoviral E1A and E1B genes have been placed under the control of two different tumor-specific promoters. Also, studies have already been conducted with both the E1A and the E4 gene under control of two different tumor-specific promoters.1-9-1 E1A, E1B, and E4 are all examples of adenoviral genes that are essential for replication of the adenovirus. The approach of a dcCRAd preferentially includes a more general promoter. For example, the telomerase promoter which has shown activity in more than 80% of all tumors and which is inactive in liver cells. The telomerase promoter might work in concert with a tissue-specific promoter such as the tyrosinase promoter to restrict the expression of two genes essential for adenoviral replication. Only in melanoma cells which contain both telomerase and tyrosinase activity will replication occur.
Another approach for designing a dcCRAd is to combine a type I and a type II CRAd. On one hand, these adenoviruses contain a deletion in the adenoviral genome to prevent replication in cells without a disturbed cell cycle. On the other hand, these viruses also contain a tumor-specific promoter to restrict the expression of adenoviral genes essential for replication to cells where this promoter is active.
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The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.