Each type of cause that initiates rheumatoid arthritis or RA flares differentially affects the response to therapy.

The autoimmune disease rheumatoid arthritis (RA) presents difficulty in diagnosis, commonly observed flare ups, polycyclical nature of RA progression, and variable response to therapies. Congruent with multiple causes, literature has documented various infectious agents, environmental factors, physical trauma, silica and food sensitivities as potential causes of RA or RA flares in different populations. We propose that these>36 events can initiate RA or RA flares which complicates treatment decisions. Each pharmaceutical medicine benefits 15-82% of RA patients. Predictive factors are needed. Because the initiating cause of RA or RA flare affects the type of joint damage, initial inflammatory response, adaptive immune response, and potential molecular mimicry, we propose the "RA cause affects response to therapy" (RACART) theory. The potential cause combined with confounding factors such as genetic risk factors, nutritional status, epigenetic status, inflammatory levels, and detoxification ability may help predict responses to various therapies.

An E2F-responsive replication-selective adenovirus targeted to the defective cell cycle in cancer cells: potent antitumoral efficacy but no toxicity to normal cell.

To improve the transduction and distribution of adenovirus in a tumor mass, we generated an adenovirus to selectively replicate in tumors. We hypothesized that after infection the replicating adenovirus would spread throughout the tumor mass and cause direct oncolysis of tumor cells. E2F transcription factors are critical regulators of cell growth and are often overexpressed in cancer cells because of the frequent aberrations in the pRb/E2F/p16(INK4a) pathway. As a result, a majority of tumor cells exist in a high proliferative state. E2F-1 is a transcription factor that activates its own transcription and that of other genes involved in the G(1) to S transition phase of the cell cycle. We constructed an adenovirus (Ad(E2F-1(RC)) so that E1A expression and viral replication were under the control of the human E2F-1 promoter element. AdE2F-1(RC) virus replicated as efficiently as the wild-type adenovirus and caused extensive cell killing in a panel of tumor cells in vitro. In contrast, nonproliferating normal epithelial, fibroblast, and endothelial cells, which express no E2F-1, were not able to support AdE2F-1(RC) replication. In animal studies, different dosing regimens of AdE2F-1(RC) administered to flank xenografts of ovarian and lung cancers led to a significant therapeutic advantage often surpassing that seen in animals treated with the wild-type adenovirus. This novel selectively replicating adenovirus offers a promising treatment platform for a variety of cancers of which the hallmark is uncontrolled cell growth.

Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation.

Herpes simplex virus type 1 (HSV-1)-based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV-1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV-1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV-1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose-dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency-dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication-selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low-dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low-dose radiation further potentiated the effect. These results suggest that replication-selective HSV-1 mutants may be potent oncolytic agents for the treatment of cervical cancer.