Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response.

Dysregulation of the ErbB family of receptor tyrosine kinases is involved in the progression of many cancers. Antibodies targeting the dimerization domains of family members EGFR and HER2 are approved cancer therapeutics, but efficacy is restricted to a subset of tumors and resistance often develops in response to treatment. A third family member, HER3, heterodimerizes with both EGFR and HER2 and has also been implicated in cancer. Consequently, there is strong interest in developing antibodies that target HER3, but to date, no therapeutics have been approved. To aid the development of anti-HER3 antibodies as cancer therapeutics, we combined antibody engineering and functional genomics screens to identify putative mechanisms of resistance or synthetic lethality with antibody-mediated anti-proliferative effects. We developed a synthetic antibody called IgG 95, which binds to HER3 and promotes ubiquitination, internalization, and receptor down-regulation. Using an shRNA library targeting enzymes in the ubiquitin proteasome system, we screened for genes that effect response to IgG 95 and uncovered the E3 ubiquitin ligase RNF41 as a driver of IgG 95 anti-proliferative activity. RNF41 has been shown previously to regulate HER3 levels under normal conditions and we now show that it is also responsible for down-regulation of HER3 upon treatment with IgG 95. Moreover, our findings suggest that down-regulation of RNF41 itself may be a mechanism for acquired resistance to treatment with IgG 95 and perhaps other anti-HER3 antibodies. Our work deepens our understanding of HER3 signaling by uncovering the mechanistic basis for the anti-proliferative effects of potential anti-HER3 antibody therapeutics.

Kyo-Green improves sexual dysfunction in men and women.

BACKGROUND: Serendipitously, we discovered the effects of Kyo-Green, a green powdered nutritional supplement, on improving sexual dysfunctions in both men and women. In this paper, we presented two case reports and an open-labeled pilot study involving 40 subjects for a period of three months to determine the effects of Kyo-Green on sexual dysfunctions. MATERIAL/METHODS: Twenty-five men and 15 women were enrolled into this study. All the male subjects had suffered erectile dysfunction (ED). All the female subjects reported lack of libido. Subjects took one teaspoonful of Kyo-Green two times a day. Subjects completed a questionnaire at the beginning, and at the end of one, two, and three months while taking Kyo-Green. The analysis of data was based on the four questionnaires completed by the subjects. RESULTS: Increase of energy was reported by all the subjects. Sixteen males and 12 females reported satisfaction with their sex life after taking Kyo-Green for three months. Twenty of the 25 male subjects reported significant improvement in erectile dysfunction, and ability to initiate and maintain sexual activity with satisfaction. CONCLUSIONS: All the subjects experienced an increase of energy levels within a few weeks after taking this supplement. Eighty percent of the male subjects with ED regained erections while taking this supplement. The study suggests that Kyo-Green, particularly when used in conjunction with a lifestyle modification approach, may be useful in the management of sexual dysfunction in men and women who prefer a non-drug approach.

Pycnogenol as an adjunct in the management of childhood asthma.

A randomized, placebo-controlled, double-blind study involving 60 subjects, aged 6-18 years old, was conducted over a period of 3 months to determine the effect of Pycnogenol (a proprietary mixture of water-soluble bioflavonoids extracted from French maritime pine) on mild-to-moderate asthma. After baseline evaluation, subjects were randomized into two groups to receive either Pycnogenol or placebo. Subjects were instructed to record their peak expiratory flow with an Assess Peak Flow Meter each evening. At the same time, symptoms, daily use of rescue inhalers (albuterol), and any changes in oral medications were also recorded. Urine samples were obtained from the subjects at the end of the run-in period, and at 1-, 2-, and 3-month visits. Urinary leukotriene C4/D4/E4 was measured by an enzyme immunoassay. Compared with subjects taking placebo, the group who took Pycnogenol had significantly more improvement in pulmonary functions and asthma symptoms. The Pycnogenol group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group. There was also a significant reduction of urinary leukotrienes in the Pycnogenol group. The results of this study demonstrate the efficacy of Pycnogenol as an adjunct in the management of mild-to-moderate childhood asthma.