Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts.

Blockade of mammalian target of rapamycin (mTOR) is a promising area in breast cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in breast cancer was modest. Biomarker studies designed to identify the responders of rapalogs are of increasing interest. We validated p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs. We also analyzed the correlation between rapamycin activity and p27KIP1 expression in the primary breast cancer cells and the patient-derived breast tumor xenograft models. The cells isolated from the breast tumor tissues expressing high levels of p27KIP1 were sensitive to rapamycin, whereas the cells from the tissues expressing low levels of p27KIP1 exhibited resistance to rapamycin. The correlation between p27KIP1 expression and rapamycin antitumor activity was also observed in the patient-derived breast tumor xenograft models. Moreover, we also found rapamycin significantly decreased phosphorylated p70S6K1 and phosphorylated 4EBP1 in both samples. It seemed that the different sensitivity of tumor cells to rapamycin did not owe to its different potency against mTOR activity. We further propose p27KIP1 expression level may be also a candidate predictive biomarker of rapalogs for breast cancer therapy, which requires additional clinical validation.

Prevalence, isolation, and partial sequence analysis of hepatitis E virus from domestic animals in China.

Evidence that hepatitis E is zoonotic is accumulating. Serum samples were collected from pigs, cattle, and goats from various regions of China to determine whether they had been infected with hepatitis E virus (HEV). An in-house enzyme immunoassay (EIA) and reverse transcriptase-polymerase chain reaction (RT-PCR) with primers from open reading frame (ORF) 2 were used to detect anti-HEV antibodies and HEV RNA. The mean positivity rates of anti-HEV antibody for pigs and cattle were 78.8% and 6.3% but none of the goat sera were positive. Pigs may be more susceptible to infection with HEV than cattle or goats. Five of 263 pig sera were positive for HEV RNA and four of these five were also positive for anti-HEV. The PCR products (nt 6007-6354) were cloned and sequenced and compared to other HEV sequences in the nucleotide databases. The five sequences shared 83-93% identity to each other at the nucleotide level and 74-79%, 73-74%, 73-78%, and 83-99% identity to HEV genotypes 1, 2, 3, and 4, respectively. They were closely related to human isolates of HEV genotype 4. Phylogenetic analyses also place these swine sequences in HEV genotype 4, resembling most closely viruses isolated from Chinese patients with acute hepatitis. These data support the hypothesis that sporadic hepatitis E in China is zoonotic.