Striking efficacy of a vaccine targeting TOP2A for triple-negative breast cancer immunoprevention.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has a poor prognosis. TOP2A is a key enzyme in DNA replication and is a therapeutic target for breast and other cancers. TOP2A-specific Th1-promoting epitopes with optimal binding affinity to MHC II were identified using a combined scoring system. The multi-peptide TOP2A vaccine elicited a robust immunologic response in immunized mice, as demonstrated by the significant production of Th1 cytokines from immunized animals' splenocytes stimulated in vitro with TOP2A peptides. Anti-tumor efficacy of the TOP2A vaccine was demonstrated in a syngeneic TNBC mouse model, in which pre-graft preventive vaccination was associated with significantly decreased tumor growth as compared to adjuvant control. In a genetically engineered mouse (GEM) model of TNBC, vaccinated animals demonstrated a significant reduction in tumor incidence and average tumor volume compared to adjuvant control. Finally, we examined TCR sequences in CD4 tumor Infiltrating lymphocytes (TIL) from vaccinated mice and found that the TIL contained TCR sequences specific to the three vaccine peptides. These data indicate that our newly developed multi-peptide TOP2A vaccine is highly immunogenic, elicits TILs with vaccine specific TCRs, and is highly effective in preventing and intercepting TNBC development and progression in vivo.

Functional Haplotype and eQTL Analyses of Genes Affecting Cadmium Content in Cultivated Rice.

BACKGROUND: Rice is a major food resource for Asian countries including Korea. However, most Asian countries are facing food safety problems due to cropland contamination by heavy metals. Thus, this study was conducted to investigate genetic factors affecting the expression of cadmium (Cd) gene, and to confirm differences in Cd translocation among cultivars because the current molecular understanding of Cd uptake-transport mechanisms remains insufficient. Associations between genotypes and gene expression level of Cd-related genes such as NRAMP, MTP, and HMA gene families in the rice core collection were analyzed at the genomic level. RESULTS: Os01g0956700, Os05g0128400 and Os11g0485200 showed strong associations between expression level and genotype in the rice core collection, the regulatory factors that associated with these genes in cis and trans were founded. The association between the expression level and genotype of the candidate gene (Os01g0611300: metal tolerance protein) predicted to affect Cd content in rice by a previous genome-wide association study (GWAS) was also analyzed. Furthermore, as a result of the phylogeny and haplotype analyses of the candidate gene, high-Cd tolerance cultivars were selected. The correlations between Cd and other inorganic components (Mg, Mn, Fe, Cu and Zn) in the roots, stems, leaves and unpolished grain of selected rice cultivars were analyzed. CONCLUSION: Therefore, these results may be useful for understanding the uptake-transport mechanisms of Cd and other inorganic components via molecular genetics and may help rice breeders develop new low-Cd cultivars in the near future.

Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer in Mice.

Bexarotene has shown inhibition of lung and mammary gland tumorigenesis in preclinical models and in clinical trials. The main side effects of orally administered bexarotene are hypertriglyceridemia and hypercholesterolemia. We previously demonstrated that aerosolized bexarotene administered by nasal inhalation has potent chemopreventive activity in a lung adenoma preclinical model without causing hypertriglyceridemia. To facilitate its future clinical translation, we modified the formula of the aerosolized bexarotene with a clinically relevant solvent system. This optimized aerosolized bexarotene formulation was tested against lung squamous cell carcinoma mouse model and lung adenocarcinoma mouse model and showed significant chemopreventive effect. This new formula did not cause visible signs of toxicity and did not increase plasma triglycerides or cholesterol. This aerosolized bexarotene was evenly distributed to the mouse lung parenchyma, and it modulated the microenvironment in vivo by increasing the tumor-infiltrating T cell population. RNA sequencing of the lung cancer cell lines demonstrated that multiple pathways are altered by bexarotene. For the first time, these studies demonstrate a new, clinically relevant aerosolized bexarotene formulation that exhibits preventive efficacy against the major subtypes of lung cancer. This approach could be a major advancement in lung cancer prevention for high risk populations, including former and present smokers.

Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer.

Gefitinib showed response in phase II clinical trials and with better clinical response in lung cancer with activating mutations in the tyrosine kinase domain of the EGFR. Questions of toxicity and potential dosing regimens impede the use in a prevention setting. This study will provide scientific evidence for the utility of testing and comparing weekly and daily dosing regimens in clinical trials. We employed the adenocarcinoma (AD) and squamous cell carcinoma (SCC) models to compare the efficacy of Gefitinib in daily or weekly dosing regimens. We also assessed the effectiveness of Gefitinib in altering growth of the H3255 xenograft. Bioluminescent imaging (BLI) and tumor size was evaluated. Relative expression of phospho-EGFR, phospho-ERK and phospho-AKT in the xenograft were evaluated by Western Blot analysis. In the lung AD model, Gefitinib showed significant inhibition of tumor load when treated with weekly or weekly intermittent dosing regimens in AJ/p53 val135/wt mice whereas a daily dosing regimen did not decrease the tumor load significantly. In the H3255-Luciferase xenograft model, weekly treatment demonstrated better inhibition than daily treatment. The weekly dosing regimen exhibited greater inhibition of phospho-EGFR, phospho-ERK and phospho-AKT than the daily dosing regimen, which may be correlated with the antitumor effects of the different dosing regimens. Weekly dosing with Gefitinib had similar or better efficacy than the daily dosing regimen in pre-clinical models of NSCLC. The data provide scientific evidences for the utility of testing and comparing weekly and intermittent dosing regimens in clinical trials.

Idiopathic thoracic epidural lipomatosis with chest pain.

Spinal epidural lipomatosis (SEL) is an overgrowth of the normally encapsulated adipose tissue in the epidural space around the spinal cord in the thoracic and lumbar spine causing compression of the neural components. Idiopathic SEL in non-obese patients is exceptional. Idiopathic SEL can result in thoracic myelopathy and lumbar radiculopathy. A thoracic radiculopathy due to idiopathic SEL has not been reported yet. We report a case of idiopathic SEL with intractable chest pain and paresthesia. We suggest that idiopathic SEL should be considered as a cause of chest pain.

Synthesis and antitumor activity of novel thermosensitive platinum(II)-cyclotriphosphazene conjugates.

Thermosensitive cyclotriphosphazenes bearing alkoxy poly(ethylene glycol) and amino acid esters as side groups could be functionalized to chelate the antitumor (diamine)platinum(II) moiety through the dicarboxylate group of the amino acid substituent on the cyclic phosphazene ring. Surprisingly, like the precursor cyclotriphosphazenes, these (diamine)platinum(II)-cyclotriphosphazene conjugates were also found to exhibit variable lower critical solution temperatures (LCST) in the wide range of 12 to 92 degrees C. Furthermore, the present conjugates have shown outstanding in vitro and in vivo antitumor activities due to controlled release of the antitumor (diamine)platinum(II) moiety with hydrolytic degradation of the phosphazene ring. A few of these conjugates have shown LCSTs below body temperature, and it has been shown from a model animal experiment that the conjugates with a LCST below body temperature may be applied to local drug delivery by direct intratumoral injection.