Phase I study of combined therapy with vorinostat and gefitinib to treat BIM deletion polymorphism-associated resistance in EGFR-mutant lung cancer (VICTROY-J) : a study protocol

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism

Phase I/II study of alectinib in lung cancer with RET fusion gene : study protocol

Background : The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. Methods/Design : RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. Conclusion : This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Morbidity and Mortality Rates in Okinawan Japanese vs. Mainland Japanese: The Honolulu Heart Program

Eight thousand and six American men of Japanese ancestry agreed to participate in a prospective cohort study of coronary heart disease, cerebrovascular disease and cancer in Hawaii. This Honolulu cohort is part of a larger, tripartite investigation taking place in Japan, Hawaii, and the U.S. mainland and is designed to study the influence of East-to-West migration on a genetically homogeneous group of Japanese men. Baseline data on physical, medical, socio-cultural, dietary, and family information were collected as were factors associated with the risk to, and manifestation of, disease outcome. To observe whether regional differences in Japan may be reflected in the experience of migrants to Hawaii, 10-year incidence and mortality of coronary heart disease (CHD) and cerebrovascular disease (CVA) were compared between subgroups according to ancestral origin in Okinawa Prefecture or in other Japanese prefectures. Somewhat higher serum cholesterol (p \u3c 0.04) and a greater body mass index (p \u3c 0.0001) in the men with ancestral origin in Okinawa prefecture were found. CHD incidence and mortality were similar, but stroke incidence (p \u3c 0.05) was modestly higher in the men of Okinawan ancestry. These analyses indicate that region of ancestral origin in Japan is unlikely to have played a major role in the incidence of CHD and stroke following immigration to Hawaii