Benefits of Pharmacogenomics in Drug Development—Earlier Launch of Drugs and Less Adverse Events

Currently, pharmaceutical companies are reluctant to introduce pharmacogenomics (PGx) in their practice, since cost–benefit of PGx is obscure and methodology to use PGx in drug development has not been fully established yet. The purpose of this study is to investigate advantages obtained by introducing PGx in clinical trials. Particularly, taking Warfarin as an example, we investigate benefits of Enrichment effect that raises response rate of the drug by PGx. When response rate is raised by only 5%, cost of a clinical trial can be reduced to about 40% of a conventional clinical trial. Furthermore, since period necessary for a trial also can be reduced, development period can be shortened by about 750 days. In summary, PGx enables earlier launch of a drug with less cost, representing benefit to pharmaceutical companies, patients and public as a whole.     

Long-term preserved renal function of a patient with mass-forming granulomatous interstitial nephritis by biopsy-based steroid therapy

In 2001, a 41-year-old Japanese woman was referred to our hospital because of severe renal dysfunction and fever of unknown origin. On admission, her serum creatinine was 8.7 mg/dL, urine protein was 0.3 g/day, and urine β₂-microglobulin was 81,007 μg/day. Computed tomography (CT) scans showed bilateral contracted kidneys with a mass projecting from the lower pole of the right kidney. Biopsy of this lesion revealed interstitial nephritis and a noncaseating granuloma. Because extrarenal organ involvement or laboratory findings specific for sarcoidosis or other primary diseases were not detected, idiopathic granulomatous interstitial nephritis (GIN) was diagnosed. Prednisolone was started at dosage of 30 mg daily, and serum creatinine decreased to 5.5 mg/dL after 1 month. Her renal function was preserved for 8 years, but maintenance hemodialysis had to be started in 2009. A surgical specimen obtained after initiation of dialysis showed resolution of GIN in the renal mass lesion, which presumably resulted in preservation of renal function over the long term. Even in patients with severe renal dysfunction, histological diagnosis of GIN might lead to prognostic improvement because of appropriate therapeutic intervention.     

A new target for therapy in squamous cell carcinoma of the lung

Investigators report the identification of novel somatic mutations in the DDR2 kinase gene in squamous cell carcinoma of the lung. Cellular, biochemical, and human data suggest that tumor cells harboring DDR2 mutations have increased sensitivity to existing tyrosine kinase inhibitors, providing rationale for clinical trials of agents that inhibit DDR2 kinase in the disease.     

Oxidized ATP inhibits T‐cell‐mediated autoimmunity

T cells directed against self antigens play an important role in several autoimmune diseases. The available immunosuppressive compounds used to treat autoimmune diseases are limited, and often they have side effects that limit their application. T cells express ATP receptors, which could be new target molecules to treat autoimmune disease. Here we analyzed the effect of oxidized ATP (oxATP), an inhibitor of the ATP receptor P2rx7, in different murine models of T‐cell‐mediated autoimmune diseases. Treatment with oxATP inhibited proliferation and effector function of T cells. In the systems we used, oxATP did not obviously interfere with the innate immune response, but strongly reduced antigen‐specific T‐cell responses. This treatment ameliorated T‐cell‐mediated autoimmune type I diabetes and autoimmune encephalitis in mice. In conclusion, oxATP was found to strongly inhibit activated T cells and could thus be used to target T‐cell‐mediated autoimmune disease.     

Spontaneous uterine rupture of a twin pregnancy after a laparoscopic adenomyomectomy: a case report

Adenomyomectomy is a treatment option to preserve fertility and reduce symptoms associated with adenomyosis. Although this procedure is reasonably expected to increase the risk of uterine rupture during pregnancy, reports on this issue are scarce. We recently encountered a 33-year-old nulliparous woman with a twin pregnancy who experienced a spontaneous uterine rupture at 30 weeks' gestation. This patient was the first to conceive after undergoing laparoscopic adenomyomectomy at our institution. Her pregnancy was established with in vitro fertilization-embryo transfer 12 months after laparoscopic adenomyomectomy. The uterine rupture was heralded by a sudden onset of severe abdominal pain while she was receiving intravenous ritodrine. This case reinforces that pregnancy after adenomyomectomy should be closely monitored with respect to uterine rupture.     

Estimation of the species-specific mutation rates at the DRB1 locus in humans and chimpanzee

To estimate the species-specific mutation rates at the DRB1 locus in humans and chimpanzee, we analyzed the nucleotide sequence of a 37.6-kb chimpanzee chromosomal segment containing the entire Patr-DRB1*0701 allele and the flanking nongenic region and we compared it with two corresponding human sequences containing the HLA-DRB1*070101 allele using the sequence of HLA-DRB1*04011 as an outgroup. Because the allelic pair of HLA-DRB1*070101 and Patr-DRB1*0701 shows the lowest number of substitutions between the two species, it appears that these sequences diverged close to the time of the humans-chimpanzee divergence (6 million years ago). Alignment of the nucleotide sequences for HLA-DRB1*070101 and Patr-DRB1*0701 alleles showed that they share a high degree of similarity, suggesting that the studied chromosomal segments with these sequences have not been subjected to recombination since the humans-chimpanzee divergence. Comparison of the flanking 10.6 kb of nongenic sequences revealed an average of 41.5 and 83 single nucleotide substitutions in humans and chimpanzee, respectively. Thus, the species-specific nucleotide substitution rates in the flanking nongenic region were estimated to be 6.53 x 10(-10) and 1.31 x 10(-9) per site per year in humans and chimpanzee, respectively. Unexpectedly, the estimated rate in humans was twofold lower than in chimpanzee (P < 10(-3), Tajima's relative rate test) and lower than the average substitution rate in the human genome. Because the nucleotide substitution rate in nongenic regions free from selection is expected to be equal to the mutation rate, the estimated substitution rate should correspond to the species-specific mutation rate at the DRB1 locus. Our results strongly suggest that the mutation rate at DRB1 locus differs among species.     

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1cm, 1-2 cm, and ≥2 cm in diameter, respectively, were analyzed. Of the 24 tumors ≤2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p<0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p=0.017). In the tumors ≤2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p=0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n=17) and 82% of the wild-type tumors (n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued.