Koji Tomaru

Armadillo Repeat Containing 8α Binds to HRS and Promotes HRS Interaction with Ubiquitinated Proteins

Recently, we reported that a complex with an essential role in the degradation of Fructose-1,6-bisphosphatase in yeast is well conserved in mammalian cells; we named this mammalian complex C-terminal to the Lissencephaly type-1-like homology (CTLH) complex. Although the function of the CTLH complex remains unclear, here we used yeast two-hybrid screening to isolate Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) as a protein binding to a key component of CTLH complex, Armadillo repeat containing 8 (ARMc8) α. The association was confirmed by a yeast two-hybrid assay and a co-immunoprecipitation assay. The proline-rich domain of HRS was essential for the association. As demonstrated through immunofluorescence microscopy, ARMc8α co-localized with HRS. ARMc8α promoted the interaction of HRS with various ubiquitinated proteins through the ubiquitin-interacting motif. These findings suggest that HRS mediates protein endosomal trafficking partly through its interaction with ARMc8α.

Long-acting muscarinic antagonist + long-acting beta agonist versus long-acting beta agonist + inhaled corticosteroid for COPD: A systematic review and meta-analysis

Some trials have been conducted to compare long‐acting muscarinic antagonist (LAMA) + long‐acting beta agonist (LABA) versus LABA + inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), but no meta‐analysis were reported.

Vitamin D binding protein genotype variants and risk of chronic obstructive pulmonary disease: A meta‐analysis

Genetic susceptibility for development of chronic obstructive pulmonary disease (COPD) is under intensive investigation. Among the three alleles of vitamin D binding protein, or group‐specific (GC) components, some have suggested that having GC‐1F and GC‐2 alleles was associated with a risk of COPD. Although previous studies have shown considerable variance, no meta‐analysis has been conducted.

Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine

The intentional release of anthrax spores in 2001 confirmed this pathogens ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy.

The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy.

Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-β1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response.

Synchronous lung and gastric cancers successfully treated with carboplatin and pemetrexed: a case report

IntroductionLung and gastric cancers are the first and second leading causes of death from cancer worldwide, and are especially prevalent in Eastern Asia. Relatively few reports are available in relation to the treatment and outcome of synchronous lung and gastric cancers, although there are increasing numbers of patients with these cancers. Efforts to develop more effective drugs for the treatment of synchronous cancers, without serious adverse effects, have been intensifying. Pemetrexed, a multi-targeted antifolate enzyme inhibitor, was approved by the United States Food and Drug Administration as a first-line chemotherapy for advanced non-squamous non-small cell lung cancer in 2007. Although clinical activity against several tumor types of adenocarcinoma, including gastric cancer, has been demonstrated, the efficacy of pemetrexed for gastric cancer remains to be fully evaluated.Case presentationWe report a case involving a 62-year-old Japanese woman with synchronous locally-advanced poorly-differentiated lung adenocarcinoma and poorly-differentiated gastric adenocarcinoma, containing signet-ring cells distinguished by immunohistochemical profiles. She had been treated with carboplatin and pemetrexed as a first-line chemotherapy for lung cancer, and had achieved partial responses for both lung and gastric cancers. These responses led to a favorable 12-month progression-free survival after the initiation of chemotherapy, and the patient is still alive more than 33 months after diagnosis.ConclusionsThis case suggests a new chemotherapeutic regimen for patients with synchronous multiple primary cancers that have an adenocarcinoma background.

Multiple nodular pulmonary metastases of lung adenocarcinoma with epidermal growth factor receptor mutation

The treatment of patients with lung adenocarcinoma depends on epidermal growth factor receptor (EGFR) mutation status. Orally administered tyrosine kinase inhibitors like gefitinib, erlotinib, and afatinib are especially effective in patients with EGFR mutation-positive lung adenocarcinoma. The use of these medications could result in much longer overall survival for patients with EGFR mutation-positive lung adenocarcinoma than those with EGFR mutationnegative lung adenocarcinoma. Therefore, clinicians must be vigilant about obtaining each patients EGFR mutation status. Although EGFR mutation status is usually determined by pathological analysis, clinicians confirm the existence of EGFR mutations using computed tomography (CT) imaging. A ground-glass opacity pattern and multiple pulmonary