[Surgical Case of Bronchial Mucoepidermoid Carcinoma Safely Diagnosed by Enucleation Under the Bronchoscopy After Bronchial Arterial Embolization].

A 28-year-old male presented to our hospital with hemoptysis and his chest computerized tomography (CT) showed the right middle and lower lobe atelectasis due to the tumor of right intermediate bronchial trunk. To reduce the blood flow to the tumor, bronchial arterial embolization was performed and the tumor was resected using Cryoprobe with a flexible endobronchial scope. Thus, we could observe the tumor localization and diagnose before the surgical procedure. We performed the right sleeve middle lobectomy and the right lower lobe was safely preserved.

Acute Generalized Exanthematous Pustulosis Caused by Erlotinib in a Patient with Lung Cancer.

Acute generalized exanthematous pustulosis (AGEP) is a rare drug-related adverse skin reaction caused mainly by antibiotics. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat lung cancer. A 69-year-old woman with primary lung cancer (adenocarcinoma, cT3N1M1b, stage IVB) developed erythema and multiple skin pustules on her abdomen and both thighs after 7 weeks of erlotinib treatment. She also had fever and general fatigue. Histological examination of a skin biopsy specimen showed intraepidermal pustules with neutrophil and eosinophil infiltration. She was diagnosed with erlotinib-induced AGEP. AGEP resolved by erlotinib discontinuation and systemic corticosteroid treatment. The lung cancer progressed when erlotinib was discontinued, so afatinib, a second-generation EGFR-TKI, was administrated without any skin adverse effects. Afatinib successfully decreased the lung cancer, and maintained the disease stable for 1 year. Although acneiform rash was the most common skin adverse event caused by EGFR, AGEP rarely occurred. The present case also demonstrated that it is possible to switch agents, from erlotinib to afatinib, even though they have the same pharmacological effects. Although AGEP is a rare drug-related skin disorder, physicians should be aware that erlotinib may induce AGEP.

TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation.

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.

Adjuvant activity of Mycobacteria-derived mycolic acids.

Successful vaccination, especially with safe vaccines such as component/subunit vaccines, requires proper activation of innate immunity and, for this purpose, adjuvant is used. For clinical use, alum is frequently used while, for experimental use, CFA, containing Mycobacterial components, was often used. In this report, we demonstrated that mycolic acids (MA), major and essential lipid components of the bacterial cell wall of the genus Mycobacterium, has adjuvant activity. MA plus model antigen-immunization induced sufficient humoral response, which was largely comparable to conventional CFA plus antigen-immunization. Importantly, while CFA plus antigen-immunization induced Th17-biased severe and destructive inflammatory responses at the injected site, MA plus antigen-immunization induced Th1-biased mild inflammation at the site. MA induced dendritic cell activation by co-stimulatory molecule induction as well as inflammatory cytokine/chemokine induction. MA plus antigen-immunization successfully protected mice from tumor progression both in prevention and in therapy models. We thus submit that MA is a promising adjuvant candidate material for clinical purposes and for experimental purposes from a perspective of animal welfare.

Chemoenzymatic oxygenation method for sesquiterpenoid synthesis based on Fe-chelate and ferric-chelate reductase.

Sesquiterpenoids are one of the most diverse groups in natural compounds with various chemical structures and bioactivities. In our previous work, we developed the chemoenzymatic oxygenation method based on the combination of Fe(II)-EDTA and ferric-chelate reductase that could synthesize (-)-rotundone, a key aroma sesquiterpenoid of black pepper. Fe(II)-EDTA catalyzed the oxygenation of sesquiterpene to sesquiterpenoid, and ferric-chelate reductase catalyzed the supply and regeneration of Fe(II)-EDTA in this system. We then investigated the effect of various Fe2+-chelates on the catalytic oxygenation of sesquiterpene and applied this system to the synthesis of odor sesquiterpenoids. We determined Fe(II)-NTA to be an efficient oxygenation catalyst by the screening approach focusing on ligand structures and coordination atoms of Fe2+-chelates. Valuable odor sesquiterpenoids such as (+)-nootkatone, (-)-isolongifolenone, and (-)-ß-caryophyllene oxide were oxygenatively synthesized from each precursor sesquiterpene by 66%, 82%, and 67% of the molar conversion rate, respectively.Abbreviations: EDTA: ethylenediaminetetraacetate; NTA: nitrilotriacetate; DTPA: diethylenetriaminepentaacetate; phen: o-phenanthroline; cyclam: 1,4,8,11-tetraazacyclotetradecane; TPA: tris(2-pyridylmethyl)amine; GlcDH: glucose dehydrogenase; HP-ß-CD: hydroxypropyl-ß-cyclodextrin.

Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury.

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C11H10FN3OS2) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

Gold-Catalyzed Cyclization of Alkyne Alcohols: Regioselective Construction of Functionalized 6,6- and 6,7-Bicyclic Ethers.

We describe an efficient regioselective formation of six-/seven-membered cyclic ethers based on gold-catalyzed intramolecular hydroalkoxylation. Sequential gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions afforded 6,6-bicyclic ethers, while reversing the reaction sequence (cross-coupling then cyclization) afforded 6,7-bicyclic ethers. This methodology should provide access to a range of functional polycyclic ethers.

[Four cases of interstitial pneumonia associated with amyopathic dermatomyositis characterized by the anti-CADM-140 antibody].

Clinically amyopathic dermatomyositis (CADM) is a subgroup of dermatomyositis that manifests with characteristic cutaneous lesions and mild or no muscle involvement. It is known that rapidly progressive interstitial pneumonia with a poor prognosis can occur in patients with CADM. The anti-CADM-140 antibody is thought to be useful as a specific serological marker for CADM. We encountered 4 patients with the anti-CADM-140 antibody. All patients complained of cutaneous lesions and dyspnea. Chest X-ray films and CT scans showed ground-glass opacities (GGO) and consolidation in the lower lobes. All cases were treated with pulse methylprednisolone, cyclophosphamide therapy and cyclosporine. Three patients died of respiratory failure and 1 improved. Anti-CADM-140 antibody-positive cases are likely to have poor prognoses and should be treated by intensive therapy as soon as possible.

[Hospitalized nursing home-acquired pneumonia--comparison with community-acquired pneumonia in older adults].

Nursing home-acquired pneumonia (NHAP) is a frequent cause of hospital admission and death among residents of long-term care facilities. We studied consecutive patients with NHAP who were admitted to our 358-bed acute care hospital from 2004 to 2007. Patients with NHAP (n = 147) were significantly older (85.8 +/- 8.0 years vs. 80.2 +/- 8.2 years); predominantly female (57.1% vs. 41.5%); had higher severity (the 2005 Japanese Respiratory Society guidelines A-DROP score: 2.5 +/- 1.1 vs. 2.1 +/- 1.2) and a higher mortality (10.4% vs. 5.8%); had a longer median length of hospital stay (17 days vs. 15 days) than elderly patients with community-acquired pneumonia (n = 545). Cerebrovascular disorders (31.3% vs. 14.1%), dementia (59.2% vs. 22.9%) and feeding tube placement (19.0% vs. 6.4%), which were associated with aspiration, were more common and bronchial asthma (0.7% vs. 8.8%) and COPD (4.1% vs. 19.8%) less common among those with NHAP. Although Methicillin-resistant Staphylococcus aureus (MRSA) was more frequently isolated from the sputa of the NHAP group (23.1% vs. 9.4%), Streptococcus pneumoniae was the most important causative agent by microbial investigations, including blood culture and urinary antigen testing in addition to sputum examination.

[A case of pulmonary aspergilloma successfully treated with transbronchial intracavitary itraconazole].

A 74-year-old woman given a diagnosis of chronic necrotizing pulmonary aspergillosis in February, 2007 was treated by intravenous voriconazole (VRCZ) and her conditions improved. Then it was switched to oral VRCZ and continued treatment. However, a fungus ball remained, and (1-3)-beta-D-glucan values increased, which had previously been within normal limit. Therefore transbronchial intracavitary itraconazole therapy was performed twice a week, for a total of 9 times (715 mg) from June, 2007. The fungus ball disappeared at the time of the fourth injection, and (1-3)-beta-D-glucan values decreased gradually. Intravenous ITCZ was administered for two weeks from July, 2007, after which it was switched to oral ITCZ 400 mg/day and treatment was continued without recurrence. Though intracavitary ITCZ therapy caused temporary fever and elevation of CRP, we were able to perform the treatment safely and confirm the elevation of enough serum ITCZ concentrations. This is the first case of pulmonary aspergilloma successfully and safely treated with transbronchial intracavitary itraconazole.

[Legionella longbeachae pneumonia infection from home garden soil].

A 72-year-old critically ill and intubated man was transferred to our hospital, because of worsening pneumonia unresponsive to Cefazolin and Meropenem, from the hospital where he had been admitted 8 days before to start maintenance hemodialysis for chronic renal failure but had fever from admission. In a few days his critical condition rapidly subsided with the initiation of Ciprofloxacin and his sputum culture on GVPC medium indicated Legionellosis, which was afterwards identified as L. longbeachae by PCR and DNA-DNA hybridization. After recovery he said that he had been fond of gardening and had been gardening immediately before the initial admission. Moreover, several reports from Australia suggested inhalation of aerosolized potting soil as the route of L. longbeacachae infection; therefore, we examined the soil of his home garden and identified it. Thus, we present this case as the first of L. longbeachae pneumonia in Japan, proved to be infected via inhalation of aerosolized home garden soil.

Synthesis and properties of the aromatic clusters arrayed along DNA strands.

Functional groups arrayed along DNA strands have been expected to show unique properties that are different from those monomers. Oligonucleotides carrying multi-pyrene groups arrayed along DNA strands showed strong excimer fluorescence emission intensities. The oligonucleotides carrying pyrene groups are surmised to be in single stranded forms in solutions. On the other hand, oligonucleotides carrying methyl red groups formed double stranded forms in which methyl red groups were tightly stacked. The structural factors which control the single strand-double strand equilibriums will be discussed.

Helix formation of oligodeoxyribonucleotides containing base-aromatic ring conjugates.

Novel nucleoside analogues with base moieties containing pyrene groups have been synthesized and incorporated into oligodeoxyribonucleotides (ODNs). ODNs containing tandem pyrene residues at the 5'-end gave fluorescence spectra characteristic of eximers that were diminished by duplex formation of the ODNs with complementary strands.

Duplex and triplex formation of oligodeoxyribonucleotides containing nucleobase-intercalater conjugates.

Novel nucleoside analogues constituting of 2'-deoxyinosine and aromatic rings, which are connected by short linker groups, were synthesized and incorporated into oligodeoxyribonucleotides (ODNs). ODNs containing the nucleoside analogues formed stable duplexes and triplexes with target nucleic acids. The stacking interaction between base residues in the target nucleic acids and the aromatic groups of the nucleoside analogues appears to be a major cause of stabilization.