Prognostic significance of cribriform adenocarcinoma of the lung: validation analysis of 1,057 Japanese patients with resected lung adenocarcinoma and a review of the literature

Background: Cribriform-predominant adenocarcinoma of the lung (Cribri-ADC) is a recently described tumor growth pattern. However, its prognostic impact has not been clearly determined. We analyzed the data of a series of 1, 057 Japanese patients with resected lung adenocarcinoma to identify the clinical significance of Cribri-ADC. Methods: Cribriform pattern (Cribri-p) is defined as invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests comprising tumors cells that produced glandular lumina. We investigated the correlations of Cribri-p and Cribri-ADC with clinicopathological factors as well as disease-free survival (DFS) and overall survival (OS). Results: Cribri-p was present in 217 patients (20.5%) and Cribri-ADC was determined in 25 patients (2.4%). Cribri-p was associated with larger tumor size, pleural invasion, vascular invasion, lymphatic invasion, and spreading through air spaces (STAS) (all, P<0.0001). Cribri-ADC was associated with younger age (P=0.019), vascular invasion (P=0.0025), STAS (P<0.0001), and ALK rearrangement (P=0.012). The DFS curve of patients with Cribri-ADC was identical to that of patients with solid adenocarcinoma; however, the OS curve was located between that of patients with papillary and acinar adenocarcinoma. Of the 10 patients who had tumor recurrences, eight had EGFR mutations or ALK rearrangement, six of whom achieved relatively long survival (median, 64.6, range, 37.4–113 months) following treatment with tyrosine kinase inhibitors (TKIs). In multivariate analysis, Cribri-ADC was not an independent prognostic factor of either recurrence or death. Conclusions: Cribri-ADC is associated with a higher risk of recurrence; however, most patients can be successfully treated with TKIs

Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

Resistance of progressive cancers against chemotherapy is a serious clinical problem. In this context, human epidermal growth factor receptor 3 (HER3) can play important roles in drug resistance to HER1- and HER2- targeted therapies. Since clinical testing of anti-HER3 monoclonal antibodies (mAbs) such as patritumab could not show remarkable effect compared with existing drugs, we generated novel mAbs against anti-HER3. Novel rat mAbs reacted with HEK293 cells expressing HER3, but not with cells expressing HER1, HER2 or HER4. Specificity of mAbs was substantiated by the loss of mAb binding with knockdown by siRNA and knockout of CRISPR/Cas9-based genome-editing. Analyses of CDR sequence and germline segment have revealed that seven mAbs are classified to four groups, and the binding of patritumab was inhibited by one of seven mAbs. Seven mAbs have shown reactivity with various human epithelial cancer cells, strong internalization activity of cell-surface HER3, and inhibition of NRG1 binding, NRG1-dependent HER3 phosphorylation and cell growth. Anti-HER3 mAbs were also reactive with in vivo tumor tissues and cancer tissue-originated spheroid. Ab4 inhibited in vivo tumor growth of human colon cancer cells in nude mice. Present mAbs may be superior to existing anti-HER3 mAbs and support existing anti-cancer therapeutic mAbs

Molecular characterization of atmospheric NO2-responsive germin-like proteins in azalea leaves

Atmospheric nitrogen dioxide (NO2) is an environmental oxidant that is removed through direct uptake by foliage, but plant responses to this highly reactive gas are not well understood at the molecular level. From NO2-exposed leaves of a woody azalea (Rhododendron mucronatum), we cloned two cDNAs (RmGLP1 and RmGLP2) for germin-like proteins (GLPs), a group of ubiquitous plant proteins that have been implicated in various plant physiological and developmental processes. Quantitative analysis of mRNA expression, together with immunoblotting data, showed that foliar exposure to NO2 caused a robust induction of these GLP-encoding genes. When produced in tobacco cell culture, recombinant RmGLP2 was secreted into the apoplast, where it exhibited superoxide dismutase activity. RmGLP1 and RmGLP2 represent the first examples of plant genes that are responsive to airborne NO2. These enzymes might have a potential role in extracellular defense mechanisms through attenuation of interactions between reactive nitrogen and oxygen species

Electrosynthesis of Layered Organo-Manganese Dioxide Framework-Doped with Cobalt for Iodide Sensing

Aqueous Mn²⁺ ions were anodized at 70 °C with Co²⁺ in the presence of cationic surfactant, cetyltrimethylammonium (CTA). X-ray diffraction (XRD) analysis revealed that the deposited film possesses a layered structure of MnO₂, the interlayer of which is occupied with the assembled CTA molecules. Inclusion of Co ions in the MnO₂ film was evidenced by X-ray photoelectron spectroscopy (XPS). They were located in the MnO₂ framework, not in the interlayer. The thus-obtained film, CTA-intercalated Co-framework-doped layered MnO₂ (CTA/Co-MnO₂), was applied as an electrochemical sensor toward iodide (I^–), a hydrophobic anion. The organic phase between MnO₂ layers could extract I^– ions from solution, providing a better sensitivity than a film consisting of layered MnO₂ with hydrated alkali metals. On the other hand, the Co-doped layers of MnO₂ achieved faster electron transfer kinetics for the oxidation of I^–, which resulted in a drastic reduction in response time compared to the nondoped CTA/MnO₂

Precise manipulation of electron transfers in clustered five redox sites

Electron transfers in multinuclear metal complexes are the origin of their unique functionalities both in natural and artificial systems. However, electron transfers in multinuclear metal complexes are generally complicated, and predicting and controlling these electron transfers is extremely difficult. Herein, we report the precise manipulation of the electron transfers in multinuclear metal complexes. The development of a rational synthetic strategy afforded a series of pentanuclear metal complexes composed of metal ions and 3,5-bis(2-pyridyl)pyrazole (Hbpp) as a platform to probe the phenomena. Electrochemical and spectroscopic investigations clarified the overall picture of the electron transfers in the pentanuclear complexes. In addition, unique electron transfer behaviours, in which the reduction of a metal centre occurs during the oxidation of the overall complex (reduction-upon-oxidation process), were discovered. We also elucidated the two dominant factors that determine the manner of the electron transfers. Our results provide comprehensive guidelines for interpreting the complicated electron transfers in multinuclear metal complexes