Topkapı Sarayı Müzesinde Türk saatleri

Taha Toros Arşivi, Dosya No: 114-Müzelerİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

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

Formation of an Ultracarbonaceous Antarctic Micrometeorite through Minimum Aqueous Alteration in a Small Porous Icy Body

A comprehensive study of the organic chemistry and mineralogy of an ultracarbonaceous micrometeorite (UCAMM D05IB80) collected from near the Dome Fuji Station, Antarctica, was carried out to understand the genetic relationship among organic materials, silicates, and water. The micrometeorite is composed of a dense aggregate of ∼5 µm-sized hollow ellipsoidal organic material containing submicrometer-sized phases such as glass with embedded metal and sulfides (GEMS) and mineral grains. There is a wide area of organic material (∼15 × 15 μm) in its interior. Low-Ca pyroxene is much more abundant than olivine and shows various Mg/(Mg + Fe) ratios ranging from ∼1.0 to 0.78, which is common to previous works on UCAMMs. By contrast, GEMS grains in this UCAMM have unusual chemical compositions. They are depleted in both Mg and S, which suggests that these elements were leached out from the GEMS grains during very weak aqueous alteration, without the formation of phyllosilicates. The organic materials have two textures—smooth and globular with an irregular outline—and these are composed of imine, nitrile and/or aromatic nitrogen heterocycles, and amide. The ratio of nitrogen to carbon (N/C) in the smooth region of the organics is ∼0.15, which is five times higher than that of insoluble organic macromolecules in types 1 and 2 carbonaceous chondritic meteorites. In addition, the UCAMM organic materials are soluble in epoxy and are thus hydrophilic; this polar nature indicates that they are very primitive. The surface of the material is coated with an inorganic layer, a few nanometers thick, that consists of C, O, Si, S, and Fe. Sulfur is also contained in the interior, implying the presence of organosulfur moieties. There are no isotopic anomalies of D, 13C, or 15N in the organic material. Interstellar photochemistry alone would not be sufficient to explain the N/C ratio of the UCAMM organics; therefore, we suggest that a very small amount of fluid on a comet must have been necessary for the formation of the UCAMM. The GEMS grains depleted in Mg and S in the UCAMM prove a very weak degree of aqueous alteration; weaker than that of carbonaceous chondrites. Short-duration weak alteration probably caused by planetesimal shock locally melted cometary ice grains and released water that dissolved the organics; the fluid would likely have not mobilized because of the very low thermal conductivity of the porous icy body. This event allowed the formation of the large organic puddle of the UCAMM, as well as organic matter sulfurization, formation of thin membrane-like layers of minerals, and deformation of organic nanoglobules.アクセプト後にタイトル・アブストラクト等変更あり、著者最終稿は変更前のタイトル"Formation of an Ultracarbonaceous Antarctic Micrometeorite through Minimum Aqueous Alteration in a Small Porous Icy Body"This work was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 22224010, PI: H. Nagahara). The STXM facility at the beamline 5.3.2.2, ALS, is supported by the Department of Energy, Basic Energy Sciences Program

Organic chemical variation between hydrous and anhydrous Antarctic micrometeorites

第6回極域科学シンポジウム[OA] 南極隕石11月17日（火）　国立国語研究所 2階 講

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

Background: Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated. Results: To identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis. Conclusions: Our data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains.ArticleBMC GENOMICS. 14:248 (2013)journal articl

Abiotic formation of amorphous carbonaceous particles by a HMX (cyclotetramethylenetetranitramine) explosion experiment: implication from organic matter and the quench effect

Poster P03 abrtract, HAYABUSA 2014: 2nd symposium of solar system materials (4-5 December 2014, Sagamihara, Japan

The noble gas and nitrogen relationship between Ryugu and carbonaceous chondrites

Carbonaceous chondrites are considered to have originated from C-type asteroids and represent some of the most primitive material in our solar system. Furthermore, since carbonaceous chondrites can contain significant quantities of volatile elements, they may have played a crucial role in supplying volatiles and organic material to Earth and other inner solar system bodies. However, a major challenge of unravelling the volatile composition of chondritic meteorites is distinguishing between which features were inherited from the parent body, and what may be a secondary feature attributable to terrestrial weathering. In December 2020, the Hayabusa2 mission of the Japan Aerospace Exploration Agency (JAXA) successfully returned surface material from the C-type asteroid (162173) Ryugu to Earth. This material has now been classified as closely resembling CI-type chondrites, which are the most chemically pristine meteorites. The analysis of material from the surface of Ryugu therefore provides a unique opportunity to analyse the volatile composition of material that originated from a CI-type asteroid without the complications arising from terrestrial contamination. Given their highly volatile nature, the noble gas and nitrogen inventories of chondrites are highly sensitive to different alteration processes on the asteroid parent body, and to terrestrial contamination. Here, we investigate the nitrogen and noble gas signature of two pelletized grains collected from the first and second touchdown sites (Okazaki et al., 2022a), to provide an insight into the formation and alteration history of Ryugu. The concentration of trapped noble gas in the Ryugu samples is greater than the average composition of previously measured CI chondrites and are primarily derived from phase Q, although a significant contribution of presolar nanodiamond Xe-HL is noted. The large noble gas concentrations coupled with a significant contribution of presolar nanodiamonds suggests that the Ryugu samples may represent some of the most primitive unprocessed material from the early solar system. In contrast to the noble gases, the abundance of nitrogen and δ15N composition of the two Ryugu pellets are lower than the average CI chondrite value. We attribute the lower nitrogen abundances and δ15N measured in this study to the preferential loss of a 15N-rich phase from our samples during aqueous alteration on the parent planetesimal. The analyses of other grains returned from Ryugu have shown large variations in nitrogen concentrations and δ15N indicating that alteration fluids heterogeneously interacted with material now present on the surface of Ryugu. Finally, the ratio of trapped noble gases to nitrogen is higher than CI chondrites, and is closer to refractory phase Q and nanodiamonds. This indicates that Ryugu experienced aqueous alteration that led to the significant and variable loss of nitrogen, likely from soluble organic matter, without modification of the noble gas budget, which is primarily hosted in insoluble organic matter and presolar diamonds and is therefore more resistant to aqueous alteration.ISSN:0016-7037ISSN:1872-953

Anti-Tumor Effect against Human Cancer Xenografts by a Fully Human Monoclonal Antibody to a Variant 8-Epitope of CD44R1 Expressed on Cancer Stem Cells

BACKGROUND: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells. METHODS AND PRINCIPAL FINDINGS: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5. CONCLUSIONS: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family