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SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity

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Bone Research 2018年第2期6卷 132-144页

作者： Chunlin Zuo Lijun Wang Raghavendra M.Kamalesh Margot e.Bowen Douglas C.Moore Mark S.Dooner Anthony M.Reginato Qian Wu christoph Schorl Yueming Song Matthew L.Warman Benjamin G.Neel Michael G.ehrlich Wentian Yang Department of Orthopaedics Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Orthopaedic Research Laboratories and Howard Hughes Medical Institute Boston Children's Hospital and Department of GeneticsHarvard Medical SchoolBostonMA 02115USA Division of Hematology and Oncology Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Division of Rheumatology Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Department of Pathology and Laboratory Medicine University of Connecticut Health CenterFarmingtonCT 06030USA Department of Molecular and Cell Biology and Biochemistry Brown University70 Ship StreetProvidenceRI 02912USA Department of Orthopedic Surgery West China Hospital of Sichuan UniversityChengdu 610041 Laura and Issac Perlmutter Cancer Center NYU Langone Medical CenterNew YourkNY 10016USA Department of endocrinology the First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor（OCP）, and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2（encoded by Ptpn11） affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using ＂Cre-lox P＂-mediated gene ***2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts. Consistent with these observations, the expression of the master chondrogenic transcription factor SOX9 and its target genes Acan, Col2a1, and Col10a1 were increased in SHP2-deficient chondrocytes, as revealed by gene expression arrays, q RT-PCR, in situ hybridization, and immunostaining. Mechanistic studies demonstrate that SHP2 regulates OCP fate determination via the phosphorylation and SUMOylation of SOX9, mediated at least in part via the PKA signaling pathway. Our data indicate that SHP2 is critical for skeletal cell lineage differentiation and could thus be a pharmacologic target for bone and cartilage regeneration.

关键词： SHP2 regulates skeletal cell modifying SOX9 expression transcriptional activity SOX

Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CeCOG trial

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World Journal of Gastroenterology 2010年第25期16卷 3133-3143页

作者： Janja Ocvirk Thomas Brodowicz Fritz Wrba Tudor e Ciuleanu Galina Kurteva Semir Beslija Ivan Koza Zsuzsanna Pápai Diethelm Messinger Ugur Yilmaz Zsolt Faluhelyi Suayib Yalcin Demetris Papamichael Miklós Wenczl Zrinka Mrsic-Krmpotic einat Shacham-Shmueli Damir Vrbanec Regina esser Werner Scheithauer christoph C Zie-linski Institute of Oncology 1000 Ljubljana Slovenia Clinical Division of Oncology Department of Medicine I Medical University of Vienna 1090 Vienna Austria Clinical Institute of Pathology Medical University of Vienna 1090 Vienna Austria Institutul Oncologic Cluj 400015 Cluj-Nap-oca Romania Department of Oncology National Specialized Hospital of Active Treatment in Oncology 1754 Sofi a Bulgaria Institute of Oncology Clinical Center of Sara-jevo University 71000 Sarajevo Bosnia-Herzegovina Department of Oncology National Cancer Institute 83310 Bratislava Slovak Republic AeK Onkologiai Osztaly 1122 Budapest Hungary Biometrics IST GmbH 68219 Mannheim Germany Department of Gastroenterology 9 Eylül Univer-sity Medical Faculty 35340 Izmir Turkey Oncology Department Veszprém County Hos-pital 8200 Veszprém Hungary Institute of Oncology Ankara Hacettepe Univer-sity 06100 Ankara Turkey Department of Medical Oncology Bank of Cyprus Oncology Center 2006 Nicosia Cyprus Department of Oncoradiology Markusovszky Teaching Hospital 9700 Szombathely Hungary Department of Medical Oncology Uni-versity Hospital for Tumors 10000 Zagreb Croatia Oncology Division Tel-Aviv Souraski Medical Center Tel Aviv 64239 Israel KBC Rebro Oncology Department 10000 Zagreb Croatia Merck KGaA D64293 Darmstadt Germany

AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). MeTHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). ReSULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.

关键词： Cetuximab 5-fluorouracil folinic acid and oxaliplatin 5-fluorouracil folinic acid and irinotecan KRAS Metastatic colorectal cancer

西南印度洋罗德里格斯岛石笋记录的新仙女木事件

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第四纪研究 2019年第4期39卷 1006-1017页

作者：李瀚瑛 Ashish Sinha 程海 Spotl christoph 宁有丰西安交通大学全球环境变化研究院陕西西安710054 加利福尼亚州立大学多明戈兹山分校美国加利福尼亚90747 Department of earth Sciences University of Minnesota Minneapolis MN 55455 USA 因斯布鲁克大学地质系奥地利因斯布鲁克6020

新仙女木(Younger Dryas,简称YD)事件是末次冰消期末期升温过程中北半球高纬一次剧烈的突变降温事件,主流机制为淡水注入北大西洋减缓了北大西洋翻转环流,使得北半球普遍降温、热带辐合带南移等全球范围的气候重组.虽然该事件研究程度较... 详细信息

新仙女木(Younger Dryas,简称YD)事件是末次冰消期末期升温过程中北半球高纬一次剧烈的突变降温事件,主流机制为淡水注入北大西洋减缓了北大西洋翻转环流,使得北半球普遍降温、热带辐合带南移等全球范围的气候重组.虽然该事件研究程度较高,然而其在南半球、尤其在西南印度洋的气候变化模态尚不明朗.本研究利用来自罗德里格斯岛(罗岛)高分辨率、高精度定年的石笋氧同位素(δ18O)记录,重建了过去13. 3~10. 8 ka期间(对应石笋样品100~169 mm)西南印度洋亚热带地区的气候变化.结果表明,在YD事件期间罗岛石笋δ18O相对偏重,指示降水相对减少.与印度洋北岸的地质记录对比显示, YD时期罗岛石笋记录与众多亚洲季风石笋氧同位素记录共同展现出偏重的"谷状结构",并且显示出"缓进快出"的不对称特征.与印度洋东岸的地质记录对比结果显示,罗岛石笋δ18O与印太暖池南北边缘记录共同显示出偏干状态,而与近赤道记录的气候特征不同.与印度洋西岸的地质记录对比结果显示,东非热带赤道地区至南部亚热带地区呈现"北干南湿"的特征.罗岛与东非赤道地区的气候变化也具有一致性. YD时期,热带辐合带南移而罗岛降水却减少,可能原因是热带辐合带强度减弱,削弱了对流降水,使得亚洲季风从源区至下游地带水汽传输均发生减弱.

关键词：新仙女木事件罗德里格斯岛印度洋石笋热带辐合带

Machine learning sparse tight-binding parameters for defects

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npj Computational Materials 2022年第1期8卷 1081-1091页

作者： christoph Schattauer Milica Todorović Kunal Ghosh Patrick Rinke Florian Libisch Institute for Theoretical Physics TU Wien1040ViennaAustria Department of Applied Physics Aalto UniversityP.O.Box 11100AaltoFI-00076Finland Department of Mechanical and Materials engineering University of TurkuFI-20014TurkuFinland Department of Information and Computer Science Aalto UniversityP.O.Box 15400AaltoFI-00076Finland

We employ machine learning to derive tight-binding parametrizations for the electronic structure of *** test several machine learning methods that map the atomic and electronic structure of a defect onto a sparse tight-binding *** Multi-layer perceptrons(i.e.,feed-forward neural networks)perform best we adopt them for our further *** demonstrate the accuracy of our parameterizations for a range of important electronic structure properties such as band structure,local density of states,transport and level spacing simulations for two common defects in single layer *** machine learning approach achieves results comparable to maximally localized Wannier functions(i.e.,DFT accuracy)without prior knowledge about the electronic structure of the defects while also allowing for a reduced interaction range which substantially reduces calculation *** is general and can be applied to a wide range of other materials,enabling accurate large-scale simulations of material properties in the presence of different defects.

关键词： structure electronic spacing

Transgenerational bone toxicity in F3 medaka (Oryzias latipes) induced by ancestral benzo[a]pyrene exposure: Cellular and transcriptomic insights

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Journal of environmental Sciences 2023年第5期127卷 336-348页

作者： Jiezhang Mo Miles Teng Wan DorisWai-Ting Au Jingchun Shi Nathan Tam Xian Qin Napo K.M.Cheung Keng Po Lai christoph Winkler Richard Yuen-Chong Kong Frauke Seemann Southern Marine Science and engineering Guangdong Laboratory(Guangzhou) Guangzhou 510000China Shenzhen Key Laboratory for the Sustainable Use of Marine Biodiversity Research Centre for the Oceans and Human HealthShenzhen Research InstituteCity University of Hong KongShenzhen 518057China State Key Laboratory of Marine Pollution and Department of Chemistry City University of Hong KongHong Kong SARChina Laboratory of environmental Pollution and Integrative Omics Guilin Medical UniversityHuan Cheng North 2nd Road 109Guilin 541004China Department of Biological Sciences National University of Singapore119077Singapore Center for Coastal Studies and Department of Life Sciences Texas A&M University-Corpus ChristiCorpus ChristiTexas 78412USA

Benzo[a]pyrene(BaP),a ubiquitous pollutant,raises environmental health concerns due to induction of bone toxicity in the unexposed *** of F0 ancestor medaka(Oryzias latipes)to 1μg/L BaP for 21 days causes reduced vertebral bone thickness in the unexposed F3 male *** reveal the inherited modifications,osteoblast(OB)abundance and molecular signaling pathways of transgenerational BaP-induced bone thinning were *** analysis showed a reduction in OB *** of the miRNA and mRNA transcriptomes revealed the dysregulation of Wnt signaling(frzb/ola-miR-1–3p,sfrp5/ola-miR-96–5p/miR-455–5p)and bone morphogenetic protein(Bmp)signaling(bmp3/ola-miR-96–5p/miR-181b-5p/miR-199a-5p/miR-205–5p/miR-455–5p).Both pathways are major indicators of impaired bone formation,while the altered Rank signaling in osteoclasts(c-fos/miR-205–5p)suggests a potentially augmented bone ***,a typical BaP-responsive pathway,the Nrf2-mediated oxidative stress response(gst/ola-miR-181b-5p/miR-199a-5p/miR-205),was also ***,mRNA levels of epigenetic modification enzymes(e.g.,hdac6,hdac7,kdm5b)were found *** findings indicated that epigenetic factors(e.g.,miRNAs,histone modifications)may directly regulate the expression of genes associated with transgenerational BaP bone toxicity and warrants further *** identified candidate genes and miRNAs may serve as potential biomarkers for BaP-induced bone disease and as indicators of historic exposures in wild fish for conservation purposes.

关键词： Polycyclic aromatic hydrocarbons (PAHs) Transcriptome Impaired bone formation Molecular pathways MicroRNAs Medaka(Oryzias latipes)

用于气体频谱分析传感器的245 GHz次谐波接收机

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微电子学 2019年第6期49卷 783-787页

作者：毛燕飞鄂世举 Klaus Schmalz J.christoph Scheytt 浙江师范大学工学院浙江金华321000 东南大学毫米波国家重点实验室南京211189 IHP Microelectronics Frankfurt(Oder)15236Germany Heinz Nixdorf Institute Paderborn UniversityPaderborn 33102Germany

提出了一种用于气体频谱分析传感器的混频器优先的245 GHz次谐波接收机。该接收机具有高线性度、高带宽、低噪声系数、低功耗和高集成度的特点。该接收机由2次无源反接并联二极管对(APDP)次谐波混频器、120 GHz推推型压控振荡器-分频器... 详细信息

提出了一种用于气体频谱分析传感器的混频器优先的245 GHz次谐波接收机。该接收机具有高线性度、高带宽、低噪声系数、低功耗和高集成度的特点。该接收机由2次无源反接并联二极管对(APDP)次谐波混频器、120 GHz推推型压控振荡器-分频器链路和120 GHz功率放大器构成。采用特征频率/最大振荡频率为300 GHz/500 GHz的SiGe BiCMOS工艺进行实现。结果表明,该接收机芯片的转换增益为-16 dB,带宽为14 GHz,单边带噪声系数为19 dB,输入1 dB压缩点为0 dBm,功耗为213 mW。

关键词：混频器优先次谐波接收机 BiCMOS工艺

Tumor initiating cells in pancreatic cancer: A critical view

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World Journal of Stem Cells 2009年第1期1卷 8-10页

作者： christoph W Michalski Jrg Kleeff Department of Surgery Technische Universitt München Ismaningerstrasse22 81675 Munich Germany

emerging evidence points to the existence of pan-creatic cancer stem cells (CSC) as the culprit in the initiation, maintenance, metastasis, and treatment resistance of pancreatic cancer. The existence of such a cell population would have an important im-pact on the design of novel therapies against this devastating disease. However, no in vivo validation or rebuttal of the pancreatic CSC hypothesis exists. Major backlashes in the discussion on CSC are firstly, the confusion between the terms CSC and cell of origin of pancreatic ductal adenocarcinoma (PDAC), secondly the ambiguity of the cell of origin itself and thirdly, the fact that the CSC hypothesis is based on cell sorting and xenografting experiments; the latter of which often precludes solid conclusions because of the lack of a natural microenvironment and differences in drug delivery. Nonetheless, recent studies in other cancers partially support the CSC hypothesis by demonstrating a link between epithelial-to-mesenchymal transdifferentiation/transition (eMT) and CSC properties. Such a link is again open to dispute as eMT is a reversible process which is highly dependent on major oncogenic pathways in PDAC [e.g. K-Ras, transforming growth factor-β (TGF-β)] rather than on presumed cancer stem cell pathways. Hence, the available evidence does not robustly support the CSC concept in PDAC and a thorough validation of this hypothesis in well-defined genetically engineered mouse models of pancreatic cancer is required.

关键词： Pancreatic cancer Cancer stem cell Tumor initiating cells Mouse models

Opposing intraspecific *** diversity effects on herbivory and growth in subtropical experimental tree assemblages

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Journal of Plant ecology 2017年第1期10卷 242-251页

作者： christoph Z.Hahn Pascal A.Niklaus Helge Bruelheide Stefan G.Michalski Miaomiao Shi Xuefei Yang Xueqin Zeng Markus Fischer Walter Durka Helmholtz Centre for environmental Research—UFZ Department of Community Ecology(BZF)Theodor-Lieser-Straße 4D-06120 HalleGermany Department of evolutionary Biology and environmental Studies University of ZürichWinterthurerstrasse 190CH-8057 ZürichSwitzerland Institute of Biology Martin Luther University Halle-WittenbergAm Kirchtor 106108 HalleGermany German Centre for Integrative Biodiversity Research(iDiv)Halle-Jena-Leipzig Deutscher Platz 5e04103 LeipzigGermany South China Botanical Garden 723 Xingke RoadGuangzhou 510650China Key Laboratory of Biodiversity and Biogeography Kunming Institute of BotanyChinese Academy of Sciences132 Lanhei RoadKunming 650204China Kadoorie Farm and Botanic Garden Lam Kam RoadTai PoNew TerritoriesHong Kong Institute of Plant Sciences University of BernAltenbergrain 21CH-3013 BernSwitzerland

Aims Positive plant diversity-ecosystem function relations are ultimately driven by variation in functional traits among individuals that form a *** date,research has largely focused on the role of species diversity for ecosystem ***,substantial intraspecific trait variation is common and a significant part of this variation caused by genetic differences among ***,we studied the relative importance of species diversity and seed family(SF)diversity within species for growth and herbivory in experimental subtropical tree *** In 2010,we set up a field experiment in subtropical China,using four species from the local species *** were raised from seeds,with seeds from the same mother tree forming an *** established 23 plots containing one or four species(species diversity treatment)and one or four SFs per species(SF diversity treatment).Tree growth(stem diameter,plant height and crown expansion)and herbivory(percentage leaf loss due to leaf chewers)were monitored annually from 2011 to *** findings Tree species richness promoted growth but had no effect on *** contrast,SF diversity reduced growth and increased herbivory but only so in species *** of the observed effects were time dependent,with the largest effect found in *** results suggest that biodiversity can affect plant performance directly via tree species-species interactions,or context dependent,via potential effects on inter-trophic *** important conclusions should be drawn from our ***,in future studies regarding biodiversity and ecosystem functioning(BeF)relationships,intraspecific genetic diversity should be given similar weight as species diversity as it has often been neglected and its effects are not well ***,we demonstrate opposite effects of biodiversity among and within species,stressing the importance to consider the effects of multiple levels of biodiversity simul

关键词： BeF-China species diversity genetic diversity growth herbivory

Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI

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World Journal of Gastroenterology 2006年第11期12卷 1699-1705页

作者： christoph F Dietrich Wolfgang Kratzer Deike Strobel etienne Danse Robert Fessl Alfred Bunk Udo Vossas Karlheinz Hauenstein Wilhelm Koch Wolfgang Blank Matthijs Oudkerk Dietbert Hahn Christian Greis Department of Internal Medicine Ⅱ Johann Wolfgang Goethe University Hospital 60590 FrankfurtGermany Department of Internal Medicine Ⅰ University Hospital Ulm 89070Germany Medical Clinic Ⅰ University Hospital Erlangen 91054Germany Department of Radiology University Hospital St.Luc Brussels 1200Belgium Department of Radiology Central Hospital Augsburg 86156Germany Department for Visceral Thoracic and Vascular Surgery University HospitalDresden 01307Germany Department of Radiology Marien Hospital DUsseldorf 40479Germany Department of Radiology University Hospital Rostock 18055Germany Medical Clinic Ⅱ Leopoldina Hospital Schweinfurt 97422Germany Department of Internal Medicine Hospital am Steinenberg Reutlingen 72764Germany Department of Radiology University Hospital Groningen 9700Netherlands Department of Radiology University Hospital Würzburg 97080Germany Clinical Research Bracco Altana Pharma Konstanz 78467Germany

AIM： To evaluate contrast-enhanced ultrasonography （CeUS） using SonoVue in the detection of liver metastases in patients with known extrahepatic primary tumors versus the combined gold standard comprising CT, MRI and clinical/histological data. MeTHODS： It is an international multicenter study, and there were 12 centres and 125 patients （64 males, 61 females, aged 59 ± 11 years） involved, with 102 patients per protocol. Primary tumors were colorectal in 35%, breast in 27%, pancreatic in 17% and others in 21%. CeUS using SonoVue was employed with a Iow-mechanical-index technique and contrast-specific software using Siemens elegra, Philips HDI 5000 and Acuson Sequoia; continuous scanning for at least five minutes. ReSULTS： CeUS with SonoVue increased significantly the number of focal liver lesions detected versus unenhanced sonography. In 31.4% of the patients, more lesions were found after contrast enhancement. The total numbers of lesions detected were comparable with CeUS （55）, triple-phase spiral CT （61） and HRI with a liverspecific contrast agent （53）. Accuracy of detection of metastatic disease （i.e. at least one metastatic lesion） was significantly higher for CeUS （91.2%） than for unenhanced sonography （81.4%） and was similar to that of triple-phase spiral CT （89.2 %）. In 53 patients whose CeUS examination was negative, a follow-up examination 3-6 months later confirmed the absence of metastatic lesions in 50 patients （94.4%）. CONCLUSION： CeUS is proved to be reliable in the detection of liver metastases in patients with known extrahepatic primary tumors and suspected liver lesions.

关键词： CT MRI Metastasis Detection SonoVue