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Spatial metabolomics for evaluating response to neoadjuvant therapy in non-small cell lung cancer patients

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Cancer Communications 2022年第6期42卷 517-535页

作者： Jian Shen Na Sun Philipp Zens Thomas Kunzke Achim Buck Verena M.Prade Jun Wang Qian Wang Ronggui Hu Annette Feuchtinger Sabina Berezowska axel walch Research Unit Analytical Pathology Helmholtz Zentrum Munchen-German Research Center for Environmental HealthNeuherberg 85764Germany Institute of Pathology University of BernBern 3008Switzerland Graduate School for Health Sciences University of BernMittelstrasse 43Bern 3012Switzerland Center for Excellence in Molecular Cell Science Chinese Academy of SciencesShanghai 200031P.R.China Department of Laboratory Medicine and Pathology Institute of PathologyLausanne University Hospital and University of LausanneLausanne 1011Switzerland

Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to assess treatment response and prognosis in patientsNSCLC *** spatial metabolomics is a promising tool for evaluating metabolic phenotypes,it has not yet been utilized to assess therapy responses in patients with *** evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC,using a metabolic classifier that utilizes mass spectrometry imaging combined with machine ***:Resected NSCLC tissue specimens obtained after NAC(n=88)were subjected to high-resolution mass spectrometry,and these data were used to develop an approach for assessing the response to NAC in patients with *** specificities of the generated tumor cell and stroma classifiers were validated by applying this approach to a cohort of biologically matched chemotherapy-naive patients with NSCLC(n=85).Results:The developed tumor cell metabolic classifier stratified patients into different prognostic groups with 81.6%accuracy,whereas the stroma metabolic classifier displayed 78.4%*** contrast,the accuracies of MPR and TNM staging for stratification were 62.5%and 54.1%,*** combination of metabolic and MPR classifiers showed slightly lower accuracy than either individual metabolic *** multivariate analysis,metabolic classifiers were the only independent prognostic factors identified(tumor:P=0.001,hazards ratio[HR]=3.823,95%confidence interval[CI]=1.716-8.514;stroma:P=0.049,HR=2.180,95%CI=1.004-4.737),whereasMPR(P=0.804;HR=0.913;95%CI=0.445-1.874)and TNM staging(P=0.078;HR=1.223;95%CI=0.977-1.550)were not independent prognostic *** Kaplan-Meier survival analyses,both tumor and stroma metabolic classifiers were able to further stratify patients as NAC responders(P<0.001)and non

关键词： cancer metabolism machine learning mass spectrometry imaging metabolic classifier Nonsmall cell lung cancer prognosis spatial metabolomics treatment response

Preclinical Evaluation of CD40-Directed Immunotherapy in B-Cell Lymphoma Using [<sup>18</sup>F]Fluorothymidine-PET

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Advances in Molecular Imaging 2015年第2期5卷 17-28页

作者： Nicolas Graf Zhoulei Li Ken Herrmann Michaela Aichler Jolanta Slawska axel walch Christian Peschel Markus Schwaiger Andreas K. Buck Tobias Dechow Ulrich Keller III. Medical Department of Hematology and Medical Oncology Technische Universitat München Munich Germany Department of Nuclear Medicine Technische Universitat München Munich Germany Department of Nuclear Medicine Universitat Sklinikum Würzburg Würzburg Germany Institute of Pathology—Analytical Pathology Helmholtz Zentrum München Neuherberg Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany

Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.

关键词： CD40 Antibody FLT-PET Lymphoma Therapy Monitoring

Proteomic and metabolic prediction of response to therapy in gastric cancer

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World Journal of Gastroenterology 2014年第38期20卷 13648-13657页

作者： Michaela Aichler Birgit Luber Florian Lordick axel walch Research Unit Analytical Pathology Institute of Pathology Helmholtz Zentrum MünchenInstitute of Pathology Technische Universit t MünchenUniversity Cancer Center Leipzig University of LeipzigResearch Unit Analytical Pathology Institute of Pathology Helmholtz Zentrum München German Research Centre for Environmental Health

Several new treatment options for gastric cancer have been introduced but the prognosis of patients diagnosed with gastric cancer is still poor. Disease prognosis could be improved for high-risk individuals by implementing earlier screenings. Because many patients are asymptomatic during the early stages of gastric cancer,the diagnosis is often delayed and patients present with unresectable locally advanced or metastatic disease. Cytotoxic treatment has been shown to prolong survival in general,but not all patients are responders. The application of targeted therapies and multimodal treatment has improved prognosis for those with advanced ***,these new therapeutic strategies do not uniformly benefit all *** whether patients will respond to specific therapies would be of particular value and would allow for stratifying patients for personalized treatment *** imaging by positron emission tomography was the first technique with the potential to predict the response of esophagogastric cancer to neoadjuvant *** and validating tissue-based biomarkers are ongoing *** this review,we discuss the status of several targeted therapies for gastric cancer,as well as proteomic and metabolic methods for investigating biomarkers for therapy response prediction in gastric cancer.

关键词： Gastric cancer Therapy Response prediction Positron emission tomography Matrix-assisted laser desorption-ionization

A Sub-element Adaptive Shock Capturing Approach for Discontinuous Galerkin Methods

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Communications on Applied Mathematics and Computation 2023年第2期5卷 679-721页

作者： Johannes Markert Gregor Gassner Stefanie walch Department for Mathematics and Computer Science University of CologneWeyertal 86-9050931 CologneGermany Department for Mathematics and Computer Science Center for Data and Simulation ScienceUniversity of CologneWeyertal 86-9050931 CologneGermany I.Physikalisches Institut Center for Data and Simulation ScienceUniversity of CologneZülpicher Str.7750937 CologneGermany

In this paper,a new strategy for a sub-element-based shock capturing for discontinuous Galerkin(DG)approximations is *** idea is to interpret a DG element as a col-lection of data and construct a hierarchy of low-to-high-order discretizations on this set of data,including a first-order finite volume scheme up to the full-order DG *** dif-ferent DG discretizations are then blended according to sub-element troubled cell indicators,resulting in a final discretization that adaptively blends from low to high order within a single DG *** goal is to retain as much high-order accuracy as possible,even in simula-tions with very strong shocks,as,e.g.,presented in the Sedov *** framework retains the locality of the standard DG scheme and is hence well suited for a combination with adaptive mesh refinement and parallel *** numerical tests demonstrate the sub-element adaptive behavior of the new shock capturing approach and its high accuracy.

关键词： High-order methods Discontinuous Galerkin spectral element method Finite volume method Shock capturing Astrophysics Stellar physics

Decline of semen quality during IVF is not associated with subjective male stress

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Asian Journal of Andrology 2014年第4期16卷 597-601页

作者： Kazem Nouri Brigitte Litschauer Michael Sator Denise Tiringer Johannes Ott Katherina walch Lukas A Hefler Clemens B Tempfer Department of Obstetrics and Gynecolog Department of Clinical Pharmacology Medical University of Vienna Vienna Department of Obstetrics and Gynecology Krankenhaus Barmherzige Schwestern Linz Austria Department of Obstetrics and Gynecology Ruhr University Bochum Bochum Germany.

The aim of the present study was to assess if semen quality declines during in vitro fertilization （IVF） and whether or not this phenomenon is triggered by chronic male stress. In order to test this hypothesis, we first investigated a retrospective cohort of 155 male IVF patients （testing cohort）. Subsequently, we started a prospective cohort study in men undergoing their first IVF and assessed semen quality and subjective male chronic stress using a validated tool, i.e. the Fertility Problem Inventory （FPI） questionnaire. The association between stress and sperm quality decline measured 4-6weeks before the start of IVF （T1） and at the day of oocyte retrieval （T2） was the primary outcome. Live birth rate, first trimester abortion and rate of poor responders were secondary outcomes. In the testing cohort, mean progressive motility, but not mean sperm density significantly declined. There were 78/154 （51%） men who showed a decline in semen density and 50/154 （32%） men who showed a decline in progressive motility. In the validation cohort, progressive motility declined, whereas, sperm density increased from T1 to T2. Of 78 men, 27 men had increased stress （FPI-score 〉 146）. Sperm density and progressive motility were not significantly different in men with and without stress. However, in the presence of male stress, couples had a higher rate of poor responders, miscarriages and a lower rate of live births. Subjective stress is not associated with a decline in semen quality observed during IVF but may be associated with adverse ore^nancv outcome.

关键词： in vitro fertilization questionnaire semen quality stress

Model Order Reduction of Complex Airframes Using Component Mode Synthesis for Dynamic Aeroelasticity Load Analysis

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Journal of Mechanics Engineering and Automation 2018年第4期8卷 145-155页

作者： Paul V. Thomas Mostafa S. A. Elsayed Denis walch Aerospace Engineering Department Carleton University Ottawa KIS 5B6 Canada Engineering Specialist Bombardier Aerospace St-Laurent H4S 1Y9 Canada

Airframe structural optimization at different design stages results in new mass and stiffness distributions which modify the critical design loads envelop. Determination of aircraft critical loads is an extensive analysis procedure which involves simulating the aircraft at thousands of load cases as defmed in the certification requirements. It is computationally prohibitive to use a GFEM （Global Finite Element Model） for the load analysis, hence reduced order structural models are required which closely represent the dynamic characteristics of the GFEM. This paper presents the implementation of CMS （Component Mode Synthesis） method for the generation of high fidelity ROM （Reduced Order Model） of complex airframes. Here, sub-structuring technique is used to divide the complex higher order airframe dynamical system into a set of subsystems. Each subsystem is reduced to fewer degrees of freedom using matrix projection onto a carefully chosen reduced order basis subspace. The reduced structural matrices are assembled for all the subsystems through interface coupling and the dynamic response of the total system is solved. The CMS method is employed to develop the ROM of a Bombardier Aerospace business jet which is coupled with aerodynamic model for dynamic aeroelasticity loads analysis under gust turbulence. Another set of dynamic aeroelastic loads is also generated employing a stick model of same aircraft. Stick model is the reduced order modelling methodology commonly used in the aerospace industry based on stiffness generation by unitary loading application. The extracted aeroelastic loads from both models are compared against those generated employing the GFEM. Critical loads modal participation factors and modal characteristics of the different ROMs are investigated and compared against those of the GFEM. Results obtained show that the ROM generated using Craig Bampton CMS reduction process has a superior dynamic characteristics compared to the stick model.

关键词： Component Mode Synthesis Craig-Bampton reduction medaod dynamic aeroelasticity analysis model order reduction,aircraft loads analysis.

Re： Commentary on ＇Decline of semen quality during IVF is not associated with subjective male stress＇

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Asian Journal of Andrology 2014年第4期16卷 640-640页

作者： Kazem Nouri Brigitte Litschauer Michael Sator Denise Tiringer Johannes Ott Katherina walch Lukas A Hefler Clemens B Tempfer Departments of Obstetrics and Gynecology Clinical Pharmacology Medical University of Vienna Vienna Department of Obstetrics and Gynecology Krankenhaus Barmherzige Schwestern Linz Austria Obstetrics and Gynecology Ruhr University Bochum Bochum Germany.

We thank the commentator for his valuable insights as expressed in the above commentary. We fully agree that numerous lines of evidence support the assumption that male as well as female stress and the interaction of the stressed couple plays a role in the success of assisted reproduction. Furthermore, it is common ground that in vitro fertilization （IVF）/intracytoplasmic sperm injection （ICSI） couples are an especially vulnerable patient collective in this respect. We have, however, not yet identified the optimal means of measuring stress or the relevant aspects of it during the management of couples undergoing IVF/ICSI. This fact is also highlighted by our findings,t Further work is necessary to identify efficient and reliable tools to measure and treat stress in males and females undergoing IVF/ICSI with the goal of further improving reproductive outcomes.

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纤溶酶原激活物抑制因子1基因启动子的一种多态性与多囊卵巢综合征

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世界核心医学期刊文摘（妇产科学分册） 2006年第3期2卷 26-27页

作者： walch K. Grimm C. Huber J.C. 柳蕴 Department of Obstetrics and Gynecology Division of Gynecological Endocrinology and Infertility Treatment Medical University of Vienna Waehringer Guertel 18-20 A-1090 Vienna Austria

Objective: To investigate the association of a common 5G/4G polymorphism of the plasminogen activator inhibitor-1 gene (PAI1) with occurrence and clinical characteristics of the polycystic ovary syndrome (PCOS). Study design: In a case-control study, we evaluated a series of 106 Caucasian women with PCOS and 102 healthy controls. Women completed a detailed questionnaire and underwent a peripheral venous puncture, ultrasonography, and a standardized oral glucose tolerance test (OGTT).The PAI1 gene promoter polymorphism was evaluated using PCR. Results: Allele and genotype frequencies were not significantly different among women with PCOS and controls (P = 0.3 and 0.6, respectively). In women with PCOS, presence of the 5G/4G polymorphism of PAI1 was not associated with changes in serum hormone levels or with clinical characteristics. Conclusions: The 5G/4G polymorphism of the PAI1 promoter is not associated with occurrence and phenotype of the PCOS.

关键词：多囊卵巢综合征纤溶酶原激活物启动子多态性抑制因子血清激素水平外周静脉穿刺病例对照研究

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涤纶的色彩

国外纺织技术 1986年第13期 40-41页

作者： Margaret walch 中国纺织大学纺织品设计821班部分同学

柔和明亮的粉红,丰满华美的大红,淡雅文静的蓝色——所有这些都是人们的主观感受,无法用仪器来精确地测定。我们不可能把它们绘制在著名的门瑟尔色相、亮度、彩度色系统中,但是我们可以观察和评价这些色泽的优劣。正如我们喜爱褪色旧夹... 详细信息

柔和明亮的粉红,丰满华美的大红,淡雅文静的蓝色——所有这些都是人们的主观感受,无法用仪器来精确地测定。我们不可能把它们绘制在著名的门瑟尔色相、亮度、彩度色系统中,但是我们可以观察和评价这些色泽的优劣。正如我们喜爱褪色旧夹克或牛仔裤一样,它们是实实在在的东西。提及天然纤维织物,我们很难解释丝绸柔和美丽的色泽,呢绒深厚沉着的色调。但是,当你穿上桃红的丝衬衫或大红羊毛衫时,这些服装所具备的高质量的色彩和质地使你

关键词：涤纶色彩形象设计师聚对苯二甲酸乙二酯纤维纤维