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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  50. Kongress für Allgemeinmedizin und Familienmedizin; 20160929-20161001; Frankfurt am Main; DOC16degam044 /20160919/
    Publication Date: 2016-09-19
    Keywords: Forschungspraxisnetzwerk ; Motivierende und Hemmende Faktoren zu Forschung in Hausarztpraxen ; Versorgungsforschung ; ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Abstract: INTRODUCTION: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. METHODS: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. RESULTS: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P 〈0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P 〈0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors. CONCLUSIONS: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment 12345678. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard 910. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue 111213. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models 14. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER 15.A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in 15).In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial 5. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR 11.The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective.
    Type of Publication: Journal article published
    PubMed ID: 23391338
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  • 3
    ISSN: 1433-7347
    Keywords: Key words Low-field MRI ; Knee joint ; Arthroscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract The results of magnetic resonance imaging (MRI) were compared with those of arthroscopy in a prospective series of 244 patients. A dedicated system for MRI of limbs and peripheral joints – the 0,2-T Artoscan (Esaote, Italy) – was used for imaging knee joint lesions. T1-weighted spin-echo sagittal images, T2-weighted gradient-echo coronal images, and axial views for lesions of the femoropatellar joint were acquired. Paraxial sagittal and oblique coronal views were obtained for imaging of the cruciate ligaments. This protocol allowed excellent visualization of the cruciate ligaments and medial and lateral meniscus in almost all patients. Compared with arthroscopy performed within 48 h after imaging, the sensitivity, specificity, and accuracy were respectively 93%, 97%, and 95% for tears of the medial meniscus; 82%, 96%, and 93% for tears of the lateral meniscus; 100%, 100%, and 100% for tears of the posterior cruciate ligament; 98%, 98%, and 97% for tears of the anterior cruciate ligament; and 72%, 100%, and 92% for full-thickness articular cartilage lesions. The examination can be performed within 30–45 min at lower cost than diagnostic arthroscopy. MRI with a 0.2-T magnet is a safe and valuable adjunct to the clinical examination of the knee and an aid to efficient preoperative planning.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2014-05-23
    Description: Growing evidence suggests that close appositions between the endoplasmic reticulum (ER) and other membranes, including appositions with the plasma membrane (PM), mediate exchange of lipids between these bilayers. The mechanisms of such exchange, which allows lipid transfer independently of vesicular transport, remain poorly understood. The presence of a synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain, a proposed lipid-binding module, in several proteins localized at membrane contact sites has raised the possibility that such domains may be implicated in lipid transport. SMP-containing proteins include components of the ERMES complex, an ER-mitochondrial tether, and the extended synaptotagmins (known as tricalbins in yeast), which are ER-PM tethers. Here we present at 2.44 A resolution the crystal structure of a fragment of human extended synaptotagmin 2 (E-SYT2), including an SMP domain and two adjacent C2 domains. The SMP domain has a beta-barrel structure like protein modules in the tubular-lipid-binding (TULIP) superfamily. It dimerizes to form an approximately 90-A-long cylinder traversed by a channel lined entirely with hydrophobic residues, with the two C2A-C2B fragments forming arched structures flexibly linked to the SMP domain. Importantly, structural analysis complemented by mass spectrometry revealed the presence of glycerophospholipids in the E-SYT2 SMP channel, indicating a direct role for E-SYTs in lipid transport. These findings provide strong evidence for a role of SMP-domain-containing proteins in the control of lipid transfer at membrane contact sites and have broad implications beyond the field of ER-to-PM appositions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135724/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135724/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schauder, Curtis M -- Wu, Xudong -- Saheki, Yasunori -- Narayanaswamy, Pradeep -- Torta, Federico -- Wenk, Markus R -- De Camilli, Pietro -- Reinisch, Karin M -- DK082700/DK/NIDDK NIH HHS/ -- GM080616/GM/NIGMS NIH HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- R01 DK082700/DK/NIDDK NIH HHS/ -- R01 GM080616/GM/NIGMS NIH HHS/ -- R37 NS036251/NS/NINDS NIH HHS/ -- R37NS36251/NS/NINDS NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 26;510(7506):552-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847877" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Endoplasmic Reticulum/metabolism ; Glycerophospholipids/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; *Lipid Metabolism ; *Lipids ; Mitochondria/metabolism ; Mitochondrial Proteins/chemistry/metabolism ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Synaptotagmins/*chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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