TY  - JOUR
AB  - The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7bΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7bΔIEC mice were compared to wildtype mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b-/-) model of WD on a C57Bl/6 background was previously generated and compared to respective WT. Hepatic copper, lipid metabolism, liver and intestine histology and electron microscopy were assessed over time up to 30 weeks of age. Whereas there was no evidence of intestine copper accumulation in the Atp7bΔIEC mice, transcriptome analysis in Atp7bΔIEC mice revealed changes in genes involved in AMPK signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b-/- and Atp7bΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that WD phenotype is at least partially influenced by organ-specific ATP7B variants.
AU  - Cáceres, A.*
AU  - Shibata, N.M.*
AU  - Davalos-Gutierrez, C.D.*
AU  - Sarode, G.V.*
AU  - Hussan, H.*
AU  - Bettencourt, M.*
AU  - Fontes, A.
AU  - Zischka, H.
AU  - Lutsenko, S.*
AU  - Heffern, M.C.*
AU  - Medici, V.*
C1  - 75815
C2  - 58102
TI  - Inactivation of Atp7b copper transporter in intestinal epithelial cells is associated with altered lipid processing and cell growth machinery independent from hepatic copper accumulation and severity of liver histology.
JO  - Am. J. Pathol.
PY  - 2025
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. In this context, we present a novel computational approach, the Graph Perceiver Network (GRAPE-Net), leveraging hematoxylin and eosin (H&E) stained whole slide images (WSIs) to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues. GRAPE-Net outperforms existing frameworks in classification accuracy predicting LUSC, lung adenocarcinoma (LUAD), and non-tumor (normal) lung tissue on The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets containing lung resection tissues while efficiently generating pathologist-aligned, class-specific heatmaps. The network was further tested using endobronchial biopsies from two data cohorts, containing normal to carcinoma in situ histology, and it demonstrated a unique capability to differentiate carcinoma in situ lung squamous PMLs based on their progression status to invasive carcinoma. The network may have utility in stratifying PMLs for chemoprevention trials or more aggressive follow-up.
AU  - Gindra, R.
AU  - Zheng, Y.*
AU  - Green, E.J.*
AU  - Reid, M.E.*
AU  - Mazzilli, S.A.*
AU  - Merrick, D.T.*
AU  - Burks, E.J.*
AU  - Kolachalama, V.B.*
AU  - Beane, J.E.*
C1  - 70419
C2  - 55611
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1285-1293
TI  - Graph perceiver network for lung tumor and bronchial premalignant lesion stratification from histopathology.
JO  - Am. J. Pathol.
VL  - 194
IS  - 7
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Bronchopulmonary dysplasia (BPD), also called chronic lung disease of immaturity, afflicts approximately one third of all extremely premature infants, causing lifelong lung damage. There is no effective treatment other than supportive care. Retinopathy of prematurity (ROP), which impairs vision irreversibly, is common in BPD, suggesting a related pathogenesis. However, specific mechanisms of BPD and ROP are not known. Herein, a neonatal mouse hyperoxic model of coincident BPD and retinopathy was used to screen for candidate mediators, which revealed that granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3, was up-regulated significantly in mouse lung lavage fluid and plasma at postnatal day 14 in response to hyperoxia. Preterm infants with more severe BPD had increased plasma G-CSF. G-CSF-deficient neonatal pups showed significantly reduced alveolar simplification, normalized alveolar and airway resistance, and normalized weight gain compared with wild-type pups after hyperoxic lung injury. This was associated with a marked reduction in the intensity, and activation state, of neutrophilic and monocytic inflammation and its attendant oxidative stress response, and protection of lung endothelial cells. G-CSF deficiency also provided partial protection against ROP. The findings in this study implicate G-CSF as a pathogenic mediator of BPD and ROP, and suggest the therapeutic utility of targeting G-CSF biology to treat these conditions.
AU  - Wickramasinghe, L.C.*
AU  - Tsantikos, E.*
AU  - Kindt, A.S.D.*
AU  - Raftery, A.L.*
AU  - Gottschalk, T.A.*
AU  - Borger, J.G.*
AU  - Malhotra, A.*
AU  - Anderson, G.P.*
AU  - van Wijngaarden, P.*
AU  - Hilgendorff, A.
AU  - Hibbs, M.L.*
C1  - 68613
C2  - 54734
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 2001-2016
TI  - Granulocyte colony-stimulating factor is a determinant of severe bronchopulmonary dysplasia and coincident retinopathy.
JO  - Am. J. Pathol.
VL  - 193
IS  - 12
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Emerging data suggest that type 1 diabetes affects not only the β-cell-containing islets of Langerhans, but also the surrounding exocrine compartment. Using digital pathology, machine learning algorithms were applied to provide high-resolution, whole-slide images of human pancreata to determine if the tissue composition in individuals with or at risk for type 1 diabetes differs from those without diabetes. Transplant-grade pancreata from organ donors were evaluated from 16 nondiabetic autoantibody negative controls, 8 nondiabetic autoantibody positive subjects who have increased type 1 diabetes risk, and 19 persons with type 1 diabetes (0 to 12 years' duration). HALO image analysis algorithms were implemented to compare architecture of the main pancreatic duct as well as cell size, density, and area of acinar, endocrine, ductal, and other nonendocrine, nonexocrine tissues. Type 1 diabetes was found to affect exocrine area, acinar cell density, and size, whereas the type of difference correlated with the presence or absence of insulin-positive cells remaining in the pancreas. These changes were not observed before disease onset, as indicated by modeling cross-sectional data from pancreata of autoantibody positive subjects and those diagnosed with type 1 diabetes. These data provide novel insights into anatomic differences in type 1 diabetes pancreata and demonstrate that machine learning can be adapted for the evaluation of disease processes from cross-sectional data sets.
AU  - Tang, X.*
AU  - Kusmartseva, I.*
AU  - Kulkarni, S.*
AU  - Posgai, A.*
AU  - Speier, S.
AU  - Schatz, D.A.*
AU  - Haller, M.J.*
AU  - Campbell-Thompson, M.*
AU  - Wasserfall, C.H.*
AU  - Roep, B.O.*
AU  - Kaddis, J,S.*
AU  - Atkinson, M.A.*
C1  - 61232
C2  - 49767
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 454-462
TI  - Image-based machine learning algorithms for disease characterization in the human type 1 diabetes pancreas.
JO  - Am. J. Pathol.
VL  - 191
IS  - 3
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Humanized mice developing functional human T cells endogenously and capable of recognizing cognate human leukocyte antigen matched tumors are emerging as relevant models for studying human immuno-oncology in vivo. Herein, mice transplanted with human CD34(+) stem cells and bearing endogenously developed human T cells for >15 weeks were infected with an oncogenic recombinant Epstein-Barr virus (EBV), encoding enhanced firefly luciferase and green fluorescent protein. EBV firefly luciferase was detectable 1 week after infection by noninvasive optical imaging in the spleen, from where it spread rapidly and systemically. EBV infection resulted into a pronounced immunologic skewing regarding the expansion of CD8(+) T cells in the blood outnumbering the CD4(+) T and CD19(+) B cells. Furthermore, within 10 weeks of infections, mice developing EBV-induced tumors had significantly higher absolute numbers of CD8(+) T cells in lymphatic tissues than mice controlling tumor development. Tumor outgrowth was paralleled by an up regulation of the programmed cell death receptor 1 on CD8(+) and CD4(+) T cells, indicative for T-cell dysfunction. Histopathological examinations and in situ hybridizations for EBV in tumors, spleen, liver, and kidney revealed foci of EBV-infected cells in perivascular regions in close association with programmed cell death receptor 1 positive infiltrating lymphocytes. The strong spatiotemporal correlation between tumor development and the T-cell dysfunctional status seen in this viral oncogenesis humanized model replicates observations obtained in the clinical setting.
AU  - Danisch, S.*
AU  - Slabik, C.*
AU  - Cornelius, A.*
AU  - Albanese, M.
AU  - Tagawa, T.
AU  - Chen, Y.-F. A.
AU  - Krönke, N.*
AU  - Eiz-Vesper, B.*
AU  - Lienenklaus, S.*
AU  - Bleich, A.*
AU  - Theobald, S.J.*
AU  - Schneider, A.*
AU  - Ganser, A.*
AU  - von Kaisenberg, C.*
AU  - Zeidler, R.
AU  - Hammerschmidt, W.
AU  - Feuerhake, F.*
AU  - Stripecke, R.*
C1  - 55071
C2  - 46082
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 521-539
TI  - Spatiotemporally skewed activation of PD-1 T cells after epstein barr virus infection and tumor development in long-term fully humanized mice.
JO  - Am. J. Pathol.
VL  - 189
IS  - 3
PB  - Elsevier Science Inc
PY  - 2019
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration (AMD) is unclear. Here we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE) or the vascular endothelium. Deletion of TGF-β signaling in the eye caused CNV, irrespectively if it was ablated in newborn or three-week-old mice. Areas of CNV showed photoreceptor degeneration, multilayered RPE, basal lamina deposits and accumulations of monocytes/macrophages. The changes progressed leading to marked structural and functional alterations of the retina. While the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype quite similar to that observed after the deletion in the entire eye. We conclude that impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as key player in the development of ocular neovascularization and indicate a fundamental role of TGF-β signaling in the pathogenesis of AMD.
AU  - Schlecht, A.*
AU  - Leimbeck, S.V.*
AU  - Jägle, H.*
AU  - Feuchtinger, A.
AU  - Tamm, E.R.*
AU  - Braunger, B.M.*
C1  - 51741
C2  - 43343
CY  - New York
SP  - 2570-2589
TI  - Deletion of endothelial TGF-β signaling leads to choroidal neovascularization.
JO  - Am. J. Pathol.
VL  - 187
IS  - 11
PB  - Elsevier Science Inc
PY  - 2017
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and a protease-rich local milieu that causes connective tissue breakdown of the lungs. As a result of its capacity to degrade lung tissue and the high risk of patients lacking α1-antitrypsin to develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar neutrophil serine proteases (NSPs), cathepsin G and proteinase 3, coexist with NE in humans and mice, but their potential tissue-destructive role(s) remains unclear. Using a gene-targeting approach, we observed that in contrast to their wild-type littermates, mice deficient in all three NSPs were substantially protected against lung tissue destruction after long-term exposure to cigarette smoke. In exploring the underlying basis for disrupted wild-type lung air spaces, we found that active NSPs collectively caused more severe lung damage than did NE alone. Furthermore, NSP activities unleashed increased activity of the tissue-destructive proteases macrophage elastase (matrix metalloproteinase-12) and gelatinase B (matrix metalloproteinase-9). These in vivo data provide, for the first time, compelling evidence of the collateral involvement of cathepsin G, NE, and proteinase 3 in cigarette smoke-induced tissue damage and emphysema. They also reveal a complex positive feed-forward loop whereby these NSPs induce the destructive potential of other proteases, thereby generating a chronic and pathogenic protease-rich milieu.
AU  - Guyot, N.*
AU  - Wartelle, J.*
AU  - Malleret, L.*
AU  - Todorov, A.A.*
AU  - Devouassoux, G.*
AU  - Pacheco, Y.*
AU  - Jenne, D.
AU  - Belaaouaj, A.*
C1  - 31617
C2  - 34629
CY  - New York
SP  - 985-995
TI  - Unopposed cathepsin G, neutrophil elastase, and proteinase 3 cause severe lung damage and emphysema.
JO  - Am. J. Pathol.
VL  - 184
IS  - 8
PB  - Elsevier Science Inc
PY  - 2014
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P < 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P < 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.
AU  - Müller-Höcker, J.*
AU  - Schäfer, S.G.*
AU  - Krebs, S.*
AU  - Blum, H.*
AU  - Zsurka, G.*
AU  - Kunz, W.S.*
AU  - Prokisch, H.
AU  - Seibel, P.*
AU  - Jung, A.*
C1  - 32688
C2  - 35585
CY  - New York
SP  - 2922-2935
TI  - Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.
JO  - Am. J. Pathol.
VL  - 184
IS  - 11
PB  - Elsevier Science Inc
PY  - 2014
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus-like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development.
AU  - Sabrautzki, S.
AU  - Janas, E.
AU  - Lorenz-Depiereux, B.
AU  - Calzada-Wack, J.
AU  - Aguilar-Pimentel, J.A.
AU  - Rathkolb, B.
AU  - Adler, T.
AU  - Cohrs, C.M.
AU  - Hans, W.
AU  - Diener, S.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Busch, D.H.*
AU  - Höfler, H.*
AU  - Ollert, M.*
AU  - Strom, T.M.
AU  - Wolf, E.*
AU  - Neff, F.
AU  - Hrabě de Angelis, M.
C1  - 25965
C2  - 32008
SP  - 352-368
TI  - An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease.
JO  - Am. J. Pathol.
VL  - 183
IS  - 2
PB  - Elsevier Science
PY  - 2013
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - The negative feedback regulation of epidermal growth factor receptor (EGFR) and other tyrosine kinase receptors, including receptor dephosphorylation and endocytosis followed by degradation, is becoming recognized as a major determinant of receptor function. To evaluate the significance of the negative regulation of EGFR during carcinogenesis in vivo, we subjected the mutant mouse line Dsk5, in which the intrinsic activation of the receptor due to a point mutation is normally counterbalanced by increased posttranslational receptor down-regulation, to skin chemical carcinogenesis. Dsk5 mice showed reduced tumor numbers and tumor burden compared with control littermates, and Dsk5-derived tumors showed a reduction in the activation and total levels of EGFR. Furthermore, the transcript levels of several molecules known to act as negative regulators of EGFR were significantly increased in Dsk5-derived tumors. Another intriguing observation was the appearance of tumors with sebaceous differentiation in the ears of Dsk5 mice after chemical carcinogenesis. Further studies are necessary to reveal whether these tumors represent a cell type-specific evasion from EGFR negative feedback machinery. In conclusion, this study reveals that several negative feedback regulators contribute to suppression of the intrinsic activation of mutant EGFR during skin carcinogenesis, stressing the potential exploitation of negative regulators as either therapeutic targets or diagnostic tools in cancer and other diseases.
AU  - Dahlhoff, M.*
AU  - Rose, C.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Schneider, M.R.*
C1  - 7389
C2  - 29696
SP  - 1378-1385
TI  - Negative feedback mechanisms surpass the effect of intrinsic EGFR activation during skin chemical carcinogenesis.
JO  - Am. J. Pathol.
VL  - 180
IS  - 4
PB  - Elsevier
PY  - 2012
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Tumor cell extravasation is a critical step in the metastatic cascade and requires interaction between the tumor cell and the endothelium. Although cancer progression depends on a complex network of mechanisms, including inflammation and coagulation, the involvement of tumor-induced endothelium activation and the subsequent release of procoagulatory factors in this process are not well understood. Using tissue sections from patients with malignant melanoma, immunofluorescence studies for the presence of von Willebrand factor (VWF) clearly demonstrated endothelium activation and the formation of ultra-large VWF fibers in these patients. In vitro analyses revealed that supernatants from highly invasive melanoma cells induced an acute endothelium activation measured by VWF, P-selectin, and angiopoietin-2 release. Proteome profiling identified vascular endothelial growth factor A (VEGF-A) as the main mediator of endothelium activation. Inhibition and knock-down of VEGF-A in melanoma cells led to a rigorous decrease in VWF exocytosis. Selective small-interfering RNA to matrix metalloproteinase-2 (MMP-2) inhibited endothelium activation, and this effect correlated with reduced VEGF-A content in the supernatants of melanoma cells. Further experiments showed that active MMP-2 regulates VEGF-A in melanoma cells on a transcriptional level via an integrin alpha v beta 5/phosphoinositide-3-kinase dependent pathway. In conclusion, these results indicate an important role of VEGF-A in acute endothelium activation and provide clear evidence that MMP-2 plays a pivotal role in the autocrine regulation of VEGF-A expression in melanoma cells. (Ani J Pathol 2012, 181: 693-705,- http://dx.doi.org/10.1016/j.ajpath.2012.04.012)
AU  - Desch, A.*
AU  - Strozyk, E.A.
AU  - Bauer, A.T.*
AU  - Huck, V.*
AU  - Niemeyer, V.*
AU  - Wieland, T.*
AU  - Schneider, S.W.*
C1  - 8438
C2  - 30147
SP  - 693-705
TI  - Highly invasive melanoma cells activate the vascular endothelium via an MMP-2/Integrin αvβ5-induced secretion of VEGF-A.
JO  - Am. J. Pathol.
VL  - 181
IS  - 2
PB  - Elsevier
PY  - 2012
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Pulmonary hypertension (PH) is a life-threatening disorder that is characterized by pulmonary arterial smooth muscle cell (PASMC) hyperplasia. Until now, little was been known about early changes that underlie the manifestation of PH. To characterize these early changes, we performed whole-genome microarray analysis of lungs from mice exposed to either 24 hours hypoxia or normoxia. TrkB, a member of the tyrosine kinase receptor family, and its ligand, brain-derived neurotrophic factor (BDNF), were strongly up-regulated in hypoxic mouse lungs, as well as in arteries of patients suffering from idiopathic pulmonary arterial hypertension (IPAH). BDNF stimulation of PASMC in vitro resulted in increased proliferation, TrkB and ERK1/2 phosphorylation, and nuclear translocation of the transcription factor early growth response factor 1 (Egr-1). In addition, increased Egr-1 expression was observed in idiopathic PAH lungs. The pro-proliferative effect of BDNF was attenuated by TrkB kinase inhibitor (K252a) or ERK1/2 inhibitor (U0126) pretreatment, and by knocking down Egr-1. Consequently, we have identified the BDNF-TrkB-ERK1/2 pathway as a proproliferative signaling pathway for PASMC in PH. Interference with this pathway may thus serve as an attractive reverse remodeling approach.
AU  - Kwapiszewska, G.*
AU  - Chwalek, K.*
AU  - Marsh, L.M.*
AU  - Wygrecka, M.*
AU  - Wilhelm, J.*
AU  - Best, J.*
AU  - Egemnazarov, B.*
AU  - Weisel, F.C.*
AU  - Osswald, S.L.*
AU  - Schermuly, R.T.*
AU  - Olschewski, A.*
AU  - Seeger, W.*
AU  - Weissmann, N.*
AU  - Eickelberg, O.
AU  - Fink, L.*
C1  - 11346
C2  - 30632
SP  - 2018-2029
TI  - BDNF/TrkB signaling augments smooth muscle cell proliferation in pulmonary hypertension.
JO  - Am. J. Pathol.
VL  - 181
IS  - 6
PB  - Elsevier
PY  - 2012
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Proteomics-based approaches allow us to investigate the biology of cancer beyond genomic initiatives. We used histology-based matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry to identify proteins that predict disease outcome in gastric cancer after surgical resection. A total of 181 intestinal-type primary resected gastric cancer tissues from two independent patient cohorts were analyzed. Protein profiles of the discovery cohort (n = 63) were directly obtained from tumor tissue sections by MALDI imaging. A seven-protein signature was associated with an unfavorable overall survival independent of major clinical covariates. The prognostic significance of three individual proteins identified (CRIP1, HNP-1, and S100-A6) was validated immunohistochemically on tissue microarrays of an independent validation cohort (n = 118). Whereas HNP-1 and S100-A6 were found to further subdivide early-stage (Union Internationale Contre le Cancer [UICC]-I) and late-stage (UICC II and III) cancer patients into different prognostic groups, CRIP1, a protein previously unknown in gastric cancer, was confirmed as a novel and independent prognostic factor for all patients in the validation cohort. The protein pattern described here serves as a new independent indicator of patient survival complementing the previously known clinical parameters in terms of prognostic relevance. These results show that this tissue-based proteomic approach may provide clinically relevant information that might be beneficial in improving risk stratification for gastric cancer patients.
AU  - Balluff, B.
AU  - Rauser, S.
AU  - Meding, S.
AU  - Elsner, M.
AU  - Schöne, C.
AU  - Feuchtinger, A.
AU  - Schuhmacher, C.*
AU  - Novotny, A.*
AU  - Jütting, U.
AU  - Maccarrone, G.*
AU  - Sarioglu, H.
AU  - Ueffing, M.
AU  - Braselmann, H.
AU  - Zitzelsberger, H.
AU  - Schmid, R.M.
AU  - Höfler, H.
AU  - Ebert, M.P.*
AU  - Walch, A.K.
C1  - 6626
C2  - 29004
CY  - New York, USA
SP  - 2720-2729
TI  - MALDI imaging identifies prognostic seven-protein signature of novel tissue markers in intestinal-type gastric cancer.
JO  - Am. J. Pathol.
VL  - 179
IS  - 6
PB  - Elsevier
PY  - 2011
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209(+) DCs in RCCs was found to be associated with an unfavorable T(H)1 cell balance in the tissue and advanced tumor stages. The CD209(+) DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for T(H)1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC.
AU  - Figel, A.-M.
AU  - Brech, D.
AU  - Prinz, P.U.
AU  - Lettenmeyer, U.K.
AU  - Eckl, J.
AU  - Turqueti-Neves, A.
AU  - Mysliwietz, J.
AU  - Anz, D.*
AU  - Rieth, N.*
AU  - Muenchmeier, N.*
AU  - Buchner, A.*
AU  - Porubsky, S.*
AU  - Siegert, S.I.*
AU  - Segerer, S.*
AU  - Nelson, P.J.*
AU  - Nößner, E.
C1  - 6606
C2  - 28974
CY  - New York, NJ
SP  - 436-451
TI  - Human renal cell carcinoma induces a dendritic cell subset that uses T-cell crosstalk for tumor-permissive milieu alterations.
JO  - Am. J. Pathol.
VL  - 179
IS  - 1
PB  - Elsevier
PY  - 2011
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Four homologs to the Drosophila homeotic gene spalt (sat) exist in both humans and mice (SALL1 to SALL4/Sall1 to Sall4, respectively). Mutations in both SALL1 and SALL4 result in the autosomal-dominant developmental disorders Townes-Brocks and Okihiro, syndrome, respectively. in contrast, no human diseases have been associated with SALL2 to date, and Sall2-deficient mice have shown no apparent abnormal phenotype. We generated mice deficient in Sall2 and, contrary to previous reports, 11% of our Sall2-deficient mice showed background-specific neural tube defects, suggesting that Sall2 has a role in neurogenesis. To investigate whether Sall4 may compensate for the absence of Sall2, we generated compound Sall2 knockout/Sall4 genetrap mutant mice. In these mutants, the incidence of neural tube defects was significantly increased. Furthermore, we found a similar phenotype in compound Sall1/4 mutant mice, and in vitro studies showed that SALL1, SALL2, and SALL4 all co-localized in the nucleus. We therefore suggest a fundamental and redundant function of the Sall proteins in murine neurulation, with the heterozygous loss of a particular SALL protein also possibly compensated in humans during development.
AU  - Böhm, J.*
AU  - Buck, A.*
AU  - Borozdin, W.*
AU  - Mannan, A.U.*
AU  - Matysiak-Scholze, U.*
AU  - Adham, I.*
AU  - Schulz-Schaeffer, W.*
AU  - Floß, T.
AU  - Wurst, W.
AU  - Kohlhase, J.*
AU  - Barrionuevo, F.*
C1  - 1806
C2  - 25887
SP  - 1455-1463
TI  - Sall1, Sall2, and Sall4 Are Required for Neural Tube Closure in Mice.
JO  - Am. J. Pathol.
VL  - 173
IS  - 5
PB  - Amer Soc Investigative Pathology, Inc.
PY  - 2008
SN  - 0002-9440
ER  - 

TY  - JOUR
AU  - Naschberger, E.*
AU  - Lubeseder-Martellato, C.
AU  - Meyer, N.*
AU  - Gessner, R.*
AU  - Kremmer, E.
AU  - Gessner, A.*
AU  - Stürzl, M.*
C1  - 5163
C2  - 24135
SP  - 1088-1099
TI  - Human guanylate binding protein-1 is a secreted GTPase present in increased concentrations in the cerebrospinal fluid of patients with bacterial meningitis.
JO  - Am. J. Pathol.
VL  - 169
PY  - 2006
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Primary lymphomas of the central nervous system (PCNSLs) were investigated for their capacity to perform further maturation steps. We studied a series of 11 PCNSLs derived from immunocompetent patients for immunoglobulin (Ig) class switch recombination (CSR) by performing reverse transcriptase-polymerase chain reaction (RT-PCR) for transcripts of Ig constant region gene segments (IGHC). This analysis revealed exclusive transcription of IgM and IgD mRNA in the absence of IgG, IgA, or IgE transcription. This finding was corroborated at the protein level by the immunohistochemical demonstration of IgM on the surface of the tumor cells. The unexpected lack of CSR may be due to internal switch μ region deletions, which were detected in 7 of 11 cases. We also found that expression of activation-induced cytidine deaminase (AID), which is required for CSR and somatic hypermutation, was detectable by RT-PCR in 4 of 10 cases and by immunohistochemistry in one of three cases analyzed. This may indicate that ongoing somatic mutation, which is often observed in PCNSL, could be due to sustained AID expression in a fraction of cases and that intraclonal V gene diversity may occur in other cases at an earlier phase of tumor clone expansion, when AID may have been expressed.
AU  - Montesinos-Rongen, M.*
AU  - Schmitz, R.*
AU  - Courts, C.*
AU  - Stenzel, W.*
AU  - Bechtel, D.*
AU  - Niedobitek, G.*
AU  - Blümcke, I.*
AU  - Reifenberger, G.*
AU  - von Deimling, A.*
AU  - Jungnickel, B.
AU  - Wiestler, O.D.*
C1  - 5391
C2  - 22708
SP  - 1773-1779
TI  - Absence of immunoglobulin class switch in primary lymphomas of the central nervous system.
JO  - Am. J. Pathol.
VL  - 166
IS  - 6
PY  - 2005
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - One limitation in understanding disease at the cellular level has been the inability to efficiently analyze DNA on a cell-to-cell basis within the natural tissue context. However, DNA analyses at a single-cell resolution should be instrumental for the understanding of cancer cell biology, cancer evolution, for chromosomal mosaic analysis and rare cell events, and should provide otherwise inaccessible information on essential biological processes. Here we present a fluorescence in situ hybridization-based multicolor deconvolution technique for three-dimensional microscopy. We use up to seven different color channels for probe detection, which allows the simultaneous high-resolution localization of multiple point-like sources within a biological specimen with a thickness of up to 30 μm. In addition, a DNA counterstain is used for volume labeling of the nuclei offering the opportunity for a simultaneous segmentation of nuclei. Furthermore, as the instrumentation consists of a standard fluorescence microscope it represents a low-cost method as compared to confocal microscopy.
AU  - Maierhofer, C.
AU  - Gangnus, R.
AU  - Diebold, J.*
AU  - Speicher, M.R.
C1  - 9738
C2  - 21588
SP  - 373-379
TI  - Multicolor deconvolution microscopy of thick biological specimens.
JO  - Am. J. Pathol.
VL  - 162
IS  - 2
PY  - 2003
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three groups in terms of proliferation rate or expression of anti-apoptotic proteins. However, cyclin D1+ cases were always well differentiated and were more likely to show a lymphoplasmocytoid differentiation (chi-square = 9.55). Overall, constitutive activation of Stat 3 was found in almost half (48%) of the investigated MM cases. However, this does not seem to have a major impact on the expression of anti-apoptotic proteins and proliferation. We showed that cyclin D1 overexpression and Stat 3 activation are, mutually exclusive events in MM (P = 0.0066). The universal expression of Mcl-1, independent of activated Stat 3, suggests that its expression is constitutive and that it might play an important role in the pathogenesis of MM.
AU  - Quintanilla-Martinez, L.
AU  - Kremer, M.
AU  - Specht, K.
AU  - Calzada-Wack, J.
AU  - Nathrath, M.
AU  - Schaich, R.
AU  - Höfler, H.*
AU  - Fend, F.*
C1  - 9736
C2  - 20976
SP  - 1449-1461
TI  - Analysis of Signal Transducer and Activator of Transcription 3 (Stat 3) Pathway in Multiple Myeloma : Stat 3 Activation and Cyclin D1 Dysregulation Are Mutually Exclusive Events.
JO  - Am. J. Pathol.
VL  - 162
IS  - 5
PY  - 2003
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Cytogenetic changes are widely unknown for nonpolypoid (synonymously termed as “flat” or “depressed”) colorectal adenomas. A comparison with polypoid adenomas will contribute to the discussion whether different genetic pathways for colorectal tumorigenesis depending on its origin from nonpolypoid or polypoid adenomas exist. Tissue samples of nonpolypoid (n = 22), polypoid (n = 28) adenomas, carcinomas ex-nonpolypoid adenomas (n = 9), carcinomas ex-polypoid adenomas (n = 14), and normal colonic mucosa (n = 9) were investigated by comparative genomic hybridization of whole genomic DNA. Chromosomal imbalances were detected from average comparative genomic hybridization profiles for each entity. Nonpolypoid adenomas show recurrent chromosomal losses on chromosomes 16, 17p, 18, 20, and 22 and gains on chromosomes 2q, 4q, 5, 6, 8q, 12q, and 13q. In polypoid adenomas losses of whole chromosomes 16, 18, and 22 and gains of chromosomes 7q and 13 were detected. The frequency of copy number changes was higher in nonpolypoid compared to polypoid adenomas and early onset of chromosomal changes became apparent in low-grade dysplasias of nonpolypoid adenomas. Gains on chromosomes 2q, 5, 6, 8q, and 12q and losses on chromosomes 17p and 20 occurred exclusively in nonpolypoid adenomas, whereas 16p deletions are significantly more frequent in nonpolypoid than in polypoid adenomas. Carcinomas ex-nonpolypoid adenomas are characterized by more complex aberration patterns compared to nonpolypoid adenomas exhibiting frequent losses on chromosomes 8p, 12q, 14, 15q, 16, 17p, 18, and 22 and gains on 3q, 5, 6, 7, 8q, 12q, and 13, respectively. Normal colonic mucosa showed no chromosomal imbalances. Distinct differences of chromosomal imbalances between nonpolypoid and polypoid colorectal adenomas have been characterized that support the hypothesis that different genetic pathways may exist in the development of colorectal adenomas exhibiting nonpolypoid and polypoid phenotype.
AU  - Richter, H.
AU  - Slezak, P.*
AU  - Walch, A.K.*
AU  - Werner, M.*
AU  - Braselmann, H.
AU  - Jaramillo, E.*
AU  - Öst, A.*
AU  - Hirata, I.*
AU  - Takahama, K.*
AU  - Zitzelsberger, H.
C1  - 9737
C2  - 21153
SP  - 287-294
TI  - Distinct Chromosomal Imbalances in Nonpolypoid and Polypoid Colorectal Adenomas Indicate Different Genetic Pathways in the Development of Colorectal Neoplasms.
JO  - Am. J. Pathol.
VL  - 163
IS  - 1
PY  - 2003
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - During angiogenesis and inflammatory processes, endothelial cells acquire different activation phenotypes, whose identification may help in understanding the complex network of angiogenic and inflammatory interactions in vivo. To this goal we investigated the expression of the human guanylate-binding protein (GBP)-1 that is highly induced by inflammatory cytokines, (ICs) and, therefore, may characterize IC-activated cells. Using a new rat monoclonal antibody raised against GBP-1, we show that GBP-1 is a cytoplasmic protein and that its expression in endothelial cells is selectively induced by interferon-gamma, interleukin-1alpha, interleukin-1beta, or tumor necrosis factor-a, but not by other cytokines, chemokines, or growth factors. Moreover, we found that GBP-1 expression is highly associated with vascular endothelial cells as confirmed by the simultaneous detection of GBP-1 and the endothelial cell-associated marker CD31 in a broad range of human tissues. Notably, GBP-1 expression was undetectable in the skin, but it was highly induced in vessels of skin diseases with a high-inflammatory component including psoriasis, adverse drug reactions, and Kaposi's sarcoma. These results indicate that GBP-1 is a novel cellular activation marker that characterizes the IC-activated phenotype of endothelial cells.
AU  - Lubeseder-Martellato, C.
AU  - Guenzi, E.
AU  - Jörg, A.
AU  - Töpolt, K.
AU  - Naschberger, E.
AU  - Kremmer, E.
AU  - Zietz, C.*
AU  - Tschachler, E.*
AU  - Hutzler, P.
AU  - Schwemmle, M.*
AU  - Matzen, K.
AU  - Grimm, Th.
AU  - Ensoli, B.*
C1  - 9735
C2  - 20425
SP  - 1749-1759
TI  - Guanylate-Binding Protein-1 Expression is Selectively Induced by Inflammatory Cytokines and is an Activation Marker of Endothelial Cells during Inflammatory Diseases.
JO  - Am. J. Pathol.
VL  - 161
IS  - 5
PB  - American Society for Investigative Pathology
PY  - 2002
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin is thought to play a fundamental role during early steps of invasion and metastasis of carcinoma cells. The aim of our study was to elucidate the role of EMT regulators Snail, SIP1 (both are direct repressors of E-cadherin), and Twist (an activator of N-cadherin during Drosophila embryogenesis), in primary human gastric cancers. Expression of Snail, SIP1, and Twist was analyzed in 48 gastric carcinomas by real-time quantitative RT-PCR in paraffin-embedded and formalin-fixed tissues. The changes of expression levels of these genes in malignant tissues compared to matched non-tumorous tissues were correlated with the expression of E- and N-cadherin. From 28 diffuse-type gastric carcinomas analyzed reduced E-cadherin expression was detected in 11 (39%) cases compared to non-tumorous tissues. Up-regulated Snail could be found in 6 cases with reduced or negative E-cadherin expression. However, there was no correlation to increased SIP1 expression. Interestingly, we could detect abnormal expression of N-cadherin mRNA in 6 cases, which was correlated with Twist overexpression in 4 cases. From 20 intestinal-type gastric cancer samples reduced E-cadherin expression was found in 12 (60%) cases, which was correlated to up-regulation of SIP1, since 10 of these 12 cases showed elevated mRNA levels, whereas Snail, Twist, and N-cadherin were not up-regulated. We present the first study investigating the role of EMT regulators in human gastric cancer and provide evidence that an increase in Snail mRNA expression is associated with down-regulation of E-cadherin in diffuse-type gastric cancer. We detected abnormally positive or increased N-cadherin mRNA levels in the same tumors, probably due to overexpression of Twist. SIP1 overexpression could not be linked to down-regulated E-cadherin in diffuse-type tumors, but was found to be involved in the pathogenesis of intestinal-type gastric carcinoma. We conclude that EMT regulators play different roles in gastric carcinogenesis depending on the histological subtype.
AU  - Rosivatz, E.*
AU  - Becker, I.*
AU  - Specht, K.
AU  - Fricke, E.*
AU  - Luber, B.*
AU  - Busch, R.*
AU  - Höfler, H.
AU  - Becker, K.-F.*
C1  - 21999
C2  - 20535
SP  - 1881-1891
TI  - Differential Expression of the Epithelial-Mesenchymal Transition Regulators Snail, SIP1 and Twist in Gastric Cancer.
JO  - Am. J. Pathol.
VL  - 161
IS  - 5
PY  - 2002
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43% each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), HGD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN (22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.
AU  - Walch, A.K.
AU  - Zitzelsberger, H.
AU  - Bruch, J.
AU  - Keller, G.*
AU  - Angermeier, D.*
AU  - Aubele, M.
AU  - Müller, J.*
AU  - Stein, H.*
AU  - Braselmann, H.
AU  - Siewert, J.R.*
AU  - Höfler, H.
AU  - Werner, M.*
C1  - 23352
C2  - 31125
SP  - 555-566
TI  - Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence.
JO  - Am. J. Pathol.
VL  - 156
IS  - 2
PB  - Elsevier
PY  - 2000
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - E-Cadherin alterations have been reported frequently in sporadic diffuse type gastric and lobular breast carcinomas. Germline mutations of this gene have been identified recently in several gastric cancer families. We analyzed seven patients with a family history of the disease who had diffuse type gastric cancer diagnosed before the age of 45 for germline mutations in CDH1, the gene encoding the E-cadherin protein. We identified a frameshift mutation in exon 3 in one patient with a strong family history of gastric cancer. The same germline mutation was found in the patient's mother, who had metachronous development of lobular breast and diffuse type gastric carcinomas. Immunohistochemistry for E-cadherin protein expression revealed an abnormal staining pattern in both of these tumors, suggesting complete inactivation of the cell adhesion molecule. Thus, our finding suggests that besides diffuse type gastric cancer, lobular breast carcinomas may be associated with germline CDH1 mutations.
AU  - Keller, G.*
AU  - Vogelsang, H.*
AU  - Becker, I.*
AU  - Grundei, T.*
AU  - Becker, K.-F.*
AU  - Müller, J.*
AU  - Siewert, J.R.*
AU  - Höfler, H.
C1  - 21182
C2  - 19228
SP  - 337-342
TI  - Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E- cadherin germline mutation.
JO  - Am. J. Pathol.
VL  - 155
IS  - 2
PY  - 1999
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Amylin was isolated from human insulinomas, but there has been only preliminary data regarding whether this peptide can also be detected in other types of gastroenteropancreatic endocrine tumors. In the present study, immunohistochemical staining of 87 gastroenteropancreatic endocrine tumors demonstrated amylin immunoreactivity in 21.8% of the neoplasmas. Thirteen of 15 insulinomas, three of 21 gastrinomas, two of 29 nonfunctioning tumors, and one of 18 carcinoids were amylin-immunoreactive. Seventeen of the 19 amylin- immunoreactive tumors were primarily located in the pancreas, but two tumors were found in the intestine. Measurements of amylin messenger RNA expression in a few tumors revealed amylin synthesis in these tumors. Amylin immunoreactivity did not correlate with invasion and metastasis. However, the rate of curative resections was significantly higher in amylin-immunoreactive tumors. These results demonstrate for the first time that amylin immunoreactivity is not restricted to insulinomas and can also occur rarely in endocrine tumors of the intestine.
AU  - Eissele, R.
AU  - Neuhaus, C.
AU  - Trautmann, M.E.
AU  - Funk, A.
AU  - Arnold, R.P.
AU  - Höfler, H.
C1  - 40407
C2  - 40030
SP  - 283-291
TI  - Immunoreactivity and expression of amylin in gastroenteropancreatic endocrine tumors.
JO  - Am. J. Pathol.
VL  - 143
IS  - 1
PY  - 1993
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - The spectrum of p53 gene mutations was determined in formalin-fixed, paraffin-embedded samples of small-cell lung cancer derived from 28 patients. By direct sequencing of exons 5, 7, and 8, including their flanking intron sequences, 18 mutations were identified in 17 tumors (61%), and in all but two of these the wild type allele was lost. In 8 cases, the mutation detected in the tumor was absent from the corresponding normal tissue, indicating that these mutations were somatically acquired. In two patients, identical mutations were found in the primary tumor and corresponding metastases. In a further case, an intrapulmonary metastasis did not show the mutation detected in the primary tumor. The local distribution of the mutations resembled that reported in non-small cell lung cancer and gave no indication of distinct bot spot regions. G-to-T transversions were the predominant type of mutation, reflecting a possible genotoxic influence of carcinogens contained in tobacco smoke. Mutations were equally distributed among tumors with intermediate and oat cell histology and did not show a significant association to age and gender of the patients. Also, no significant relationship was observed between the presence of a mutation and tumor stage (T, N, M) or survival. However, transitions at CpG dinucleotides were restricted to tumors without detectable metastases at the time of biopsy, whereas all other mutations occurred in metastasizing small cell lung cancer.
AU  - Lohmann, D.
AU  - Pütz, B.
AU  - Reich, U.
AU  - Böhm, J.
AU  - Präuer, H.W.
AU  - Höfler, H.
C1  - 20237
C2  - 13420
SP  - 907-915
TI  - Mutational Spectrum of the p53 Gene in Human Small-Cell Lung Cancer and Relationship to Clinicopathological Data.
JO  - Am. J. Pathol.
VL  - 142
IS  - 3
PY  - 1993
SN  - 0002-9440
ER  - 

TY  - JOUR
AU  - Goralczyk, R.
AU  - Luz, A.
AU  - Erfle, V.
AU  - Schmidt, J.
C1  - 18086
C2  - 10934
TI  - In Vitro Progression and Metastasizing Potential of Murine Osteosarcoma Virus (FBR MSV) - induced Tumors.
JO  - Am. J. Pathol.
PY  - 1989
SN  - 0002-9440
ER  - 

TY  - JOUR
AU  - Schmidt, J.
AU  - Luz, A.
AU  - Casser-Bette, M.
AU  - Erfle, V.
C1  - 18087
C2  - 10935
TI  - The Target Cell of FBR Murine Osteosarc oma Virus (FBR MSV) - induced Neoplasia.
JO  - Am. J. Pathol.
PY  - 1989
SN  - 0002-9440
ER  - 

TY  - JOUR
AB  - Newborn female strain NMRI mice were given injections of a mouse retrovirus (OA MuLV) known to induce osteopetrosis, osteoma, and lymphoma. Femur metaphyses and lumbar vertebrae were investigated ultrastructurally 3 d, 7 d and 28 d after infection. Budding, immature and mature virus was observed associated with osteoblasts and osteocytes, but not with osteoclasts or chondrocytes, 28 d after infection with the virus. No production of virus particles was observed in bone-tissue in mock-treated controls. Thus, the primary target cell for OA virus in bone appears to belong to the osteoblastic/osteocytic cell lineage.
AU  - Murray, A.B.
AU  - Schmid, J.
AU  - Rieke, L.
C1  - 40900
C2  - 36120
SP  - 319-323
TI  - Retrovirus-induced osteopetrosis in mice : Ultrastructural evidence of early virus production in osteoblasts and osteocytes.
JO  - Am. J. Pathol.
VL  - 124
IS  - 2
PY  - 1986
SN  - 0002-9440
ER  -