Publications by authors named "Christina Perske"

25 Publications

  • Page 1 of 1

Mucoricin is a ricin-like toxin that is critical for the pathogenesis of mucormycosis.

Nat Microbiol 2021 Mar 18;6(3):313-326. Epub 2021 Jan 18.

Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, USA.

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We demonstrate that Mucorales fungi produce a toxin, which plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro and prevent hypovolemic shock, organ necrosis and death in mice with mucormycosis. Inhibition of the toxin in Rhizopus delemar through RNA interference compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin ricin, including the ability to inhibit protein synthesis through its N-glycosylase activity, the existence of a motif that mediates vascular leak and a lectin sequence. Antibodies against the toxin inhibit R. delemar- or toxin-mediated vascular permeability in vitro and cross react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name 'mucoricin' for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricin-like toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target.
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http://dx.doi.org/10.1038/s41564-020-00837-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914224PMC
March 2021

Breast lesion size assessment in mastectomy specimens: Correlation of cone-beam breast-CT, digital breast tomosynthesis and full-field digital mammography with histopathology.

Medicine (Baltimore) 2019 Sep;98(37):e17082

Institute for Pathology, University Medical Center Goettingen, Germany.

To compare the accuracy of breast lesion size measurement of cone-beam breast-CT (CBBCT), digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM).Patients scheduled for mastectomy due to at least 1 malignant breast lesion were included. Mastectomy specimens were examined by CBBCT, DBT, FFDM, and histopathology.A total of 94 lesions (40 patients) were included. Histopathological analyses revealed 47 malignant, 6 high-risk, and 41 benign lesions. Mean histopathological lesion size was 20.8 mm (range 2-100). Mean absolute size deviation from histopathology was largest for FFDM (5.3 ± 6.7 mm) and smallest for CBBCT 50 mA, high-resolution mode (4.3 ± 6.7 mm). Differences between imaging modalities did not reach statistical significance (P = .85).All imaging methods tend to overestimate breast lesion size compared to histopathological gold standard. No significant differences were found regarding size measurements, although in tendency CBBCT showed better lesion detection and cT classification over FFDM.
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http://dx.doi.org/10.1097/MD.0000000000017082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750260PMC
September 2019

Of Cestodes and Men: Surgical Treatment of a Spinal Hydatid Cyst.

J Neurol Surg A Cent Eur Neurosurg 2020 Jan 4;81(1):86-90. Epub 2019 Sep 4.

Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August-University of Göttingen, Göttingen, Germany.

Background:  The cestode causes hydatid disease. In addition to manifestations in the liver and lung, it can lead to cystic lesions in the spine.

Case Description:  We report a 42-year-old male patient with primary hydatid disease in the eighth thoracic vertebra. The only clinical symptom was chronic back pain. Although laboratory findings were normal, imaging displayed lytic destruction that raised the suspicion of a metastatic disease. Diagnostics of the thoraces and abdomen did not reveal other pathologic abnormalities. Follow-up magnetic resonance imaging (MRI) depicted a progressive compression of the spinal cord and inhomogeneous structure in the fat-suppressed sequences. Because the Jamshidi biopsy was inconclusive, the tumor board recommended surgery. Dorsal decompression, spondylodesis of T6-T10, and vertebral column resection of T8 with complete cyst removal were performed. The resected vertebrae showed a mucous-like lesion with white granular tissue interfusing the whole vertebral body. A pathologic examination and enzyme-linked immunosorbent assay confirmed . Thus chemotherapy with albendazole was initiated. A follow-up MRI of the whole spine confirmed complete remission and found no additional resettlements. The patient's back pain was resolved without neurologic deficits.

Conclusions:  For lytic manifestations of the vertebral column, hydatid cysts should be considered a differential diagnosis in addition to malignant metastasis, tuberculosis, and osteomyelitis. Thorough surgical resection and strict follow-up are necessary.
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http://dx.doi.org/10.1055/s-0039-1693707DOI Listing
January 2020

Validation of the Endothelial Cell Receptor GRP78 in a Case of Rhinocerebral Mucormycosis.

Antimicrob Agents Chemother 2018 05 26;62(5). Epub 2018 Apr 26.

Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany

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http://dx.doi.org/10.1128/AAC.00172-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923111PMC
May 2018

Generation of highly differentiated BHY oral squamous cell carcinoma multicellular spheroids.

Mol Clin Oncol 2018 Feb 27;8(2):323-325. Epub 2017 Nov 27.

Department of Oral and Maxillofacial Surgery, University Medical Centre Goettingen, D-37075 Goettingen, Germany.

Three-dimensional (3D) multicellular spheroids (MCS) are considered suitable models in cancer research and anticancer drug development. Although studying the complex tumour characteristics from all different degrees of malignancy is vital, MCS generation has only been described in a few moderately- and poorly differentiated oral squamous cell carcinoma (OSCC) cell lines. No previous study has demonstrated the MCS formation in a highly differentiated OSCC cell line. For the first time, the present study aimed to generate MCS from the highly differentiated OSCC cell line BHY. BHY spheroids were grown in three independent experiments in 96-well plates through the use of the liquid overlay technique. Although BHY cells are grow slowly and are difficult to culture, they formed compact MCS within 24 h. After 3 days of incubation, no further increase in spheroid size was observed. MCS were harvested, paraffin-embedded and 2 µm tissue sections were prepared for further analysis. The diameter and volume of each spheroid were determined. BHY MCS diameter ranged between 46.76 and 233.26 µm, with a volume range from 5.35×10-6.65×10 µm. In conclusion, using the liquid overlay technique, the highly differentiated OSCC cell line BHY forms different sized spheroids, which may be used for further investigations.
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http://dx.doi.org/10.3892/mco.2017.1514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774389PMC
February 2018

Leucaemia cutis bei einem Patienten mit chronischer myelomonozytärer Leukämie.

J Dtsch Dermatol Ges 2018 Jan;16(1):82-84

Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen.

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http://dx.doi.org/10.1111/ddg.13398_gDOI Listing
January 2018

Leukemia cutis in a patient with chronic myelomonocytic leukemia.

J Dtsch Dermatol Ges 2018 Jan 30;16(1):81-83. Epub 2017 Dec 30.

Department of Dermatology, Venereology, and Allergology, University Medicine Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1111/ddg.13398DOI Listing
January 2018

High mast cell density indicates a longer overall survival in oral squamous cell carcinoma.

Sci Rep 2017 11 7;7(1):14677. Epub 2017 Nov 7.

Department of Pathology, University Medical Centre Goettingen, Goettingen, Germany.

This study evaluates the effects of tumour-associated mast cells on the prognosis of patients suffering from oral squamous cell carcinoma (OSCC). Tryptase-positive (MCT) and CD117-positive (CD117) mast cells were immunohistochemically evaluated in tissue samples of 118 OSCC patients. Besides, various clinicopathological parameters, the influence of the MCT and CD117 mast cell density on overall survival and the incidence of first local recurrence was analysed by Cox regression and competing risk regression. Among all investigated parameters, multiple Cox regression revealed a significant influence of the MCT (cut-off at 14.87 mast cells/mm stroma; p = 0.0027) and CD117 mast cell density (cut-off at 33.19 mast cells/mm stroma; p = 0.004), the age at primary diagnosis, and the T and N stage (all p-values < 0.05) on overall survival. Patients with a low mast cell density showed a significantly poorer overall survival rate compared to those with a high mast cell density in the tumour-associated stroma. Competing risk regression revealed a significant influence of the resection status (R) on the incidence of first local recurrence (p = 0.0023). A high mast cell density in the tumour-associated stroma of oral squamous cell carcinoma indicates a longer patient survival.
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http://dx.doi.org/10.1038/s41598-017-15406-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677084PMC
November 2017

Contrast Enhancement on Cone-Beam Breast-CT for Discrimination of Breast Cancer Immunohistochemical Subtypes.

Transl Oncol 2017 Dec 22;10(6):904-910. Epub 2017 Sep 22.

Institute for Diagnostic and Interventional Radiology, University Medical Center Göttingen, Göttingen, Germany. Electronic address:

Purpose: To evaluate whether contrast enhancement on cone-beam breast-CT (CBBCT) could aid in discrimination of breast cancer subtypes and receptor status.

Methods: This study included female patients age >40 years with malignant breast lesions identified on contrast-enhanced CBBCT. Contrast enhancement of malignant breast lesions was standardized to breast fat tissue contrast enhancement. All breast lesions were approved via image-guided biopsy or surgery. Immunohistochemical staining was conducted for expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor-2 (HER2) and Ki-67 index. Contrast enhancement of breast lesions was correlated with immunohistochemical breast cancer subtypes (Luminal A, Luminal B, HER2 positive, triple negative), receptor status and Ki-67 expression.

Results: Highest contrast enhancement was seen for Luminal A lesions (93.6 HU) compared to Luminal B lesions (47.6 HU, P=.002), HER2 positive lesions (83.5 HU, P=.359) and triple negative lesions (45.3 HU, P=.005). Contrast enhancement of HER2 positive lesions was higher than Luminal B lesions (P=.044) and triple negative lesions (P=.039). No significant difference was evident between Luminal B and triple negative lesions (P=.439). Lesions with high Ki-67 index showed lower contrast enhancement than those with low Ki-67 index (P=.0043). ER, PR and HER2 positive lesions demonstrated higher contrast enhancement than their receptor negative counterparts, although differences did not reach statistical significance (P=.1714; P=.3603; P=.2166).

Conclusions: Contrast enhancement of malignant breast lesions on CBBCT correlates with immunohistochemical subtype and proliferative potential. Thereby, CBBCT might aid in selecting individualized treatment strategies for breast cancer patients based on pre-operative imaging.
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http://dx.doi.org/10.1016/j.tranon.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614638PMC
December 2017

Cone-beam Breast Computed Tomography: CT Density Does Not Reflect Proliferation Potential and Receptor Expression of Breast Carcinoma.

Transl Oncol 2017 Aug 27;10(4):599-603. Epub 2017 Jun 27.

Department of Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany.

Purpose: Recently, cone-beam breast computed tomography (CBCT) is established for the breast investigation. The purpose of the present study was to investigate possible associations between CBCT findings and histopathological features in breast cancer.

Methods: Overall, 59 female patients, mean age of 64.6 years with histological proven breast cancer were included into the study. In all cases, non-contrast CBCT examination was done. The diagnosis of the identified lesions was confirmed histologically by biopsy. Immunohistochemical staining against estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 was performed for every lesion. Collected data were evaluated by means of descriptive statistics. Spearman's correlation coefficient was used to analyze the association between CT density and Ki-67 values. P values <0.05 were taken to indicate statistical significance in all instances.

Results: The size of the lesion varied from 2.7 to 90.0, mean size, 15.88±13.0 mm. The mean value of CT density of the lesions was 63.95±38.18 HU. The density tended to be higher in tubular carcinoma. Correlation analysis identified no significant correlations between CT density and Ki-67 level (r=-0.031, P=.784). There were no statistically significant differences of CT density between tumors with different receptor status.

Conclusions: No significant associations between CT density and receptor status in breast cancer. Tubular carcinoma tended to have higher CT density in comparison to other subtypes of breast carcinomas.
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http://dx.doi.org/10.1016/j.tranon.2017.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491450PMC
August 2017

The Early Adaptive Immune Response in the Pathophysiological Process of Pneumococcal Meningitis.

J Infect Dis 2017 Jan 31;215(1):150-158. Epub 2016 Oct 31.

Institute of Neuropathology, University Medical Center Göttingen, Georg-August University.

Background:  The adaptive immune system has been considered to play a minimal role in the early host response during bacterial meningitis.

Methods:  We investigated the progression and outcome of pneumococcal meningitis in Rag1 mice lacking functional B and T cells by assessing overall and symptom-free survival, bacteriological and histological studies, as well as flow cytometry and measurements of proinflammatory mediators.

Results:  The intracerebral injection of S. pneumoniae D39 induced the recruitment of B and T cells (CD4, γδ and natural killer) into the brain of wild-type mice. Mice with no functional B and T cells developed clinical symptoms and succumbed to the infection earlier than the wild-type group. In the CNS, Rag1 mice showed lower levels of interleukin 1β, reduced microglial proliferation, and impaired granulocyte recruitment with an earlier spread of pneumococci into the bloodstream, compared with wild-type mice. Lack of B and T cells resulted in a severe impairment of bacterial clearance in blood, spleen, and liver and an exaggerated systemic inflammatory response.

Conclusions:  B and T cells are important effector cells delaying the spread of pneumococci from the brain to the systemic circulation and shaping the immune response, thereby prolonging the survival of the host in the absence of antibiotic treatment.
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http://dx.doi.org/10.1093/infdis/jiw517DOI Listing
January 2017

FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation.

Blood 2015 Mar 20;125(12):1936-47. Epub 2015 Jan 20.

Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;

Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive AML, BTK mediates FLT3-ITD-dependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor κΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.
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http://dx.doi.org/10.1182/blood-2014-06-585216DOI Listing
March 2015

The BCL9-2 proto-oncogene governs estrogen receptor alpha expression in breast tumorigenesis.

Oncotarget 2014 Aug;5(16):6770-87

Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.

The majority of human breast cancers express estrogen receptor alpha (ER), which is important for therapy with anti-estrogens. Here we describe the role of BCL9-2, a proto-oncogene previously characterized as co-activator of Wnt/ß-catenin signaling, for mammary tumorigenesis in mice and human. ER positive human breast cancers showed overexpression of BCL9-2 and tamoxifen treated patients with high BCL9-2 demonstrated a better survival. BCL9-2 was upregulated during puberty and pregnancy in normal mammary epithelia, but downregulated in the involuted gland. BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia. Moreover, aged BCL9-2 transgenic mice developed ductal-like mammary tumors with high nuclear ER expression. We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment. Moreover, BCL9-2 regulated the expression of ER and the proliferation of human breast cancer cells independently of ß-catenin. Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter. In summary, BCL9-2 induces ER positive breast cancers in vivo, regulates ER expression by a novel ß-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196162PMC
http://dx.doi.org/10.18632/oncotarget.2252DOI Listing
August 2014

Membrane connexin 43 acts as an independent prognostic marker in oral squamous cell carcinoma.

Int J Oncol 2014 Jul 23;45(1):273-81. Epub 2014 Apr 23.

Department of Pathology, University of Goettingen, D-37075 Goettingen, Germany.

The aim of the present study was to evaluate the expression and localization of connexin (Cx) 26, -43 and -45 in a group of 35 patients with primary oral squamous cell carcinoma (OSCC) with the objective of making a more accurate disease prognosis. We analysed the expression of connexins in tissue samples of primary OSCC, matching oral mucosa free of dysplasia, and its associated lymph node metastases (LNM) by semi-quantitative immunohistochemistry of membrane, cytoplasmic and nuclear connexin expression. The levels of expression were correlated with the overall survival time (OS). Cx43 was overexpressed in tumour cells compared to epithelia in dysplasia-free mucosa. High membrane expression of Cx43 on tumour cells was the only statistically significant and independent prognostic factor of short OS (P=0.0088). Membrane expression of Cx43 in matching dysplasia-free mucosa acted similarly, but did not reach statistical significance (P=0.059). No correlation was found between the Cx26, Cx45 expression and OS. We conclude that Cx43 expression in dysplasia-free mucosa may indicate a very early stage of tumour promotion. Although overexpression of Cx43 is found in invasive tumours we only found membrane Cx43 expression to correlate with OS. This observation suggests that cytoplasmic Cx43 serves as storage and only membrane translocation may promote the formation of gap junctions and gap junctional intercellular communication (GJIC) with prognostic relevance.
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http://dx.doi.org/10.3892/ijo.2014.2394DOI Listing
July 2014

Mandibular reconstruction using a calcium phosphate/polyethylene glycol hydrogel carrier with BMP-2.

J Clin Periodontol 2014 Aug 13;41(8):820-6. Epub 2014 Jun 13.

Department of Oral and Maxillofacial Surgery, Georgia Augusta University, Goettingen, Germany.

Aim: To test the hypothesis that a synthetic hydroxyapatite/β-tricalcium phosphate (HA/TCP) construct combined with polyethylene glycol (PEG) hydrogel including recombinant human bone morphogenetic proteins-2 (rhBMP-2) enhances new bone formation compared with bone morphogenetic proteins-2 (BMP-2) delivered using the HA/TCP construct alone.

Material And Methods: Bilateral mandibular partial thickness 20 × 8 × 8 mm (L × W × H) alveolar defects were surgically created in the edentulated posterior mandible in 18 female minipigs. Randomized into two groups of nine animals each, the alveolar defects either received HA/TCP or HA/TCP/PEG with or without BMP-2 (105 μg/defect) in contra-lateral sites using a split-mouth design. Primary outcome, bone density (%) within four regions of interest, was evaluated following a 4-week healing interval when the animals were killed for histometric analysis.

Results: Bone morphogenetic proteins-2 loaded onto HA/TCP constructs significantly enhanced new bone formation compared with HA/TCP controls. Adding PEG apparently obstructed BMP-2 induced bone formation.

Conclusion: Polyethylene glycol compromises the osteogenic effect of BMP-2.
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http://dx.doi.org/10.1111/jcpe.12264DOI Listing
August 2014

Fungal encephalitis in human autopsy cases is associated with extensive neuronal damage but only minimal repair.

Neuropathol Appl Neurobiol 2014 Aug;40(5):610-27

Department of Neurology, RWTH University Hospital, Aachen, Germany.

Aims: The present study aimed at examining neuronal injury and repair in post mortem brain sections of humans who died from fungal central nervous system infections.

Methods: Histological and immunohistochemical abnormalities in 15 autopsy cases with fungal central nervous system infections from 1990 to 2008 were compared with findings in 10 age- und sex-matched control cases that died from acute non-neurological causes. The fungal pathogens were identified by culture or polymerase chain reaction and morphology in post mortem tissue. Seven patients with fungal encephalitis had either an organ transplantation or a malignant haematological disorder; five out of 15 did not have a classical predisposing illness but suffered from severe septic infections as the principal cause of immunosuppression, and three from alcoholism.

Results: Fungal organisms detected were Aspergillus spp. and other moulds, Candida spp. and black yeast-like fungi including Cladosporium spp. Histological analyses identified microglial activation, astrocytosis and axonal injury in the white matter without additional demyelination as characteristic features of this infectious disease. An increased rate of hippocampal neuronal apoptosis was detected in fungal encephalitis, while the number of recently generated TUC-4 and calretinin-expressing neurones in the dentate gyrus did not differ between patients and controls.

Conclusions: Unlike in other infectious diseases of the nervous system where a coexistence of damage and repair was observed, fungal encephalitis is characterized by strong damage and minimal neuronal regeneration.
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http://dx.doi.org/10.1111/nan.12044DOI Listing
August 2014

Effects of acute intracranial hypertension on extracerebral organs: a randomized experimental study in pigs.

J Neurol Surg A Cent Eur Neurosurg 2012 Sep 16;73(5):289-95. Epub 2012 Aug 16.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Hospital Göttingen, Göttingen, Germany.

Background: The study was conducted to determine the effects of isolated acute intracranial hypertension (AICH) on extracerebral organs.

Design: A total of 14 mechanically ventilated pigs were randomized to two groups of seven each: (1) control and (2) AICH.

Methods: AICH was induced by inflating an intracranial balloon catheter. The inflation volume was adjusted to keep intracranial pressure between 30 and 40 cm H2O. Hemodynamics, gas-exchange, and global oxygen delivery parameters were observed over a 4-hour period. At the end of the 4-hour period, tissue samples of heart, lungs, liver, and kidneys were collected and histologically graded for inflammation, edema, and cell damage (necrosis) using semiquantitative scores.

Results: Animals with AICH had increased heart rate and cardiac output, and higher scores for inflammation, edema, and necrosis in heart, lung, kidney, and liver tissues (all p < 0.05). Peripheral and mixed-venous oxygen saturations were unaffected.

Conclusions: Isolated AICH induces injury to multiple extracerebral organs, even in the absence of hypoperfusion or hypoxemia.
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http://dx.doi.org/10.1055/s-0032-1304813DOI Listing
September 2012

Reelin signalling in neuroblastoma: migratory switch in metastatic stages.

Int J Oncol 2012 Aug 18;41(2):681-9. Epub 2012 May 18.

Department of Anatomy and Cell Biology, University Medicine Goettingen, Goettingen, Germany.

The essential functions of Reelin for the migratory behaviour of neuroblasts in the central nervous system are well documented. Its role in the dissemination of neuronal tumours of the peripheral nervous system has not been studied in detail. Here, we examined neuroblastoma (NB), a tumour derived from sympathoadrenal cells of neural crest origin. We studied the expression of Reelin, its receptors VLDLR and LRP8 and the adapter protein DAB1 in primary tumour samples and cell lines. We used real-time RT-PCR, immunohistology and western blot analysis. In NB cell lines we studied effects of all-trans retinoic acid and the in vitro effects of Reelin. In primary tumour samples of untreated patients, a significant downregulation of Reelin and DAB1 mRNA was found in the metastatic stages 3, 4 and 4s. Immunohistochemical studies revealed expression of Reelin, LRP8 and DAB1 in differentiating-type low-grade NB. In vitro, western blot analysis of selected NB cell lines showed variable expression patterns. Differentiation induction with all-trans retinoic acid induced the upregulation of Reelin and DAB1. Reelin acted as a chemoattractant for various NB cell lines but inhibited migration when applied together with the NB cells. In normal tissue, we found Reelin in lymphatic endothelial cells (LECs) but not in blood vessel endothelium (BECs). In primary NB, both BECs and LECs were positive. Our data strongly suggest that Reelin has a dual role in NB. Autocrine expression marks low-grade differentiating tumour cells, whereas paracrine Reelin presented by LECs and BECs may act as a chemoattractant and promote hematogenic and lymphogenic dissemination in progressed stages.
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http://dx.doi.org/10.3892/ijo.2012.1488DOI Listing
August 2012

Effects of pulmonary acid aspiration on the lungs and extra-pulmonary organs: a randomized study in pigs.

Crit Care 2012 Dec 12;16(2):R35. Epub 2012 Dec 12.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Göttingen Medical Center, Robert-Koch-Straße 40, 37075 Göttingen, Germany.

Introduction: There is mounting evidence that injury to one organ causes indirect damage to other organ systems with increased morbidity and mortality. The aim of this study was to determine the effects of acid aspiration pneumonitis (AAP) on extrapulmonary organs and to test the hypothesis that these could be due to circulatory depression or hypoxemia.

Methods: Mechanically ventilated anesthetized pigs were randomized to receive intrabronchial instillation of hydrochloric acid (n = 7) or no treatment (n = 7). Hydrochloric acid (0.1 N, pH 1.1, 2.5 ml/kg BW) was instilled into the lungs during the inspiratory phase of ventilation. Hemodynamics, respiratory function and computer tomography (CT) scans of lung and brain were followed over a four-hour period. Tissue samples of lung, heart, liver, kidney and hippocampus were collected at the end of the experiment.

Results: Acid instillation caused pulmonary edema, measured as increased extravascular lung water index (ELWI), impaired gas exchange and increased mean pulmonary artery pressure. Gas exchange tended to improve during the course of the study, despite increasing ELWI. In AAP animals compared to controls we found: a) cardiac leukocyte infiltration and necrosis in the conduction system and myocardium; b) lymphocyte infiltration in the liver, spreading from the periportal zone with prominent areas of necrosis; c) renal inflammation with lymphocyte infiltration, edema and necrosis in the proximal and distal tubules; and d) a tendency towards more severe hippocampal damage (P > 0.05).

Conclusions: Acid aspiration pneumonitis induces extrapulmonary organ injury. Circulatory depression and hypoxemia are unlikely causative factors. ELWI is a sensitive bedside parameter of early lung damage.
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http://dx.doi.org/10.1186/cc11214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681347PMC
December 2012

CSF cytology--the ongoing dilemma to distinguish neoplastic and inflammatory lymphocytes.

Diagn Cytopathol 2011 Aug 22;39(8):621-6. Epub 2010 Nov 22.

Department of Pathology, University of Göttingen, Göttingen, Germany.

To evaluate different morphological criteria for the distinction between inflammatory and neoplastic lymphocytes in the cerebrospinal fluid (CSF). Forty-two cytospin preparations of CSF from patients with confirmed CSF involvement by aggressive B-cell lymphoma or acute leukemia were compared with 26 samples of inflammatory diseases. CSF cytology was analyzed morphologically for preselected parameters of cell, cytoplasm and nucleic appearance, and the presence of mitoses or apoptoses. None of the evaluated parameters sharply discerns neoplastic and inflammatory changes. However, neoplastic cells were significantly larger. Moreover, irregular shape and pointed borders of the cytoplasm, and deep notches in the nucleus were significantly more frequent in neoplastic than in inflammatory lymphocytes. No single parameter is sufficient to detect neoplastic lymphocytes. Considering a combination of cell size and irregular shape of cell and nucleus, however, may improve the diagnostic accuracy of CSF dissemination by aggressive hematological malignancies.
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http://dx.doi.org/10.1002/dc.21510DOI Listing
August 2011

Acute effects of intracranial hypertension and ARDS on pulmonary and neuronal damage: a randomized experimental study in pigs.

Intensive Care Med 2011 Jul 5;37(7):1182-91. Epub 2011 May 5.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Göttingen Medical Center, Göttingen, Germany.

Purpose: To determine reciprocal and synergistic effects of acute intracranial hypertension and ARDS on neuronal and pulmonary damage and to define possible mechanisms.

Methods: Twenty-eight mechanically ventilated pigs were randomized to four groups of seven each: control; acute intracranial hypertension (AICH); acute respiratory distress syndrome (ARDS); acute respiratory distress syndrome in combination with acute intracranial hypertension (ARDS + AICH). AICH was induced with an intracranial balloon catheter and the inflation volume was adjusted to keep intracranial pressure (ICP) at 30-40 cmH2O. ARDS was induced by oleic acid infusion. Respiratory function, hemodynamics, extravascular lung water index (ELWI), lung and brain computed tomography (CT) scans, as well as inflammatory mediators, S100B, and neuronal serum enolase (NSE) were measured over a 4-h period. Lung and brain tissue were collected and examined at the end of the experiment.

Results: In both healthy and injured lungs, AICH caused increases in NSE and TNF-alpha plasma concentrations, extravascular lung water, and lung density in CT, the extent of poorly aerated (dystelectatic) and atelectatic lung regions, and an increase in the brain tissue water content. ARDS and AICH in combination induced damage in the hippocampus and decreased density in brain CT.

Conclusions: AICH induces lung injury and also exacerbates pre-existing damage. Increased extravascular lung water is an early marker. ARDS has a detrimental effect on the brain and acts synergistically with intracranial hypertension to cause histological hippocampal damage.
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http://dx.doi.org/10.1007/s00134-011-2232-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127009PMC
July 2011

Loss of inducible nitric oxide synthase expression in the mouse renal cell carcinoma cell line RENCA is mediated by microRNA miR-146a.

Am J Pathol 2010 Oct 13;177(4):2046-54. Epub 2010 Aug 13.

Institute of Pathology, Georg-August University Hospital, Göttingen, Germany.

Tumor-associated macrophages can potentially kill tumor cells via the high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS); however, tumor-associated macrophages actually support tumor growth, as they are skewed toward M2 activation, which is characterized by low amounts of NO production and is proangiogenic. We show that the mouse renal cell carcinoma cell line, RENCA, which, on stimulation, expresses high levels of iNOS mRNA, loses its ability to express the iNOS protein. This effect is mediated by the microRNA miR-146a, as inhibition of RENCA cells with anti-miR- 146a restores iNOS expression and NO production (4.8 ± 0.4 versus 0.3 ± 0.1 μmol/L in uninhibited cells, P < 0.001). In vivo, RENCA tumor cells do not stain for iNOS, while infiltrating tumor-associated macrophages showed intense staining, and both cell types expressed iNOS mRNA. Restoring iNOS protein expression in RENCA cells using anti-miR-146a increases macrophage-induced death of RENCA cells by 73% (P < 0.01) in vitro and prevents tumor growth in vivo. These results suggest that, in addition to NO production by macrophages, tumor cells must produce NO to induce their own deaths, and some tumor cells may use miR-146a to reduce or abolish endogenous NO production to escape macrophage-mediated cell death. Thus, inhibiting miR-146a may render these tumor cells susceptible to therapeutic strategies, such as adoptive transfer of M1-activated macrophages.
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http://dx.doi.org/10.2353/ajpath.2010.091111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947298PMC
October 2010

Tumor-associated macrophages in clear cell renal cell carcinoma express both gastrin-releasing peptide and its receptor: a possible modulatory role of immune effectors cells.

World J Urol 2010 Jun 13;28(3):335-41. Epub 2009 Dec 13.

Department of Urology, Eberhard Karls University of Tübingen, Tübingen, Germany.

Purpose: Renal cell carcinomas (RCC) frequently express the gastrin-releasing peptide receptor (GRP-R). Gastrin-releasing peptide (GRP) stimulates tumor cell proliferation and neoangiogenesis. Tumor-associated macrophages (TAM) comprise an important cellular component of these tumors. We analyzed the GRP/GRP-R network in clear cell RCC (ccRCC) and non-clear cell RCC (non-ccRCC) with special regard to its expression by macrophages, tumor cells and microvessels.

Methods: Gastrin-releasing peptide and GRP-R expression in 17 ccRCC and 9 non-ccRCC were analyzed by RT-PCR, immunohistochemistry and double immunofluorescence staining.

Results: Tumor-associated macrophages expressed GRP and GRP receptor in ccRCC. Tumor cells and microvessels showed low to intermediate GRP-R expression in nearly all cases. In 12 ccRCC tumor epithelia also expressed low levels of GRP. Microvascular GRP expression was found in nine cases of ccRCC. For non-RCC, the expression of GRP and GRP receptor expression pattern was similar.

Conclusions: Tumor-associated macrophages are the main source of GRP in RCC. GRP receptor on TAM, tumor epithelia and microvessels might be a molecular base of a GRP/GRP receptor network, potentially acting as a paracrine/autocrine modulator of TAM recruitment, tumor growth and neoangiogenesis.
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http://dx.doi.org/10.1007/s00345-009-0492-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874056PMC
June 2010

Establishment and characterization of two distinct malignant mesothelioma cell lines with common clonal origin.

Cancer Genet Cytogenet 2007 Jul;176(1):35-47

Institute of Pathology, Georg-August-University of Göttingen, Robert-Koch-Strasse 40, 37099 Göttingen, Germany.

We describe two newly established malignant mesothelioma (MM) cell lines derived from a pleural effusion of a male. One cell line, designated as MM-Z03E, reveals an epithelioid cobblestone morphology, while the second one, designated as MM-Z03S and subcloned after in vivo selection, exhibits a sarcomatoid storiform growth pattern. Both cell lines showed the immunologic profile characteristic for MM (i.e., expression of cytokeratin, CK18, calretinin, and vimentin in both phenotypes). Cytogenetics, multicolor fluorescence in situ hybridization, comparative genomic hybridization, and oligonucleotide array CGH were performed on both cell lines. Aberrations shared by both cell lines included chromosomal losses of 1q34 approximately qter, 4, 9p, 10p, 13, 14, 16q, 18, and 22, as well as a complex structural aberration involving chromosome 17. Aberrations exclusive to MM-Z03E included gains of 3q11q27 and 5p, while gain of 9q and losses of 3q27qter, 11q, and 18 in MM-Z03S were exclusive to MM-Z03E. Both cell lines were able to develop solid transplant tumors in nude mice within 16 weeks, and immunophenotyping of tumor xenografts revealed an overall retained expression profile of the markers used. Remarkably, one xenograft from MM-Z03E revealed overexpression of p53 and widely invasive growth. In conclusion, both cell lines are useful in vivo and in vitro model systems to study the underlying genetic mechanisms of biphasic differentiation in MM, which can be of certain value considering the increasing relevance of assessing MM tumor biology for the clinical management of this disease.
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http://dx.doi.org/10.1016/j.cancergencyto.2007.03.005DOI Listing
July 2007

Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis.

Eur J Pediatr 2005 May 22;164(5):306-10. Epub 2005 Feb 22.

Department of Paediatrics and Paediatric Neurology, Georg August University, Faculty of Medicine, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.

Unlabelled: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that characteristically presents with colon cancer in early adult life. We describe a Pakistani FAP family in which two sons had an unusually early manifestation of colorectal cancer. The index patient presented at 11 years of age with abdominal pain, rectal bleeding and iron deficiency anaemia. Colonoscopy showed that the colon was carpeted with a myriad of polyps. Oesophago-gastric and duodenal endoscopy revealed that polyps had also developed in the duodenum. Multiple biopsies indicated neoplastic lesions. The patient underwent a proctocolectomy and endoscopic duodenal mucosectomy. The diagnosis of an adenocarcinoma of the colon and further adenomatous polyps with low-grade and high-grade dysplasia was confirmed by histology. Family screening including a blood test for anaemia and bowel examination revealed that his 12-year-old brother was also affected.

Conclusion: Children with familial adenomatous polyposis are at risk for colon cancer and emphasise the need for early tumour recognition. Gastrointestinal symptoms in children should be thoroughly evaluated and standard screening for colonic polyposis should be performed in all individuals with a positive family history and/or known mutations in cancer-associated genes, particularly in children who are under 10 years of age.
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http://dx.doi.org/10.1007/s00431-004-1602-yDOI Listing
May 2005