Publications by authors named "Lucien Frappart"

48 Publications

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin.

Int J Cancer 2020 11 23;147(9):2564-2577. Epub 2020 Jun 23.

First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2-mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4β1 (very late antigen-4, VLA-4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA-4 β1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis-promoting role in the absence of Merlin.
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http://dx.doi.org/10.1002/ijc.33144DOI Listing
November 2020

Correlation Between p16/Ki-67 Expression and the Grade of Cervical Intraepithelial Neoplasias.

Int J Gynecol Pathol 2020 Jul;39(4):384-390

Chittaranjan National Cancer Institute, Kolkata, West Bengal, India (R.M., I.G., D.B., S.M., C.R., C.P., M.V.) International Agency for Research on Cancer, Lyon, France (R.M., P.B.) CHU Dijon Bourgogne, Dijon, France (L.F.).

Interpretation of histopathology of cervical premalignant lesions suffers from marked interobserver variability due to its subjective nature. We aimed to evaluate the usefulness of the biomarkers p16 and Ki-67 in improving the diagnostic accuracy of cervical histopathology and assess the correlation between p16 expression and human papillomavirus test in different grades of cervical intraepithelial neoplasia (CIN). Cervical tissue specimens with a diagnosis of CIN 1 or worse (CIN 1+) on hematoxylin and eosin staining were selected for immunohistochemistry (IHC) staining for p16 and Ki-67. The IHC slides were examined by a gynecologic pathologist along with a review of hematoxylin and eosin slides. The review histopathology diagnosis was used to correlate with the IHC results. We observed that the proportion of women with overexpression of p16 increased with increasing histologic severity: 0% in women with normal histology; 33.3% in women with CIN 1; 58.1% in women with CIN 2; and 73.8% in women with CIN 3. Among the human papillomavirus-positive women, 76.3% (58/76) women with CIN 2/CIN 3 expressed p16, and only 8.9% (4/45) women with normal histopathology or CIN 1 expressed the same. A combination of p16 positivity and abnormal expression of Ki-67 beyond the lower third of the epithelium was observed in 0% of normal/CIN 1 and 60.5% (40/66) of CIN 3 detected on routine histopathology. We concluded that dual staining could be used as an adjunctive test to improve the diagnostic accuracy of histopathology. In addition, p16/Ki-67 IHC has a role in guiding management decisions in cases with discordant colposcopy and histopathology diagnoses.
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http://dx.doi.org/10.1097/PGP.0000000000000617DOI Listing
July 2020

cd44 deletion suppresses atypia in the precancerous mouse testis.

Mol Carcinog 2019 05 28;58(5):621-626. Epub 2019 Jan 28.

Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.

Loss-of-function of RHAMM causes hypofertility and testicular atrophy in young mice, followed by germ cell neoplasia in situ (GCNIS) of the testis, cellular atypia, and development of the testicular germ cell tumor (TGCT) seminoma. These pathologies reflect the risk factors and phenotypes that precede seminoma development in humans and-given the high prevalence of RHAMM downregulation in human seminoma-link RHAMM dysfunction with the aetiology of male hypofertility and GCNIS-related TGCTs. The initiating event underlying these pathologies, in RHAMM mutant testis, is premature displacement of undifferentiated progenitors from the basal compartment. We hypothesized that cd44 (both cancer initiating cell- and oncogenic progression marker) will drive GCNIS development, induced by RHAMM-loss-of-function in the mouse. We report that cd44 is expressed in a specific subset of GCNIS testes. Its genetic deletion has no effect on GCNIS onset, but it ameliorates oncogenic progression. We conclude that cd44 expression, combined with RHAMM dysfunction, promotes oncogenic progression in the testis.
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http://dx.doi.org/10.1002/mc.22961DOI Listing
May 2019

Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis.

Ann Rheum Dis 2018 11 11;77(11):1610-1618. Epub 2018 Jul 11.

Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.

Background: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation.

Objectives: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis.

Methods: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GR) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GR primary murine fibroblast-like synoviocytes (FLS) was performed.

Results: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6C, MHCII) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GR FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1β.

Conclusion: We report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.
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http://dx.doi.org/10.1136/annrheumdis-2017-212762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225806PMC
November 2018

acts in the PLK1-dependent spindle positioning pathway and supports neural development.

Elife 2017 10 10;6. Epub 2017 Oct 10.

Department of Paediatrics, University of British Columbia, Vancouver, Canada.

Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of -knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.
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http://dx.doi.org/10.7554/eLife.28672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681225PMC
October 2017

Spindle Misorientation of Cerebral and Cerebellar Progenitors Is a Mechanistic Cause of Megalencephaly.

Stem Cell Reports 2017 10 21;9(4):1071-1080. Epub 2017 Sep 21.

Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany. Electronic address:

Misoriented division of neuroprogenitors, by loss-of-function studies of centrosome or spindle components, has been linked to the developmental brain defects microcephaly and lissencephaly. As these approaches also affect centrosome biogenesis, spindle assembly, or cell-cycle progression, the resulting pathologies cannot be attributed solely to spindle misorientation. To address this issue, we employed a truncation of the spindle-orienting protein RHAMM. This truncation of the RHAMM centrosome-targeting domain does not have an impact on centrosome biogenesis or on spindle assembly in vivo. The RHAMM mutants exhibit misorientation of the division plane of neuroprogenitors, without affecting the division rate of these cells, resulting against expectation in megalencephaly associated with cerebral cortex thickening, cerebellum enlargement, and premature cerebellum differentiation. We conclude that RHAMM associates with the spindle of neuroprogenitor cells via its centrosome-targeting domain, where it regulates differentiation in the developing brain by orienting the spindle.
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http://dx.doi.org/10.1016/j.stemcr.2017.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639290PMC
October 2017

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma.

Cancer Res 2016 11 19;76(21):6382-6395. Epub 2016 Aug 19.

Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.

Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM-a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self-renewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382-95. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0179DOI Listing
November 2016

Epidermal Nbn deletion causes premature hair loss and a phenotype resembling psoriasiform dermatitis.

Oncotarget 2016 Apr;7(17):23006-18

Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Nijmegen Breakage Syndrome is a disease caused by NBN mutations. Here, we report a novel function of Nbn in skin homeostasis. We found that Nbn deficiency in hair follicle (HF) progenitors promoted increased DNA damage signaling, stimulating p16Ink4a up-regulation, Trp53 stabilization and cytokines secretion leading to HF-growth arrest and hair loss. At later stages, the basal keratinocytes layer exhibited also enhanced DNA damage response but in contrast to the one in HF progenitor was not associated with pro-inflammatory cytokines expression, but rather increased proliferation, lack of differentiation and immune response resembling psoriasiform dermatitis. Simultaneous Nbn and Trp53 inactivation significantly exacerbated this phenotype, due to the lack of inhibition of pro-inflammatory cytokines secretion by Trp53. Altogether, we demonstrated novel functions of Nbn in HF maintenance and prevention of skin inflammation and we provide a mechanistic explanation that links cell intrinsic DNA maintenance with large scale morphological tissue alterations.
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http://dx.doi.org/10.18632/oncotarget.8470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029606PMC
April 2016

Merlin Isoforms 1 and 2 Both Act as Tumour Suppressors and Are Required for Optimal Sperm Maturation.

PLoS One 2015 10;10(8):e0129151. Epub 2015 Aug 10.

Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany.

The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the autosomal dominant disorder neurofibromatosis type II, characterised primarily by the development of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functionality. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129151PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530865PMC
May 2016

Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1.

Nat Commun 2015 Jul 17;6:7796. Epub 2015 Jul 17.

Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.

Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies.
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http://dx.doi.org/10.1038/ncomms8796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518295PMC
July 2015

RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.

Biol Open 2015 Mar 6;4(4):562-71. Epub 2015 Mar 6.

Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany

The postnatal mammalian ovary contains the primary follicles, each comprising an immature oocyte surrounded by a layer of somatic granulosa cells. Oocytes reach meiotic and developmental competence via folliculogenesis. During this process, the granulosa cells proliferate massively around the oocyte, form an extensive extracellular matrix (ECM) and differentiate into cumulus cells. As the ECM component hyaluronic acid (HA) is thought to form the backbone of the oocyte-granulosa cell complex, we deleted the relevant domain of the Receptor for HA Mediated Motility (RHAMM) gene in the mouse. This resulted in folliculogenesis defects and female hypofertility, although HA-induced signalling was not affected. We report that wild-type RHAMM localises at the mitotic spindle of granulosa cells, surrounding the oocyte. Deletion of the RHAMM C-terminus in vivo abolishes its spindle association, resulting in impaired spindle orientation in the dividing granulosa cells, folliculogenesis defects and subsequent female hypofertility. These data reveal the first identified physiological function for RHAMM, during oogenesis, and the importance of this spindle-associated function for female fertility.
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http://dx.doi.org/10.1242/bio.201410892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400598PMC
March 2015

Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency.

Endocrinology 2014 Jan 20;155(1):315-25. Epub 2013 Dec 20.

Leibniz Institute for Age Research/Fritz Lipmann Institute (J.M., S.M., L.F., H.H.), Jena, Germany; Department of Internal Medicine (T.J.V.), Erasmus Medical Center, Rotterdam, The Netherlands; Laboratory of Comparative Endocrinology (V.M.D.), Biology Department, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Endocrinology and Metabolism (A.B.), Academic Medical Center, Amsterdam, The Netherlands; Institute of Physiology and Zürich Center for Integrative Human Physiology (L.M., F.V.), University of Zürich, Zürich, Switzerland; and Leibniz Institute for Environmental Medicine (H.H.), Düsseldorf, Germany.

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.
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http://dx.doi.org/10.1210/en.2013-1800DOI Listing
January 2014

Nbn and atm cooperate in a tissue and developmental stage-specific manner to prevent double strand breaks and apoptosis in developing brain and eye.

PLoS One 2013 30;8(7):e69209. Epub 2013 Jul 30.

Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728324PMC
April 2014

Differential expression of E-cadherin, β-catenin, and Lewis x between invasive hydatidiform moles and post-molar choriocarcinomas.

Virchows Arch 2013 Jun 17;462(6):653-63. Epub 2013 May 17.

INSERM U972 Les Cellules Souches: de leurs niches aux applications thérapeutiques, Hôpital P. Brousse, Bâtiment Lavoisier, 14 avenue P.V. Couturier, 94800 Villejuif, France.

Trophoblast cell adhesion and migration are carefully coordinated during normal placental development. We have compared the expression of three adhesion molecules, E-cadherin, β-catenin, and Lewis x, by immunohistochemistry during normal trophoblast differentiation, and in hydatidiform moles and choriocarcinomas. Both E-cadherin and β-catenin were expressed in normal placenta cytotrophoblast, and this expression decreased with trophoblast maturation. E-cadherin was mainly localized along the contact between cytotrophoblast and syncytiotrophoblast, which indicates its role in the differentiation of the syncytial layer. Lewis x disappeared progressively during differentiation of normal villous vessels, and was expressed in molar pregnancies. Interestingly, whereas choriocarcinomas were not, or poorly, stained, invasive hydatidiform moles (invHMs) strongly expressed Lewis x in vascular structures. This observation correlated well with E-cadherin and β-catenin expression and suggests that these three markers are associated with the invasive transformation. The presence of robust endothelial structures in invHMs could also explain their ability to maintain organized villous architecture (contrary to metastatic choriocarcinomas) during their invasion of extrauterine tissues such as the lung or the brain after dissemination through the blood flow. In our hands, Lewis x appeared to be a new, reliable marker that can be used to clearly distinguish invHMs from choriocarcinomas.
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http://dx.doi.org/10.1007/s00428-013-1427-zDOI Listing
June 2013

High incidence of mammary intraepithelial neoplasia development in Men1-disrupted murine mammary glands.

J Pathol 2013 Mar;229(4):546-58

Université Lyon, F-69000, Lyon, France.

Mutations of the MEN1 tumour suppressor gene predispose patients to the development of multiple endocrine neoplasia type 1 (MEN1) syndrome, which is characterized by multiple endocrine tumours, including prolactinomas. The recent findings of the interaction between menin, encoded by the MEN1 gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygous Men1 mutant mice, led us to investigate a putative tumour suppressor function of the Men1 gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia (MIN) was observed in mutant WapCre-Men1(F/F) mice (51.5%) than in WapCre-Men1(+/+) (0%) or Men1(F/F) (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage of WapCre transgene expression, prolactinomas were observed in 83.3% of mutant mice, leading to premature death. As there was no correlation between MIN development and elevated serum prolactin levels, and phospho-STAT5 expression was decreased in mammary lesions, the increased incidence of MIN lesions was most likely due to Men1 disruption rather than to prolactinoma development. Interestingly, in MIN lesions, we found a decrease in membrane-associated E-cadherin and beta-catenin expression, the latter of which is a menin partner. Finally, reduced menin expression was found in a large proportion of two independent cohorts of patients with breast carcinomas. Taken together, the current work indicates a role of Men1 inactivation in the development of mammary pre-cancerous lesions in mice and a potential role in human mammary cancer.
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http://dx.doi.org/10.1002/path.4146DOI Listing
March 2013

Altered p16 and Bcl-2 expression reflects pathologic development in hydatidiform moles and choriocarcinoma.

Pathol Oncol Res 2013 Apr 13;19(2):217-27. Epub 2012 Oct 13.

INSERM U782 Endocrinologie et génétique de la reproduction et du développement, 32 rue des Carnets, 92140, Clamart, France.

Abnormal trophoblast differentiation is the main cause of gestational trophoblast diseases in the case of hydatidiform moles and choriocarcinomas. Here we investigated the expression patterns of two gene products, p16 and Bcl-2, implicated in cell cycle regulation and apoptosis, respectively, using immunohistochemistry during normal placenta differentiation, hydatidiform moles (partial, complete and invasive) and post-molar choriocarcinomas. The p16 protein shows a gradual expression in cytotrophoblast of normal villous, from a p16 weak proliferative phenotype to a p16 strong invasive phenotype reaching a maximum around 17 weeks of gestation. The expression pattern in cytotrophoblast was similar in moles in contrast to the villous mesenchyme of invasive moles where p16 was strongly expressed. Bcl-2 expression was syncytiotrophoblast specific in normal placenta and moles and increased gradually during normal differentiation. The results explain the persistence of normal and molar villous fragments during their development and their dramatic invasion in the uterine arteries in case of invasive moles. In choriocarcinomas the weak Bcl-2 expression is associated with weak p16 expression indicating a great apoptotic and proliferative potentials. The results suggest that strong p16 expression in the villous mesenchyme may be responsible in part of the morbidity of the moles, and the key of cancer progression in the choriocarcinomas would be a fast cell-cycle turnover.
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http://dx.doi.org/10.1007/s12253-012-9572-2DOI Listing
April 2013

[Gynecopathology: Case 2: placental site trophoblastic tumor].

Ann Pathol 2012 Jun 12;32(3):189-93. Epub 2012 Jun 12.

Service d'anatomie et cytologie pathologiques, hôpital de la Croix Rousse, 103 Grande-Rue-de-la-Croix-Rousse, Lyon cedex 04, France.

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http://dx.doi.org/10.1016/j.annpat.2012.04.009DOI Listing
June 2012

Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia.

FASEB J 2012 Jun 13;26(6):2424-36. Epub 2012 Mar 13.

Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.

Community-acquired pneumonia presents a spectrum of clinical phenotypes, from lobar pneumonia to septic shock, while mechanisms underlying progression are incompletely understood. In a transcriptomic and metabolomic study across tissues, we examined serotype-specific regulation of signaling and metabolic pathways in C57BL/6 mice intratracheally instilled with either serotype 19F Streptococcus pneumoniae (S19; causing lobar pneumonia), or serotype 2 S. pneumoniae (S2; causing septic pneumococcal disease,) or vehicle (Todd-Hewitt broth). Samples of lung, liver, and blood were collected at 6 and 24 h postinfection and subjected to microarray analysis and mass spectrometry. Results comprise a preferential induction of cholesterol biosynthesis in lobar pneumonia at low-infection doses (10(5) colony forming units/mouse) leading to increased plasma cholesterol (vehicle: 1.8±0.12 mM, S2: 2.3±0.10 mM, S19: 2.9±0.15 mM; P<0.05, comparing S19 to vehicle and S2). This induction was pneumolysin dependent, as a pneumolysin-deficient strain of serotype 19F failed to induce cholesterol biosynthesis (S19ΔPLY: 1.9±0.03 mM). Preincubation of pneumolysin with purified cholesterol or plasma from hypercholesterolemic mice prior to intratracheal instillation protected against lung barrier dysfunction and alveolar macrophage necrosis. Cholesterol may attenuate disease severity by neutralizing pneumolysin in the alveolar compartment and thus prevent septic disease progression.
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http://dx.doi.org/10.1096/fj.11-191957DOI Listing
June 2012

Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells.

Proc Natl Acad Sci U S A 2011 Nov 14;108(48):19317-22. Epub 2011 Nov 14.

Tissue Specific Hormone Action, Leibniz Institute for Age Research-Fritz Lipmann Institute, 07745 Jena, Germany.

Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA. Furthermore, the resistance of mice expressing a DNA binding-defective GR (GR(dim)) to GC treatment reveals that dimerization of the GR is indispensable for the antiinflammatory effects. In these mice, the GC-induced suppression of T(H)1 and T(H)17 cell-derived proinflammatory cytokines is impaired. Our finding that IL-17A(-/-) mice are resistant to GC therapy, whereas IFN-γ(-/-) mice respond as efficiently as WT mice implies that IL-17-producing T cells and not IFN-γ-producing T cells are the most important targets for an efficient GC therapy. The present study's identification of the critical cell type and the mode of GR action in steroid therapy of AIA significantly advances our understanding of steroid therapy and should lead to therapies with greater efficiency and fewer side effects.
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http://dx.doi.org/10.1073/pnas.1105857108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228447PMC
November 2011

Contribution of referent pathologists to the quality of trophoblastic diseases diagnosis.

Hum Reprod 2011 Oct 12;26(10):2651-7. Epub 2011 Aug 12.

Department of Obstetrics and Gynecology, Lyon 1 University, Lyon Hospital, Lyon Sud University Hospital, Lyon, France.

Objective: To evaluate the contribution of referent pathologists (RPs) to the quality of diagnosis of trophoblastic diseases and to study the level of diagnostic agreement between the initial pathologists and the RPs.

Methods: This observational retrospective study was carried between 1 November 1999 and 11 January 2011 using the database of the French Trophoblastic Disease Reference Centre in Lyon. All files for hydatiform moles (HMs), trophoblastic tumours and non-molar pregnancies for which there was an initial suspicion of trophoblastic disease were included, whenever there was rereading of the slides by an RP. A total of 1851 HMs and 150 gestational trophoblastic tumours were analysed.

Results: When the initial pathologist diagnosed a complete mole, the RP confirmed the diagnosis in 96% of cases. When the initial pathologist diagnosed a partial mole, the RP confirmed the diagnosis in only 64% of cases. For trophoblastic tumours, when the initial pathologist diagnosed a choriocarcinoma, the RP confirmed the diagnosis in 86% of cases. When the initial anatomopathology suggested an invasive mole, the diagnosis was confirmed in 96% of cases. Finally, when the initial diagnosis was a placental site trophoblastic tumour or an epithelioid trophoblastic tumour, the RP confirmed the diagnosis in 60 and 100% of cases, respectively.

Conclusion: A systematic policy of rereading of slides for all suspicious moles improves the quality of management of trophoblastic diseases at a national level.
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http://dx.doi.org/10.1093/humrep/der265DOI Listing
October 2011

Comparison of ThinPrep and SurePath liquid-based cytology and subsequent human papillomavirus DNA testing in China.

Cancer Cytopathol 2011 Dec 19;119(6):387-94. Epub 2011 Jul 19.

Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.

Background: Liquid-based cytology (LBC) has been compared with conventional cytology in numerous studies. In the current study of 2 LBC systems, the accuracy, rates of unsatisfactory cytology, and sufficiency of residual LBC specimens for Hybrid Capture 2 (HC2) HPV DNA testing were compared.

Methods: Eligible women ages 30 to 49 years were recruited for this cross-sectional population-based study in rural China. Women were assessed by visual inspection with acetic acid (VIA), LBC, and high-risk HPV HC2 DNA assay. Cervical specimens were preserved according to SurePath or ThinPrep protocols. LBC results were manually read. HC2 testing was performed on specimens with sufficient residual volume. Colposcopies and biopsies were performed on women who were VIA positive at the time of initial screening. Women with abnormal LBC or HC2 test results were called back for colposcopies and 4-quadrant cervical biopsies.

Results: Of 2005 eligible women, 972 were tested by SurePath and 1033 by ThinPrep. Compared with SurePath samples, ThinPrep samples had higher rates of unsatisfactory cytology (0.2% for SurePath and 1.5% for ThinPrep) and insufficient residual volume for HC2 (0.0% for SurePath and 18.2% for ThinPrep). SurePath samples yielded higher sensitivities and similar specificities for LBC and HC2 testing of residual specimens, but these differences were not determined to be significant by area-under-the-curve analysis (LBC performance: 0.89 for SurePath and 0.85 for ThinPrep; HC2 performance: 0.91 for SurePath and 0.89 for ThinPrep).

Conclusions: Both methods yielded similar validity in detecting significant cervical lesions. However, SurePath samples yielded higher rates of satisfactory LBC slides and sufficient residual volume for HC2.
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http://dx.doi.org/10.1002/cncy.20177DOI Listing
December 2011

Global DNA methylation in precancerous and cancerous lesions of the uterine cervix.

Asian Pac J Cancer Prev 2010 ;11(6):1741-4

UMR INSERM 590 Oncogenèse et Progression Tumorale, Centre Léon Bérard, France.

Introduction: Persistent human papillomavirus (HPV) infection is the primary causal agent in the development of the uterine cervix carcinoma. Nevertheless, only a minority of high-risk HPV-associated lesions progress to cervical cancer, suggesting involvement of other molecular alterations. Among putative changes, aberrant methylation might be a crucial event.

Design: Paraffin-embedded samples of benign lesions, cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinomas (SCC) were analyzed for DNA 5-methylcytosine content by immunohistochemistry with anti-5-methylcytosine antibodies and by high-performance liquid capillary electrophoresis (HPCE).

Results: No significant difference of DNA 5-methylcytosine content was observed between normal tissues, benign lesions, low-grade lesions and high-grade lesions (p=0.6). In contrast, DNAs extracted from invasive SCC were hypomethylated when compared with normal and preneoplastic lesions (p=0.0004). An association between global DNA hypomethylation and the SCC stage was confirmed by HPCE.

Conclusions: The transition from CIN lesions to invasive carcinoma seems to be closely linked to global DNA hypomethylation, which could be a useful marker of invasive uterine cervical lesions.
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July 2011

Promoter hypermethylation of CDH13, DAPK1 and TWIST1 genes in precancerous and cancerous lesions of the uterine cervix.

Pathol Res Pract 2011 Jan 3;207(1):37-42. Epub 2010 Dec 3.

Research Unit 03/UR/08-13, Cancer Epidemiology and Cytopathology in Tunisian Center, Medicine Faculty, Sousse, Tunisia.

Aberrant DNA methylation is an early event in carcinogenesis and could serve as an additional molecular marker for the early diagnosis. The study was performed to investigate the promoter methylation of DAPK1, CDH13, and TWIST1 genes in uterine cervix lesions in an effort to examine whether this epigenetic event is involved in the process of cervical carcinogenesis, and whether it might be used as a molecular marker of cervical lesions. We conducted a retrospective study of 60 uterine cervix specimens, including 8 normal tissue samples, 10 benign lesions, 28 precancerous lesions (CIN1-3), and 14 squamous cell carcinomas (SCC). DNA hypermethylation was investigated using methylation-specific PCR. Immunohistochemistry was used to find p16(INK4A) overexpression. No hypermethylated promoters were detected in normal tissues and benign lesions. However, promoter hypermethylation of CDH13, TWIST1, and DAPK1 increased progressively from CIN1 to cancer, reaching values higher than 50% for cancer. DAPK1 and CDH13 displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (p<0.05). A statistically significant association was observed between p16(INK4A) expression and hypermethylation of DAPK1, TWIST1, and CDH13 (p<0.0001). Hypermethylation of CDH13, DAPK1, and TWIST1 promoters is an early event in the initiation and progression of cervix neoplasia. CDH13, DAPK1, and TWIST1 genes are potential biomarkers of cervical cancer risk.
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http://dx.doi.org/10.1016/j.prp.2010.11.001DOI Listing
January 2011

Molecular characterization of breast cancer in young Brazilian women.

Rev Assoc Med Bras (1992) 2010 May-Jun;56(3):278-87

Curso de Medicina, Centro Universitário Lusíada, UNILUS.

Objective: To evaluate the distribution of molecular subtypes of breast tumors diagnosed in young Brazilian women and to analyze the frequency of loss of heterozygocity (LOH) in BRCA1 among different molecular subtypes of early-onset breast cancer.

Methods: Samples from 72 cases of invasive breast carcinoma diagnosed in women aged between 19 and 40 years were evaluated using an immunohistochemical panel of biomarkers. Three intragenic BRCA1 locus microsatellites, D17S1322, D17S1323, and D17S855, were PCR amplified from matched normal (lymphocyte) and tumor DNAs for (LOH) analysis.

Results: We found 13 cases (18%) that had an immunohistochemical profile consistent with being basal-like. Forty cases (55%) were luminal A type; 11% (8 cases) were luminal B type, 13% (9 cases) were HER2-overexpressing tumors and two cases were ER-/HER2- carcinomas lacking basal marker expression. Four of the 16 informative cases at D17S1322, one of the four informative cases at D17S855, and none of the five informative cases at D17S1323 displayed LOH (four basal-like and one Luminal A). Microsatellite instability (MSI) at D17S855 and D17S1322 was found in two cases (one a basal-like and one Luminal A).

Conclusion: In our study, basal-like tumor was the second most frequent molecular type among young Brazilian women and was only observed in women diagnosed under the age of 35 years. There was no significant difference of LOH at BRCA1 locus rates between basal-like breast tumors and not-basal-like breast tumors (p=0.62). LOH in BRCA1 and MSI in these breast cancers were not frequent but may indicate a small group of breast cancers with a specific molecular makeup.
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http://dx.doi.org/10.1590/s0104-42302010000300010DOI Listing
August 2011

Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice.

BMC Cancer 2010 Jul 27;10:395. Epub 2010 Jul 27.

CNRS UMR5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, Centre Léon Bérard, Lyon F-69008, France.

Background: Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. Our group and others have shown that Men1 disruption in mice recapitulates MEN1 pathology. Intriguingly, rare lesions in hormone-dependent tissues, such as prostate and mammary glands, were also observed in the Men1 mutant mice.

Methods: To study the occurrence of prostate lesions, we followed a male mouse cohort of 47 Men1+/- mice and 23 age-matched control littermates, starting at 18 months of age, and analysed the prostate glands from the cohort.

Results: Six Men1+/- mice (12.8%) developed prostate cancer, including two adenocarcinomas and four in situ carcinomas, while none of the control mice developed cancerous lesions. The expression of menin encoded by the Men1 gene was found to be drastically reduced in all carcinomas, and partial LOH of the wild-type Men1 allele was detected in three of the five analysed lesions. Using immunostaining for the androgen receptor and p63, a basal epithelial cell marker, we demonstrated that the menin-negative prostate cancer cells did not display p63 expression and that the androgen receptor was expressed but more heterogeneous in these lesions. Furthermore, our data showed that the expression of the cyclin-dependent kinase inhibitor CDKN1B (p27), a Men1 target gene known to be inactivated during prostate cell tumorigenesis, was notably decreased in the prostate cancers that developed in the mutant mice.

Conclusion: Our work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.
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http://dx.doi.org/10.1186/1471-2407-10-395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920881PMC
July 2010

[p16INK4A overexpression is a useful marker for uterine cervix lesions].

Ann Biol Clin (Paris) 2010 Jul-Aug;68(4):409-14

Laboratoire central de pathologie, Hôpital Edouard Herriot, Lyon, France.

The histological criteria of uterine cervix lesions are well known. However, there is a poor diagnostic reproducibility especially concerning low-grade precancerous lesions. Therefore, the aim of our study was to evaluate the utility of p16INK4A overexpression as a surrogate biomarker of precancerous lesions of the uterine cervix. A retrospective study was carried out by the International Center for Research on Cancer, Lyon, on 79 uterine cervix lesions. Specimens included 4 normal tissue samples, 24 benign lesions, 9 low-grade precancerous lesions (CIN1), 40 high-grade precancerous lesions (CIN2-3) and 2 squamous cell carcinomas. Immunohistochemistry was used to find p16INK4A expression. HPV infection was detected by HPV testing. No p16INK4A expression was detected in normal tissues and benign lesions of the uterine cervix. p16INK4A immunolabeling was weak in CIN1 cases (77.8%). Strong and diffuse p16INK4A expression was detected among all precancerous lesions (CIN2-3) and squamous cell carcinomas. p16INK4A overexpression was associated to the CIN grade (p<0.0001) and high-risk HPV infection (p<0.0001). In conclusion, p16INK4A overexpression should be regarded as a surrogate biomarker of precancerous lesions of the uterine cervix. p16INK4A overexpression is useful in reducing the variability during evaluation of suspicious biopsies of the uterine cervix.
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http://dx.doi.org/10.1684/abc.2010.0458DOI Listing
September 2010

Cervix cancer in Tunisia: clinical and pathological study.

Asian Pac J Cancer Prev 2010 ;11(1):235-8

Cancer Epidemiology and Cytopathology in the Center of Tunisia, Medicine Faculty, Farhet Hached University Hospital, Sousse, Tunisia.

Introduction: Uterine cervix cancer is the second most commonly diagnosed cancer among women worldwide.

Design: In order to review the clinical and pathological features of cervix cancer in the center of Tunisia, a retrospective study was carried out on 410 cancer cases diagnosed in the Pathology Department, Farhet Hached University Hospital, Sousse, Tunisia (1993-2006).

Results: The mean age was 52.1 years. Of the 410 patients, 90.5% had squamous cell carcinoma and 7.3% had adenocarcinoma. One hundred thirty-eight patients were identified as being in early stages (0 and I) (33.6%) and 58.2% in advanced stages (II-IV). Therapy consisted mainly in combination of radiotherapy and surgery in early stages (28.8%), and radiotherapy alone or associated with the chemotherapy in advanced stage (29.7%). Surgery was the only treatment in 29.5% of cases.

Conclusion: A relatively large proportion of patients presented in stages II to IV, as compared to only 36% with early stages, emphasizing the need to reinforce the early detection of this cancer and its precursor lesions in the center of Tunisia.
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November 2010

[Prevalence of HPV infection in precancerous and cancerous lesions of the uterine cervix in Tunisia].

Ann Biol Clin (Paris) 2010 May-Jun;68(3):297-303

Unité de Recherche 03/UR/08-13, Cytopathologie et Epidémiologie des Cancers dans le Centre Tunisien, Faculté de Médecine, Sousse, Tunisie.

Objectives: To investigate the distribution of HPV genotypes inuterine cervical lesions in Central Tunisia in order to predict the impact ofHPV vaccines and HPV-based screening tests among Tunisian women.

Material And Methods: We performed a retrospective study of 146 fixed tissues including 30 benign lesions, 36 low-grade cervical intraepithelial neoplasias (CIN1), 45 high-grade cervical intraepithelial neoplasias (CIN2/3), 26 invasive squamous cell carcinomas (SCC) and 9 adenocarcinomas. HPV infection detection and typing were investigated by PCR technique using consensus GP5/GP6 primers and type specific primers for HPV6/11, 16, 18, 31 and 33.

Results: Among our patients, overall HPV prevalence was 73.6% (p = 0.0001). HPV infection was associated to 84% of precancerous lesions and 83.9% of cancers. High-risk HPV infection (HPV16 and 18) was detected in 17.4% of CIN1, 74.3% of CIN2/3 (p = 0.002) and 73.1% of cancers (p = 0.001). HPV16 was the most common type among CIN2/3 (51.2%, p < 0.001), invasive SCC (47.6%, p = 0.001) and adenocarcinomas (80%, p < 0.001).

Conclusion: This study supports previous population-based studies in which similar HPV detection rates were found among random samples of women. HPV-based screening tests and HPV vaccination would be efficient in uterine cervix cancer prevention among women in the Central Tunisia.
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http://dx.doi.org/10.1684/abc.2010.0431DOI Listing
July 2010

p16INK4A overexpression in precancerous and cancerous lesions of the uterine cervix in Tunisian women.

Pathol Res Pract 2010 Aug 18;206(8):550-5. Epub 2010 Apr 18.

Research Unit 03/UR/08-13, Cancer Epidemiology and Cytopathology in Tunisian Center, Medicine Faculty, Sousse, Tunisia.

Uterine cervix cancer is an important public health problem in developing countries. However, there is a substantial lack of inter-observer diagnostic reproducibility for its precursor lesions (CIN1). The study was performed to evaluate the usefulness of p16(INK4A) overexpression as a surrogate marker for uterine cervix precancerous lesions and high-risk human papillomavirus (HPV) infection. We conducted a retrospective study of 87 uterine cervix specimens, including 7 normal tissue samples, 17 benign lesions, 34 precancerous lesions, 22 invasive squamous cell carcinomas (SCC), and 7 adenocarcinomas. Immunohistochemistry was used to find p16(INK4A) overexpression. HPV infection was detected by PCR. No immunoreactivity for p16(INK4A) was detected in normal tissue or benign lesions. p16(INK4A) immunoreactivity was focal in CIN1, whereas strong and diffuse immunoreactivity for p16(INK4A) was uniformly observed in both the nucleus and the cytoplasm of all CIN2 and 3, as well as in those of invasive SCC and adenocarcinomas. A statistically significant association was observed between p16(INK4A) overexpression, lesion grade, and high-risk HPV infection (p<0.0001). p16(INK4A) overexpression is a useful additional marker for the interpretation of problematic uterine cervical lesions and can help to reduce the variability during evaluation of suspicious biopsies of the uterine cervix.
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http://dx.doi.org/10.1016/j.prp.2010.02.014DOI Listing
August 2010

In vitro and in vivo evaluation of an alumina-zirconia composite for arthroplasty applications.

Biomaterials 2010 Mar 6;31(8):2043-54. Epub 2010 Jan 6.

Université de Lyon, UPSP 2007.03.135, Lyon Cedex 08, France.

In order to improve the reliability and the mechanical properties of orthopaedic hip prosthesis, new ceramic composites starting with nanosized powders of alumina and zirconia have been recently developed. The aim of the present study was to investigate the biological tolerance of one of these sintered ceramics and of its alumina and zirconia constitutive nanosized powders with both in vitro and in vivo approaches. At first, osteoblasts and fibroblasts were cultured either upon sintered ceramic discs with polished or rough surfaces or in the presence of the corresponding alumina or zirconia powders at various concentrations. Thereafter, we chronically injected these powders in the knee articulation of rats. In vitro, the materials showed no deleterious effect on cell proliferation, extra-cellular matrix production (human type I collagen and fibronectin) or on cell morphology. In vivo, the histological examination showed only a very moderate and non-specific granulomatous response of the synovial membrane but no major inflammation as clinically described with metals or polyethylene wear debris. Besides its improved physical properties, this recently developed alumina-zirconia composite showed satisfactory biocompatibility.
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http://dx.doi.org/10.1016/j.biomaterials.2009.11.107DOI Listing
March 2010