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  1. Article: Un transporteur d'anions est essentiel à la mobilité des spermatozoïdes.

    Lhuillier, Pierre / Escalier, Denise / Gacon, Gérard / Touré, Aminata

    Medecine sciences : M/S

    2008  Volume 24, Issue 3, Page(s) 226–228

    Title translation An anion transporter is essential for spermatozoa motility.
    MeSH term(s) Animals ; Anion Transport Proteins/deficiency ; Anion Transport Proteins/genetics ; Anion Transport Proteins/physiology ; Antiporters/deficiency ; Antiporters/genetics ; Antiporters/physiology ; Contraception/methods ; Humans ; Infertility, Male/genetics ; Infertility, Male/physiopathology ; Male ; Mice ; Mice, Knockout ; Phenotype ; Phosphorylation ; Protein Processing, Post-Translational ; Sperm Capacitation/physiology ; Sperm Motility/physiology ; Sperm Tail/ultrastructure
    Chemical Substances Anion Transport Proteins ; Antiporters ; SLC26A8 protein, human ; Slc26a8 protein, mouse
    Language French
    Publishing date 2008-03
    Publishing country France
    Document type News
    ZDB-ID 632733-3
    ISSN 1958-5381 ; 0767-0974
    ISSN (online) 1958-5381
    ISSN 0767-0974
    DOI 10.1051/medsci/2008243226
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Asthénozoospermie humaine et anomalies de l'annulus.

    Lhuillier, Pierre / Escalier, Denise / Gacon, Gérard / Dulioust, Emmanuel / Touré, Aminata

    Medecine sciences : M/S

    2010  Volume 26, Issue 8-9, Page(s) 688–689

    Title translation Human asthenozoospermia and structural defects of the annulus.
    MeSH term(s) Animals ; Asthenozoospermia/diagnosis ; Asthenozoospermia/etiology ; Fertility ; Humans ; Infertility, Male ; Male ; Mice ; Sperm Motility
    Language French
    Publishing date 2010-08
    Publishing country France
    Document type News
    ZDB-ID 632733-3
    ISSN 1958-5381 ; 0767-0974
    ISSN (online) 1958-5381
    ISSN 0767-0974
    DOI 10.1051/medsci/2010268-9688
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The testis anion transporter 1 (Slc26a8) is required for sperm terminal differentiation and male fertility in the mouse.

    Touré, Aminata / Lhuillier, Pierre / Gossen, Jan A / Kuil, Cor W / Lhôte, David / Jégou, Bernard / Escalier, Denise / Gacon, Gérard

    Human molecular genetics

    2007  Volume 16, Issue 15, Page(s) 1783–1793

    Abstract: The Slc26 family is a conserved family of anion transporters. In the human, their physiological relevance was highlighted with the discovery of pathogenic mutations in several Slc26 transporters that lead to distinctive clinical disorders (Pendred ... ...

    Abstract The Slc26 family is a conserved family of anion transporters. In the human, their physiological relevance was highlighted with the discovery of pathogenic mutations in several Slc26 transporters that lead to distinctive clinical disorders (Pendred syndrome, deafness, diastrophic dysplasia, congenital chloride diarrhoea) that are related to the specific distribution of these genes. We previously identified TAT1 as a new family member (Slc26A8), very specifically expressed in male germ cells in both the human and the mouse. To investigate Tat1 function in the male germline, we generated mice with a targeted disruption of the Tat1 gene. Heterozygous and homozygous Tat1 mutant mice were indistinguishable from wild-type littermates concerning survival rate, general appearance and gross behaviour; however, Tat1 null males were sterile due to complete lack of sperm motility and reduced sperm fertilization potential. Ultra-structural analysis revealed defects in flagellar differentiation leading to an abnormal annulus, disorganization of the midpiece-principal piece junction, hairpin bending of the sperm tail with disruption of the axial structures, and abnormal mitochondrial sheath assembly. While ATP levels were normal, ATP consumption was strongly reduced in Tat1 null spermatozoa. Interestingly, Tat1 is located at the annulus, a septin-based circular structure connecting the midpiece to the principal piece. Altogether, our results indicate that Tat1 is a critical component of the sperm annulus that is essential for proper sperm tail differentiation and motility.
    MeSH term(s) Acrosome/metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Animals ; Anion Transport Proteins/genetics ; Anion Transport Proteins/physiology ; Antiporters/genetics ; Antiporters/physiology ; Cell Differentiation ; Female ; Fertility/physiology ; Flagella/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Sperm Motility ; Spermatozoa/metabolism ; Testis/metabolism ; Testis/ultrastructure
    Chemical Substances Amino Acid Transport Systems, Neutral ; Anion Transport Proteins ; Antiporters ; Slc16a10 protein, mouse ; Slc26a8 protein, mouse ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2007-08-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddm117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation.

    Rode, Baptiste / Dirami, Thassadite / Bakouh, Naziha / Rizk-Rabin, Marthe / Norez, Caroline / Lhuillier, Pierre / Lorès, Patrick / Jollivet, Mathilde / Melin, Patricia / Zvetkova, Ilona / Bienvenu, Thierry / Becq, Frédéric / Planelles, Gabrielle / Edelman, Aleksander / Gacon, Gérard / Touré, Aminata

    Human molecular genetics

    2012  Volume 21, Issue 6, Page(s) 1287–1298

    Abstract: The Slc26 gene family encodes several conserved anion transporters implicated in human genetic disorders, including Pendred syndrome, diastrophic dysplasia and congenital chloride diarrhea. We previously characterized the TAT1 (testis anion transporter 1; ...

    Abstract The Slc26 gene family encodes several conserved anion transporters implicated in human genetic disorders, including Pendred syndrome, diastrophic dysplasia and congenital chloride diarrhea. We previously characterized the TAT1 (testis anion transporter 1; SLC26A8) protein specifically expressed in male germ cells and mature sperm and showed that in the mouse, deletion of Tat1 caused male sterility due to a lack of sperm motility, impaired sperm capacitation and structural defects of the flagella. Ca(2+), Cl(-) and HCO(3)(-) influxes trigger sperm capacitation events required for oocyte fertilization; these events include the intracellular rise of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA)-dependent protein phosphorylation. The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in mature sperm and has been shown to contribute to Cl(-) and HCO(3)(-) movements during capacitation. Furthermore, several members of the SLC26 family have been described to form complexes with CFTR, resulting in the reciprocal regulation of their activities. We show here that TAT1 and CFTR physically interact and that in Xenopus laevis oocytes and in CHO-K1 cells, TAT1 expression strongly stimulates CFTR activity. Consistent with this, we show that Tat1 inactivation in mouse sperm results in deregulation of the intracellular cAMP content, preventing the activation of PKA-dependent downstream phosphorylation cascades essential for sperm activation. These various results suggest that TAT1 and CFTR may form a molecular complex involved in the regulation of Cl(-) and HCO(3)(-) fluxes during sperm capacitation. In humans, mutations in CFTR and/or TAT1 may therefore be causes of asthenozoospermia and low fertilizing capacity of sperm.
    MeSH term(s) Animals ; Anion Transport Proteins/physiology ; Antiporters/physiology ; Bicarbonates/metabolism ; COS Cells ; Cells, Cultured ; Cercopithecus aethiops ; Chlorides/metabolism ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Electrophysiology ; Humans ; Immunoblotting ; Immunoprecipitation ; Male ; Mice ; Mice, Transgenic ; Oocytes/cytology ; Oocytes/metabolism ; Phosphorylation ; Sperm Capacitation/physiology ; Sperm Motility ; Testis/cytology ; Testis/metabolism ; Xenopus laevis
    Chemical Substances Anion Transport Proteins ; Antiporters ; Bicarbonates ; Chlorides ; Slc26a8 protein, mouse ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Cyclic AMP (E0399OZS9N) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
    Language English
    Publishing date 2012-03-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddr558
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  5. Article ; Online: Preoperative concurrent radiation therapy and chemotherapy for bulky stage IB2, IIA, and IIB carcinoma of the uterine cervix with proximal parametrial invasion.

    Huguet, Florence / Cojocariu, Oana-Maria / Levy, Pierre / Lefranc, Jean-Pierre / Darai, Emile / Jannet, Denis / Ansquer, Yan / Lhuillier, Pierre-Eugène / Benifla, Jean-Louis / Seince, Nathalie / Touboul, Emmanuel

    International journal of radiation oncology, biology, physics

    2008  Volume 72, Issue 5, Page(s) 1508–1515

    Abstract: Purpose: To evaluate toxicity, local tumor control, and survival after preoperative chemoradiation for operable bulky cervical carcinoma.: Methods and materials: Between December 1991 and July 2006, 92 patients with operable bulky stage IB2, IIA, and ...

    Abstract Purpose: To evaluate toxicity, local tumor control, and survival after preoperative chemoradiation for operable bulky cervical carcinoma.
    Methods and materials: Between December 1991 and July 2006, 92 patients with operable bulky stage IB2, IIA, and IIB cervical carcinoma without pelvic or para-aortic nodes on pretreatment imaging were treated. Treatment consisted of preoperative external beam pelvic radiation therapy (EBRT) and concomitant chemotherapy (CT) during the first and fourth weeks of radiation combining 5-fluorouracil and cisplatin. The pelvic radiation dose was 40.5 Gy over 4.5 weeks. EBRT was followed by low-dose rate uterovaginal brachytherapy with a total dose of 20 Gy in 62 patients. After a median rest period of 44 days, all patients underwent Class II modified radical hysterectomy with bilateral pelvic lymphadenectomy. Thirty patients who had not received preoperative uterovaginal brachytherapy underwent postoperative low-dose-rate vaginal brachytherapy at a dose of 20 Gy. The mean follow-up was 46 months.
    Results: Pathologic residual tumor was observed in 43 patients. After multivariate analysis, additional preoperative uterovaginal brachytherapy was the single significant predictive factor for pathologic complete response rate (p = 0.019). The 2- and 5-year disease-free survival (DFS) rates were 80.4% and 72.2%, respectively. Pathologic residual cervical tumor was the single independent factor decreasing the probability of DFS (p = 0.020). Acute toxicities were moderate. Two severe ureteral complications requiring surgical intervention were observed.
    Conclusions: Concomitant chemoradiation followed by surgery for operable bulky stage I-II cervical carcinoma without clinical lymph node involvement can be used with acceptable toxicity. Pathologic complete response increases the probability of DFS.
    MeSH term(s) Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Adenocarcinoma/radiotherapy ; Adenocarcinoma/surgery ; Adult ; Aged ; Brachytherapy/methods ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/pathology ; Carcinoma, Squamous Cell/radiotherapy ; Carcinoma, Squamous Cell/surgery ; Combined Modality Therapy ; Endometrium/pathology ; Female ; Humans ; Hysterectomy ; Lymph Node Excision ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; Preoperative Care ; Recurrence ; Retrospective Studies ; Uterine Cervical Neoplasms/drug therapy ; Uterine Cervical Neoplasms/pathology ; Uterine Cervical Neoplasms/radiotherapy ; Uterine Cervical Neoplasms/surgery
    Language English
    Publishing date 2008-12-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2008.03.054
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  6. Article ; Online: SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.

    Hanchate, Naresh Kumar / Giacobini, Paolo / Lhuillier, Pierre / Parkash, Jyoti / Espy, Cécile / Fouveaut, Corinne / Leroy, Chrystel / Baron, Stéphanie / Campagne, Céline / Vanacker, Charlotte / Collier, Francis / Cruaud, Corinne / Meyer, Vincent / García-Piñero, Alfons / Dewailly, Didier / Cortet-Rudelli, Christine / Gersak, Ksenija / Metz, Chantal / Chabrier, Gérard /
    Pugeat, Michel / Young, Jacques / Hardelin, Jean-Pierre / Prevot, Vincent / Dodé, Catherine

    PLoS genetics

    2012  Volume 8, Issue 8, Page(s) e1002896

    Abstract: Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/ ... ...

    Abstract Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
    MeSH term(s) Animals ; Axons/metabolism ; Disease Models, Animal ; Embryo, Mammalian/metabolism ; Female ; Fetus/metabolism ; Gonadotropin-Releasing Hormone/metabolism ; Humans ; Kallmann Syndrome/genetics ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mutation ; Neuropilin-1/genetics ; Neuropilin-1/metabolism ; Nose/innervation ; Semaphorin-3A/chemistry ; Semaphorin-3A/genetics ; Semaphorin-3A/metabolism
    Chemical Substances Semaphorin-3A ; Neuropilin-1 (144713-63-3) ; Gonadotropin-Releasing Hormone (33515-09-2)
    Language English
    Publishing date 2012-08-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1002896
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  7. Article: Operable Stages IB and II cervical carcinomas: a retrospective study comparing preoperative uterovaginal brachytherapy and postoperative radiotherapy.

    Atlan, Dan / Touboul, Emmanuel / Deniaud-Alexandre, Elisabeth / Lefranc, Jean-Pierre / Antoine, Jean-Marie / Jannet, Denis / Lhuillier, Pierre / Uzan, Michèle / Huart, Judith / Genestie, Catherine / Antoine, Martine / Jamali, Myriam / Ganansia, Valérie / Milliez, Jacques / Uzan, Serge / Blondon, Jean

    International journal of radiation oncology, biology, physics

    2002  Volume 54, Issue 3, Page(s) 780–793

    Abstract: Purpose: To evaluate our data concerning prognostic factors and treatment toxicity in a series of operable cervical carcinomas.: Methods and materials: Between May 1972 and January 1994, 414 patients with cervical carcinoma, staged according to the ... ...

    Abstract Purpose: To evaluate our data concerning prognostic factors and treatment toxicity in a series of operable cervical carcinomas.
    Methods and materials: Between May 1972 and January 1994, 414 patients with cervical carcinoma, staged according to the 1995 FIGO staging system (286 Stage IB1, 38 Stage IB2, 56 Stage IIA, and 34 Stage IIB with 1/3 proximal parametrial involvement), underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection (N+: n = 68). Group I included 168 patients who received postoperative radiation therapy (RT): 64 patients had low-dose-rate vaginal brachytherapy with a median total dose (MTD) of 50 Gy; 93 patients had external beam pelvic RT (EBPRT) with an MTD of 45 Gy over 5 weeks, followed by low-dose-rate vaginal brachytherapy (MTD: 20 Gy); and 11 patients had EBPRT alone (MTD: 50 Gy over 6 weeks). Group II included 246 patients treated with preoperative low-dose-rate uterovaginal brachytherapy (MTD: 65 Gy); 32 of these 246 patients also received postoperative EBPRT (MTD: 45 Gy over 5 weeks) delivered to the parametria and pelvic nodes. Mean follow-up from the beginning of treatment was 106 months.
    Results: First events included isolated locoregional recurrences (35 patients), isolated distant metastases (27 patients), and locoregional recurrences with synchronous metastases (13 patients). The 10-year disease-free survival (DFS) rate was 88% for Stage IB1, 44% for Stage IB2, 65% for Stage IIA, and 48% for Stage IIB. Multivariate analysis showed that independent factors influencing the probability of DFS were as follows: cervical site (exocervical or endocervical vs. both endo- and exocervical, relative risk [RR]: 1.77, p = 0.047), vascular space invasion (no vs. yes, RR: 1.95, p = 0.041), age (>51 years vs. <or=51 years, RR: 1.90, p = 0.013), 1995 FIGO staging system (IB1 vs. IIA, RR: 2.95, p = 0.004; IB1 vs. IB2, RR: 3.49, p = 0.0009; and IB1 vs. IIB, RR: 4.54, p = 0.00002), and histologic pelvic lymph node involvement (N- vs. N+, RR: 2.94, p = 0.00009). The sequence of adjuvant RT did not influence the probability of DFS (Group I vs. Group II, p = 0.10). In Group II, after univariate analysis, DFS was significantly influenced by histologic residual cervical tumor in the hysterectomy specimen (yes vs. no: 71% vs. 93%, respectively, p < 10(-6)) and by the size of the residual tumor (<or=1 cm vs. >1 cm: 83% vs. 41%, respectively, p = 0.001). The overall postoperative complication rate was 10% in Group I and 9% in Group II (p = 0.7). The rate of postoperative ureteral complications requiring surgical intervention was lower in Group I than in Group II (0.6% vs. 2.3%, respectively, p = 0.03). The overall 10-year rate for Grade 3 and 4 late radiation complications was 10.4%. Postoperative EBPRT significantly increased the 10-year rate for Grade 3 and 4 late radiation complications (yes vs. no: 22% vs. 7%, respectively, p = 0.0002).
    Conclusion: The prognosis for patients with cervical carcinoma was not influenced by the sequence of adjuvant RT (preoperative uterovaginal brachytherapy vs. postoperative RT) for Stages IB, IIA, and IIB with 1/3 proximal parametrial involvement. However, postoperative EBPRT increased the risk of late radiation complications.
    MeSH term(s) Adenocarcinoma/mortality ; Adenocarcinoma/pathology ; Adenocarcinoma/radiotherapy ; Adenocarcinoma/surgery ; Adult ; Aged ; Aged, 80 and over ; Analysis of Variance ; Carcinoma, Adenosquamous/mortality ; Carcinoma, Adenosquamous/pathology ; Carcinoma, Adenosquamous/radiotherapy ; Carcinoma, Adenosquamous/surgery ; Female ; Humans ; Middle Aged ; Neoplasm Staging ; Postoperative Complications ; Radiotherapy/adverse effects ; Recurrence ; Retrospective Studies ; Uterine Cervical Neoplasms/mortality ; Uterine Cervical Neoplasms/pathology ; Uterine Cervical Neoplasms/radiotherapy ; Uterine Cervical Neoplasms/surgery
    Language English
    Publishing date 2002-11-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/s0360-3016(02)02971-1
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