RESUMO
CONTEXT: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with high heritability, justifying systematic genetic screening for a germline variant in one of the twenty predisposing genes described to date. PURPOSE: To describe the experience of one endocrine oncogenetic laboratory over a period of 21 years (2001-2022), from the beginning of PPGL genotyping with Sanger sequencing in 2001 to the implementation of next-generation sequencing (NGS). METHOD: The activity database of an academic oncogenetic laboratory was searched to extract patients/relatives identified with a pathogenic variant/likely pathogenic variant (PV/LPV) over a period of 21 years. Clinical and genetic data were compared. RESULTS: In total, 606 index cases with PPGL and 444 relatives were genotyped. Genotyping of index cases was performed by Sanger sequencing and gene deletion analysis in 327 cases and by NGS in 279. Germline PV/LPV spanning 10 genes was identified in 165 index cases (27.2%). Several recurrent PV/LPVs in SDHx were observed in non-related index cases, the most frequent being SDHD, c.170-1G>T (n=28). This subgroup showed great phenotypic variability both between and within families in terms of both tumor location and number. Four patients (1.1%) with PV/LPV in SDHx had 3PA (Pituitary Adenoma and pheochromocytoma/paraganglioma) syndrome. 258 relatives (58.1%) had inherited a PV/LPV in one driver gene. The rate of PV/LPV carriers who were symptomatic at first imaging evaluation was 32%, but varied between<20% in SDHB and SDHC and >50% in SDHD, VHL and MAX. CONCLUSION: Our experience confirmed previously established genotype-phenotype correlations, but also highlights atypical clinical presentations, even for the same genetic variant. These data must be taken into account for optimal patient follow-up and management.
Assuntos
Neoplasias das Glândulas Suprarrenais , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Feocromocitoma/epidemiologia , Paraganglioma/genética , Paraganglioma/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/epidemiologia , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Testes Genéticos , Idoso , Sequenciamento de Nucleotídeos em Larga Escala , Criança , Genótipo , Succinato Desidrogenase/genéticaRESUMO
BACKGROUND: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling. METHODS: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/). RESULTS: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11. CONCLUSION: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.
Assuntos
Neoplasias Renais , Doença de von Hippel-Lindau , Humanos , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Testes Genéticos , Predisposição Genética para Doença , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Estudos de Associação Genética , Neoplasias Renais/genética , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood. METHODS: We studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity. FINDINGS: Increased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS. INTERPRETATION: We uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS. FUNDING: INSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).
Assuntos
Síndrome do Ovário Policístico , Humanos , Animais , Camundongos , Feminino , Hormônio Luteinizante , Hormônio Antimülleriano , Imagem de Tensor de Difusão , Hormônio Liberador de Gonadotropina , Neuroglia/patologiaRESUMO
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with SDHx pathogenic variants (PVs) are characterized by a higher intratissular succinate/fumarate ratio (RS/F) than non-SDHx-mutated ones. Also, an increase in serum succinate levels has been reported in patients with germline SDHB or SDHD PV. OBJECTIVE: To assess whether measurement of serum succinate, fumarate levels, and RS/F might aid identification of an SDHx germline PV/likely pathogenic variant (LPV) in patients with PPGL or in asymptomatic relatives; and to guide identification of a PV/LPV among the variants of unknown significance (VUS) identified in SDHx by next-generation sequencing. METHODS: This prospective monocentric study included 93 patients attending an endocrine oncogenetic unit for genetic testing. Succinate and fumarate were measured in serum by gas chromatography coupled to mass spectrometry. The RS/F was calculated to assess SDH enzymatic function. Diagnostic performance was assessed by receiver operating characteristic analysis. RESULTS: RS/F had a higher discriminant power than succinate alone to identify an SDHx PV/LPV in patients with PPGL. However, SDHD PVs/LPVs are frequently missed. Only RS/F differed between asymptomatic SDHB/SDHD PV/LPV carriers and SDHB/SDHD-linked patients with PPGL. Finally RS/F could be helpful to easily evaluate the functional impact of VUS in SDHx. CONCLUSION: Measurement of serum RS/F in patients with PPGL and in asymptomatic relatives is a valuable initial workup tool to detect those carrying a germline PV/LPV in SDHx. Its discriminative power is equal or superior to those of succinate measured alone. SDHD PVs/LPVs are less frequently identified by these biochemical tools. Use of RS/F for SDHx VUS reclassification needs to be evaluated further.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Ácido Succínico , Fumaratos , Estudos Prospectivos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patologia , Carcinogênese , Transformação Celular Neoplásica , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Mutação em Linhagem GerminativaRESUMO
Apart from the oncometabolite succinate, little studies have appeared on extra-mitochondrial pathways in Succinate Dehydrogenase (SDH) genetic deficiency. The role of NADH/NAD+ redox status and dependent pathways was recently emphasized. Therein, fatty acid (FA) metabolism data were collected here in 30 patients with a loss of function (LOF) variant in one SDHx gene (either with a pheochromocytoma/paraganglioma (PPGL) or asymptomatic) and in 22 wild-type SDHx controls (with PPGL or asymptomatic). Blood acylcarnitines in two patients, peroxisomal biomarkers, very long-chain saturated FA (VLCFA), and C20 to C24 n-3 polyunsaturated fatty acids (PUFA), in all patients were measured by mass spectrometry. Preliminary data showed elevated even and odd long- and very long-chain acylcarnitines in two patients with a SDHB variant. In the whole series, no abnormalities were observed in biomarkers of peroxisomal ß-oxidation (C27-bile acids, VLCFAs and phytanic/pristanic acids) in SDHx patients. However, an increased hexaene to pentaene PUFA ratio ([TetraHexaenoic Acid + DocosaHexaenoic Acid]/[n-3 DocosaPentaenoic Acid + EicosaPentaenoic Acid]) was noticed in patients with SDHC/SDHD variants vs patients with SDHA/SDHB variants or controls, suggesting a higher degree of unsaturation of PUFAs. Within the group with a SDHx variant, Eicosapentaenoate/Tetracosahexaenoate ratio, as an empiric index of shortening/elongation balance, discriminated patients with PPGL from asymptomatic ones. Present findings argue for stimulated elongation of saturated FAs, changes in shortening/elongation balance and desaturation rates of C20-C24 PUFAs in SDH-deficient patients with PPGL. Overall, oxidation of NADH sustained by these pathways might reflect or impact glycolytic NAD+ recycling and hence tumor proliferation.
Assuntos
Neoplasias das Glândulas Suprarrenais , Ácidos Graxos/sangue , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Ácidos e Sais Biliares , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Complexo II de Transporte de Elétrons/deficiência , Humanos , Erros Inatos do Metabolismo , Doenças Mitocondriais , Mutação , NAD/metabolismo , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/genética , Succinato Desidrogenase/genética , Ácido Succínico/metabolismoRESUMO
INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.
Assuntos
Acromegalia , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Acromegalia/tratamento farmacológico , Preparações de Ação Retardada/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I , Peptídeos Cíclicos , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Estudos Retrospectivos , Somatostatina/análogos & derivadosRESUMO
Young individuals, aged <40 years, represent 7% of all patients with early breast cancer (EBC), most of whom receive chemotherapy. Preserving future fertility in these patients has become a major concern. This prospective study assessed ovarian function during and after chemotherapy according to patient and tumor characteristics and evaluated the outcome of controlled ovarian hyperstimulation (COH). Ovarian reserve was evaluated in terms of amenorrhea duration and by longitudinal serum anti-Müllerian hormone (AMH) level variations measured at study entry, during treatment and until 24 months thereafter. COH has been proposed for patients receiving adjuvant chemotherapy. We studied the association between clinical factors and ovarian function using Cox models and logistic regression. In this young population (age < 38 years, median = 32), 85 of 90 evaluable patients (94%) experienced chemo-induced amenorrhea, including six persistent amenorrhea and one chemotherapy-induced definitive ovarian failure. Overall, 33% of patients still had undetectable AMH values 12 months after the end of chemotherapy, although most had recovered spontaneous and regular menstrual function. No specific factor was associated with clinical or biological late ovarian dysfunction, except for age and baseline AMH value. Overall, 58 patients underwent COH. The mean number of total retrieved oocytes and metaphase II oocytes were of 11.7 and 6.9, respectively. Thus, our study confirms the importance of fertility preservation in young patients with EBC. Our findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation or recovery of ovarian reserve.
Assuntos
Neoplasias da Mama , Preservação da Fertilidade , Reserva Ovariana , Hormônio Antimülleriano , Neoplasias da Mama/patologia , Feminino , Preservação da Fertilidade/efeitos adversos , Humanos , Ovário/patologia , Estudos ProspectivosRESUMO
BACKGROUND: It is still debated whether differences in bone turnover markers (BTMs) exist between the 2 most popular bariatric surgery procedures (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]). OBJECTIVES: To compare changes in BTMs after RYGB and SG, and to investigate their association with predefined markers of interest. SETTING: University hospital, Lille, France. METHODS: An ancillary investigation of a prospective cohort was conducted. SG patients with severe obesity ≥40 years were matched one-to-one to RYGB patients for age, sex, body mass index (BMI), and menopausal status. BTMs, as well as predefined markers of interest, were measured at baseline, 12, and 24 months after bariatric surgery. RESULTS: Sixty-four patients (66% women) had a mean (standard deviation [SD]) age of 49.6 years (5.1) and a mean (SD) BMI of 45.0 kg/m2 (6.0). From baseline to 12 months, a significant increase in BTMs was observed in both groups (P < .001). Moreover, RYGB was associated with a greater increase in C-terminal telopeptide (ß-CTX) and procollagen type 1 N-terminal propeptide (PINP) compared with SG (P < .0001). From 12 to 24 months, a significant decrease in BTMs was observed in both groups, but no significant differences were found between RYGB and SG. However, BTMs did not return to baseline levels. The changes in PINP and ß-CTX at 12 months were independently associated with the type of surgical procedure, after adjusting for weight or each predefined marker of interest (all P < .0001). CONCLUSION: RYGB was associated with a greater increase in BTMs than SG at 12 and 24 months.
Assuntos
Derivação Gástrica , Obesidade Mórbida , Remodelação Óssea , Feminino , Gastrectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/cirurgia , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND INFORMATION: Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. RESULTS: We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. CONCLUSIONS: We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. SIGNIFICANCE: To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos , Irinotecano/uso terapêutico , Leucovorina , Organoides , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
BACKGROUND: SDHB is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic SDHB variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the 'NGS and PPGL (NGSnPPGL) Study Group' initiated an international effort to collect, annotate and classify SDHB variants and to provide an accurate, expert-curated and freely available SDHB variant database. METHODS: A total of 223 distinct SDHB variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field. RESULTS: This multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB). CONCLUSION: This international initiative by a panel of experts allowed us to establish a consensus classification for 223 SDHB variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of SDHB genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Succinato Desidrogenase/genéticaRESUMO
Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.
Assuntos
Epigênese Genética , Síndrome do Ovário Policístico/genética , Animais , Hormônio Antimülleriano/farmacologia , Hormônio Antimülleriano/uso terapêutico , Estudos de Casos e Controles , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Humanos , Hormônio Luteinizante/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigenases de Função Mista/genética , Ovário/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Cuidado Pré-Natal , Proteínas Proto-Oncogênicas/genética , S-Adenosilmetionina/farmacologia , S-Adenosilmetionina/uso terapêutico , Transcriptoma/efeitos dos fármacosRESUMO
RESEARCH QUESTION: Which clinical features, along with biological features, ultrasound features, or both, are the most strongly associated with either high or low anti-Müllerian hormone (AMH) levels in patients with polycystic ovary syndrome (PCOS)? DESIGN: A retrospective cross-sectional study conducted within a university-affiliated reproductive endocrinology unit in Lille, France. A total of 639 patients with PCOS according to the Rotterdam Criteria and 137 control women were included. A comparison of clinical, hormonal, metabolic and ultrasound data in patients with PCOS and controls belonging to the first (Q1) and fourth (Q4) quartiles of their respective AMH ranges (discriminant analysis) was conducted. RESULTS: In the PCOS group, patients in Q4 had higher LH levels and a more severe phenotype, but they were thinner and had lower levels of hyperinsulinaemia than patients in Q1. In the PCOS group, discriminant analysis yielded a highly significant model in which follicle number per ovary (FNPO) and serum LH were strongly and equally discriminating between Q4 and Q1 (R2 at 0.371 and 0.304, respectively, both P < 0.0001), whereas body mass index had less, although significant, effect (R2â¯=â¯0.075, P < 0.0001). In control women, discriminant analysis yielded a significant discriminant model, including only FNPO and age (R2 at 0.62 and 0.27, both P < 0.0001). CONCLUSION: High serum AMH levels are associated with high serum LH levels and more severe features of PCOS. Conversely, the effect of hyperinsulinism may be greater in patients with lower serum AMH levels, suggesting independent effects of AMH and insulin on the phenotypic expression of PCOS.
Assuntos
Hormônio Antimülleriano/sangue , Resistência à Insulina , Síndrome do Ovário Policístico/sangue , Adulto , Estudos Transversais , Feminino , Humanos , Síndrome do Ovário Policístico/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Adulto JovemRESUMO
The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss.NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.
Assuntos
Ácidos e Sais Biliares/metabolismo , Sistema Biliar/patologia , Ducto Colédoco/patologia , Derivação Gástrica/métodos , Glucose/metabolismo , Anastomose Cirúrgica/métodos , Animais , Ácidos e Sais Biliares/sangue , Sistema Biliar/metabolismo , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Glicemia/metabolismo , Ducto Colédoco/metabolismo , Ducto Colédoco/cirurgia , Feminino , Modelos Animais , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Período Pós-Prandial , Distribuição Aleatória , Suínos , Porco Miniatura , Redução de Peso/fisiologiaRESUMO
RESEARCH QUESTION: Does the relative distribution of anti-Müllerian hormone (AMH) isoforms differ between patients depending on their body mass index (BMI) and polycystic ovary syndrome (PCOS) status in serum and follicular fluid? DESIGN: Obese and normal weight patients (PCOS [nâ¯=â¯70]; non-PCOS [nâ¯=â¯37]) were selected for this case-control study in the serum. Between 2018 and 2019, obese (nâ¯=â¯19) and normal weight (nâ¯=â¯20) women with or without PCOS who were receiving IVF treatment were included in the follicular fluid study. The bio-banked serums and follicular fluid were tested for total AMH (proAMH and AMHN,C combined) and proAMH using an automatic analyzer. The AMH prohormone index (APIâ¯=â¯[proAMH]/[total AMH]x 100) was calculated as an inverse marker of conversion of proAMH to AMHN,C, with only the latter isoform that could bind to the AMH receptor complex. RESULTS: The API was not significantly different between controls and women with PCOS, whereas obese women had a lower API compared with their normal weight counterparts. Grouping PCOS and controls, a lower API was found in obese versus normal weight women, suggesting a greater conversion of proAMH to AMHN,C. The API in the serum was significantly correlated with metabolic parameters. In the follicular fluid, API is not different between obese and normal weight women independently of PCOS and is higher than in the concomitant serum. CONCLUSIONS: The proportion of inactive form of AMH in the serum is higher in normal weight versus obese women but not in the follicular fluid, independently of PCOS. The conversion of proAMH into the cleaved isoform is likely to occur in extra-ovarian tissues and to exacerbate in obese individuals.
Assuntos
Hormônio Antimülleriano/metabolismo , Líquido Folicular/metabolismo , Obesidade/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adolescente , Adulto , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/química , Biomarcadores/sangue , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Líquido Folicular/química , França/epidemiologia , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/sangue , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/sangue , Precursores de Proteínas/metabolismo , Adulto JovemRESUMO
OBJECTIVE: We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband's brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. DESIGN AND METHODS: Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. RESULTS: A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband's brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. CONCLUSION: In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.
RESUMO
OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.
RESUMO
Cellular stress response contributes to epithelial defense in adaptation to environment changes. Galectins play a pivotal role in the regulation of this response in malignant cells. However, precise underlying mechanisms are largely unknown. Here we demonstrate that Galectin-3, a pro and anti-apoptotic lectin, is required for setting up a correct cellular response to stress by orchestrating several effects. First, Galectin-3 constitutes a key post-transcriptional regulator of stress-related mRNA regulons coordinating the cell metabolism, the mTORC1 complex or the unfolded protein response (UPR). Moreover, we demonstrated the presence of Galectin-3 with mitochondria-associated membranes (MAM), and its interaction with proteins located at the ER or mitochondrial membranes. There Galectin-3 prevents the activation and recruitment at the mitochondria of the regulator of mitochondria fission DRP-1. Accordingly, loss of Galectin-3 impairs mitochondrial morphology, with more fragmented and round mitochondria, and dynamics both in normal and cancer epithelial cells in basal conditions. Importantly, Galectin-3 deficient cells also display changes of the activity of the mitochondrial respiratory chain complexes, of the mTORC1/S6RP/4EBP1 translation pathway and reactive oxygen species levels. Regarding the ER, Galectin-3 did not modify the activities of the 3 branches of the UPR in basal conditions. However, Galectin-3 favours an adaptative UPR following ER stress induction by Thapsigargin treatment. Altogether, at the ER-mitochondria interface, Galectin-3 coordinates the functioning of the ER and mitochondria, preserves the integrity of mitochondrial network and modulates the ER stress response.
Assuntos
Proteínas Sanguíneas/metabolismo , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Galectinas/metabolismo , Mitocôndrias/metabolismo , Apoptose/genética , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Membranas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tapsigargina/metabolismo , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
OBJECTIVES: The prevalence of ovulation disorder (OD) is 3-fold higher in obese than normal-weight women. Most ODs are associated with concomitant polycystic ovary syndrome (PCOS), but obesity by itself can cause OD, through mechanisms that remain poorly documented. The literature on obese non-PCOS women with OD is sparse. The aim of the present study was to analyze a population of obese non-PCOS women with OD to shed further light on the mechanism of ovulation disorder. MATERIAL AND METHODS: This retrospective observational study of infertile obese women without PCOS compared a control group without OD (n=45) to a study group with OD (n=30) (OD group). Clinical, hormonal, and ultrasound characteristics were collected between cycle days 2 and 5. Women older than 37 years and women with PCOM (polycystic ovarian morphology) or hormonal disorder were excluded. RESULTS: Body mass index (BMI) was significantly higher in the OD group, as were waist circumference and insulin and leptin serum levels. Conversely, serum follicle stimulating hormone (FSH) levels were significantly lower. After adjustment for BMI, only serum FSH level remained significantly different between the 2 groups. Discriminant analysis suggested that FSH may have a much stronger effect on OD than BMI. CONCLUSION: Low serum FSH level may contribute to OD in some obese women, independently of BMI. The pathophysiological mechanism of this finding and its impact on therapeutic strategies must be clarified.