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1.
eNeuro ; 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34880111

RESUMO

A metanalysis identified Regulator of G protein Signaling 6 (RGS6) as one of 23 loci with pleiotropic effects on four or more human psychiatric disorders. This finding is significant as it confirms/extends the findings of numerous other studies implicating RGS6 in CNS function and pathology. RGS6 is a highly conserved member of the RGS protein family whose cellular roles are likely affected by mRNA splicing and alternative domain inclusion/exclusion. Indeed, we previously identified multiple RGS6 splice variants predicted to produce 36 distinct protein isoforms containing either long (RGS6L) or short (RGS6S) N-terminal domains, an incomplete or intact GGL domain, and 9 alternative C-termini. Unfortunately, sequence similarities between the isoforms have made it difficult to confirm their individual existence and/or to determine their unique functions. Here, we developed 3 RGS6-specific antibodies that recognize all RGS6 protein isoforms (RGS6-fl), the N-terminus of RGS6L isoforms (RGS6-L), and an 18 amino acid alternate C-terminal sequence (RGS6-18). Using these antibodies, we demonstrate that RGS6L(+GGL) isoforms, predominating in both mouse (both sexes) CNS and peripheral tissues, are most highly expressed in the CNS. We further identify 3 novel RGS6 protein bands that are larger (61, 65, and 69kDa) than the ubiquitously expressed 53-57kDa RGS6L(+GGL) proteins. Importantly, we show that the 69kDa protein is a brain-specific dephospho- form of the 65 kDa band, the first identified phosphorylated RGS6 isoform. Together, these data begin to define the functional significance behind the complexity of RGS6 gene processing and further clarifies RGS6's physiological roles by resolving tissue-specific RGS6 protein expression.Significance StatementPsychiatric disorders are highly associated with polygenic variation. Consistent with this, a SNP (rs2332700) in Regulator of G protein Signaling 6 (RGS6) is linked to autism spectrum disorder, bipolar disorder, major depression, and schizophrenia. RGS6 is a highly conserved gene whose complex alternative mRNA splicing produces numerous protein isoforms with high sequence similarity, hindering their functional characterization. Therefore, while aberrant RGS6 signaling and/or expression have been linked to various neuropsychiatric disorders, it is unclear which isoforms are important. This study functionally delineates between the various RGS6 isoforms within mouse. We demonstrate that RGS6 is most highly expressed in CNS, characterize the predominant isoforms, and identify a brain-specific RGS6 protein highly expressed in brain regions associated with various psychiatric disorders.

2.
BJOG ; 127(9): 1102-1107, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32146729

RESUMO

OBJECTIVE: To investigate the demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma. DESIGN: A retrospective national population-based study. SETTING: UK 1995-2015. POPULATION: A total of 234 women with a diagnosis of gestational choriocarcinoma, in the absence of a prior molar pregnancy, managed at the UKs two gestational trophoblast centres in London and Sheffield. METHODS: Retrospective review of the patient's demographic and clinical data. Comparison with contemporary UK birth and pregnancy statistics. MAIN OUTCOMES: Incidence statistics for non-molar choriocarcinoma across the maternal age groups. Cure rates for patients by FIGO prognostic score group. RESULTS: Over the 21-year study period, there were 234 cases of non-molar gestational choriocarcinoma, giving an incidence of 1:66 775 relative to live births and 1:84 226 to viable pregnancies. For women aged under 20, the incidence relative to viable pregnancies was 1:223 494, for ages 30-34, 1:80 227, and for ages 40-45, 1:41 718. Treatment outcomes indicated an overall 94.4% cure rate. Divided by FIGO prognostic groups, the cure rates were low-risk group 100%, high-risk group 96% and ultra-high-risk group 80.5%. CONCLUSIONS: Non-molar gestational choriocarcinoma is a very rare diagnosis with little prior detailed information on the demographics and natural history. The data in this study give age-related incidence data based on a large national population study. The results also demonstrated the widely varying natural history of this rare malignancy and the marked correlation of disease incidence with rising maternal age. TWEETABLE ABSTRACT: National gestational choriocarcinoma database indicates a close association between increasing maternal age and incidence.


Assuntos
Coriocarcinoma/epidemiologia , Neoplasias Uterinas/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Coriocarcinoma/complicações , Coriocarcinoma/secundário , Coriocarcinoma/terapia , Feminino , Número de Gestações , Humanos , Incidência , Nascido Vivo/epidemiologia , Idade Materna , Pessoa de Meia-Idade , Gravidez , Complicações Neoplásicas na Gravidez/epidemiologia , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/terapia , Prognóstico , Fatores de Risco , Resultado do Tratamento , Reino Unido/epidemiologia , Hemorragia Uterina/etiologia , Neoplasias Uterinas/complicações , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Adulto Jovem
3.
BJOG ; 127(3): 389-395, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794098

RESUMO

OBJECTIVE: Presence of lung metastases in low-risk gestational trophoblastic neoplasia (GTN) is generally considered not to influence prognosis. However, in a recent study in the Netherlands, GTN patients with lung metastases had a higher recurrence rate and more disease-specific deaths compared with patients without metastases. The aim of the present study was to validate these findings in a different country. DESIGN: Historical cohort study. SETTING: Charing Cross Hospital, United Kingdom. POPULATION: A total of 1040 low-risk GTN patients treated with methotrexate (MTX) between 2002 and 2016 were identified: 65 with lung metastases (group 1) and 975 without metastases (group 2). METHODS: Baseline characteristics, MTX resistance, survival and recurrence rates were recorded and compared between both groups. MAIN OUTCOME MEASURES: MTX resistance, recurrence rate and survival. RESULTS: The occurrence of MTX resistance and median number of MTX courses to achieve remission was significantly higher in patients with lung metastases than patients without metastases (60% versus 38.9%, P = 0.001; and nine versus six courses, P < 0.001). All choriocarcinoma patients (n = 4) with lung metastases developed MTX resistance. The recurrence rate was also higher in group I (9.2% versus 2.7%; P = 0.012). Disease-specific survival was 100% in both groups. CONCLUSIONS: The presence of lung metastases at the start of MTX therapy is associated with increased incidence of MTX resistance and recurrence in low-risk GTN without affecting overall survival, which remains 100%. However, individuals with low-risk choriocarcinoma with lung metastases are likely to become resistant to MTX and primary multi-agent chemotherapy should be considered. TWEETABLE ABSTRACT: The presence of lung metastases appears to increase the risk of recurrence in low-risk GTN, but does not affect overall cure rates and survival.


Assuntos
Coriocarcinoma , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doença Trofoblástica Gestacional , Neoplasias Pulmonares , Metotrexato , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Estudos de Coortes , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Recidiva , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Reino Unido/epidemiologia
4.
Eur J Cancer ; 109: 162-171, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30731277

RESUMO

OBJECTIVE: The objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs). METHODS: Databases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS). RESULTS: HDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred. CONCLUSIONS: Despite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Trofoblástica Gestacional/terapia , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Complicações Neoplásicas na Gravidez/terapia , Adulto , Terapia Combinada , Feminino , Seguimentos , Doença Trofoblástica Gestacional/patologia , Humanos , Pessoa de Meia-Idade , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
5.
Eur J Obstet Gynecol Reprod Biol ; 234: 117-119, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30684876

RESUMO

OBJECTIVE: To determine whether post-pregnancy human chorionic gonadotrophin screening after previous hydatidiform mole identifies patients with recurrent gestational trophoblastic disease. STUDY DESIGN: A retrospective evaluation of 9315 patients who underwent post-pregnancy screening from 2000 to 2009, as part of the National Gestational Trophoblastic Disease Service in the UK. RESULTS: Patients with previous hydatidiform mole, who had human chorionic gonadotrophin screening after one or more subsequent pregnancies, were identified (n = 9315). Of these, 8630 patients had an initial hydatidiform mole that did not require chemotherapy. In 12,329 subsequent pregnancy events, screening with human chorionic gonadotrophin identified 3 cases of gestational trophoblastic neoplasm. The remaining 685 patients developed gestational trophoblastic neoplasm, following their initial hydatidiform mole and required chemotherapy. In this group there were 1012 further pregnancy events, human chorionic gonadotrophin screening identified 3 patients with gestational trophoblastic neoplasm. The overall recurrence rate was 6 in 13,341 events (risk 1: 2227). The rate was 3 in 12,329 (risk 1:4110) for HM that did not require chemotherapy and 3 in 1012 (1:337) for previously treated gestational trophoblastic neoplasm. All 6 patients with recurrent disease were successfully treated with chemotherapy. CONCLUSION: Routine post-pregnancy human chorionic gonadotrophin screening may be safely discontinued in patients with one previous uncomplicated hydatidiform mole.


Assuntos
Gonadotropina Coriônica/sangue , Doença Trofoblástica Gestacional/diagnóstico , Mola Hidatiforme/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Uterinas/sangue , Adulto , Feminino , Doença Trofoblástica Gestacional/etiologia , Humanos , Mola Hidatiforme/complicações , Recidiva Local de Neoplasia/etiologia , Período Pós-Parto/sangue , Gravidez , Estudos Retrospectivos , Fatores de Risco , Neoplasias Uterinas/complicações
6.
Int J Epidemiol ; 48(1): 7-10, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-28025258
7.
Dis Esophagus ; 30(5): 1-10, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28375436

RESUMO

Esophageal replacement by colonic interposition is an uncommon procedure. This study sought to identify the frequency of this operation in England, identify techniques and associated problems, and also assess health-related quality of life (HR QOL) from the two largest centers performing this procedure. Hospital Episode Statistics were used to identify patients and centers undertaking colon interposition between March 2001 and March 2015. An online survey of UK consultants discussed methods and experience. HR QOL was assessed using the Short Form 36(SF-36v2) with additional gastrointestinal questions. Hospital Episode Statistics identified 328 interpositions (22 in pediatric hospitals). The two highest volume units did 42 and 45 operations, respectively. Thirty-four surgeons (79% response rate) replied to the survey. Fifty-two percent preferred to use the left colon with 81% preferring a substernal placement. The HR QOL survey was performed on 24 patients with a median of 3 years after surgery (ranging from 9 months to 10 years) from the two largest centers and a 56% response rate. Five patients had physical QOL scores above population average and 10 had mental scores above population average. All patients had early satiety, 20 described dysphagia, and 18 regularly took antireflux medication. There was an estimated mean loss of 13.1% body weight (10.6 kg) postoperatively and three patients still relied on a feeding tube for nutrition after an average of 3 years. Colon interposition results in an acceptable long-term QOL. Few centers regularly perform this operation, and centralizing to high-volume centers may lead to better outcomes.


Assuntos
Colo/cirurgia , Colo/transplante , Doenças do Esôfago/cirurgia , Esofagectomia/métodos , Esôfago/cirurgia , Qualidade de Vida , Idoso , Anastomose Cirúrgica/métodos , Criança , Pré-Escolar , Inglaterra , Esofagectomia/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Lactente , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Período Pós-Operatório , Inquéritos e Questionários
8.
Am J Transplant ; 17(4): 1081-1096, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27647626

RESUMO

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.


Assuntos
Transplante de Fígado , Doadores Vivos/psicologia , Fatores Socioeconômicos , Obtenção de Tecidos e Órgãos/economia , Adulto , Feminino , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Apoio Social , Inquéritos e Questionários
9.
Am J Transplant ; 17(5): 1267-1277, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27865040

RESUMO

Although single-center and cross-sectional studies have suggested a modest impact of liver donation on donor psychological well-being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0-3%), alcohol abuse (2-5%), and anxiety syndromes (2-3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well-being at various time points. We identified significant predictors for donors' perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data-driven follow-up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.


Assuntos
Transtorno Depressivo Maior/psicologia , Transplante de Fígado/psicologia , Doadores Vivos/psicologia , Qualidade de Vida , Adulto , Estudos Transversais , Transtorno Depressivo Maior/epidemiologia , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Inquéritos e Questionários
11.
Am J Transplant ; 16(2): 594-602, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26461803

RESUMO

The purpose of this study was to explore long-term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan-Meier method, and predictors were tested in Cox proportional hazards models. Median follow-up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End-Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary-related complications and hepatic artery thrombosis. In DDLT, ascites, intra-abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/etiologia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Complicações Pós-Operatórias , Adulto , Cadáver , Feminino , Seguimentos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Transplantados
12.
Hum Reprod ; 30(9): 2055-63, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26202916

RESUMO

STUDY QUESTION: What is the risk of further molar pregnancies for women with one or more hydatidiform moles (HM) in relation to molar subtype. SUMMARY ANSWER: Women with a complete hydatidiform mole (CM) have a 1 in 100 and 1 in 4 risk of further CM after one or two consecutive CM, respectively, while women with a partial hydatidiform mole (PM) have only a small increase in risk for further molar pregnancies. WHAT IS KNOWN ALREADY: Women with a molar pregnancy have an increased risk of further HM. A small subgroup of women with recurrent HM has an autosomal recessive condition, familial recurrent hydatidiform moles (FRHM), that predisposes them to molar pregnancies. STUDY DESIGN, SIZE, DURATION: A retrospective study of subsequent pregnancies in 16 000 women registered at a centralized referral centre, with a CM or PM, between 1990 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and sixty-six women with two or more molar pregnancies were identified from electronic records and patient notes. Histopathological features of all molar tissue were reviewed in these cases and genotyping performed where diagnosis was not possible on the basis of histopathological features alone. In addition, genotyping of molar tissue was performed in all cases of women with three or more CM to establish whether the tissue was diploid and biparental or androgenetic. MAIN RESULTS AND THE ROLE OF CHANCE: This study confirms an increased recurrence risk of ∼1% for a second molar pregnancy and in addition that this risk is associated with CM rather than PM. The data further indicate that the risk of a third HM is associated almost exclusively with CM and enabled an estimate that 1 in 640 women registered with a CM has the rare condition FRHM. The study also found that there was no significant difference between the risk of developing gestational trophoblastic neoplasia (GTN) for typical sporadic CM and the diploid biparental CM associated with FRHM (GTN; proportion difference 0.05, Z = 0.87, P = 0.29). LIMITATIONS, REASONS FOR CAUTION: While pathology was reviewed for all women with two or more molar pregnancies, not all cases registered underwent central review particularly those women registered in the early 1990s. It is therefore possible that the total number of CM and PM may differ slightly from that stated. While women were followed for a minimum of 5 years, it is possible that some women may subsequently have further molar pregnancies that will not have been included in the present study. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date on recurrence for molar pregnancies, and as such provides the most detailed information so far regarding the risk of further molar pregnancies for women with a PM or CM. Furthermore, the data provide new insights into the incidence of the rare autosomal recessive condition, FRHM, important information for counselling women with molar pregnancies. STUDY FUNDING/COMPETING INTERESTS: No competing interests declared. No funding was obtained for this study.


Assuntos
Mola Hidatiforme/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Uterinas/epidemiologia , Adolescente , Adulto , Feminino , Humanos , Mola Hidatiforme/genética , Londres/epidemiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Gravidez , Estudos Retrospectivos , Risco , Neoplasias Uterinas/genética , Adulto Jovem
13.
Hum Reprod ; 30(1): 232-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25376457

RESUMO

STUDY QUESTION: Are mutations in NLRP2/7 (NACHT, LRR and PYD domains-containing protein 2/7) or KHDC3L (KH Domain Containing 3 Like) associated with recurrent pregnancy loss (RPL) or infertility? SUMMARY ANSWER: We found no evidence for mutations in NLRP2/7 or KHDC3L in unexplained RPL or infertility. WHAT IS KNOWN ALREADY: Mutations in NLRP7 and KHDC3L are known to cause biparental hydatidiform moles (BiHMs), a rare form of pregnancy loss. NLRP2, while not associated with the BiHM pathology, is known to cause recurrent Beckwith Weidemann Syndrome (BWS). STUDY DESIGN, SIZE, AND DURATION: Ninety-four patients with well characterized, unexplained infertility were recruited over a 9-year period from three IVF clinics in Sweden. Blood samples from 24 patients with 3 or more consecutive miscarriages of unknown etiology were provided by the Recurrent Miscarriage Clinic at St Mary's Hospital, London, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were recruited into both cohorts following extensive clinical studies. Genomic DNA was isolated from peripheral blood and subject to Sanger sequencing of NLRP2, NLRP7 and KHDC3L. Sequence electropherograms were analyzed by Sequencher v5.0 software and variants compared with those observed in the 1000 Genomes, single nucleotide polymorphism database (dbSNP) and HapMap databases. Functional effects of non-synonymous variants were predicted using Polyphen-2 and sorting intolerant from tolerant (SIFT). MAIN RESULTS AND THE ROLE OF CHANCE: No disease-causing mutations were identified in NLRP2, NLRP7 and KHDC3L in our cohorts of unexplained infertility and RPL. LIMITATIONS, REASONS FOR CAUTION: Due to the limited patient size, it is difficult to conclude if the low frequency single nucleotide polymorphisms observed in the present study are causative of the phenotype. The design of the present study therefore is only capable of detecting highly penetrant mutations. WIDER IMPLICATIONS OF THE FINDINGS: The present study supports the hypothesis that mutations in NLRP7 and KHDC3L are specific for the BiHM phenotype and do not play a role in other adverse reproductive outcomes. Furthermore, to date, mutations in NLRP2 have only been associated with the imprinting disorder BWS in offspring and there is no evidence for a role in molar pregnancies, RPL or unexplained infertility. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the following sources: Estonian Ministry of Education and Research (Grant SF0180044s09), Enterprise Estonia (Grant EU30020); Mentored Resident research project (Department of Obstetrics and Gynecology, Baylor College of Medicine); Imperial NIHR Biomedical Research Centre; Grant Number C06RR029965 from the National Center for Research Resources (NCCR; NIH). No competing interests declared.


Assuntos
Aborto Habitual/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Infertilidade Feminina/genética , Proteínas/genética , Proteínas Reguladoras de Apoptose , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Mutação , Gravidez
14.
Oncogene ; 33(27): 3604-11, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23995786

RESUMO

The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.


Assuntos
Apoptose , Transformação Celular Neoplásica , DNA (Citosina-5-)-Metiltransferases/metabolismo , Histona Acetiltransferases/metabolismo , Proteólise , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas RGS/metabolismo , Transativadores/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , Humanos , Lisina Acetiltransferase 5 , Camundongos , Transdução de Sinais
16.
J Obstet Gynaecol ; 33(4): 406-11, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23654327

RESUMO

The national registration and treatment service for molar pregnancies in the UK allows for the collection of accurate data on this relatively rare diagnosis. In England and Wales, between 2000 and 2009, 5,793 patients with complete moles and 7,790 with partial moles were registered, compared with a total of 8,242,511 conceptions. The overall molar pregnancy incidence was 1 for every 607 conceptions (complete mole 1:1,423; partial mole 1:1,058), but with major variations with age. For complete moles, the risk varied from < 1:1,000 for ages 18-40, to 1:156 for women aged 45 and 1:8 for those aged 50 and above. The overall risk of requiring chemotherapy after a complete mole was 13.6% and 1.1% for partial mole, while the risk of a further molar pregnancy in the next conception was 1:68 but each of these figures have considerable variations with age. These modern statistics on molar pregnancy risks and outcomes should be of value to clinicians and their patients, while discussing this rare diagnosis.


Assuntos
Mola Hidatiforme/epidemiologia , Idade Materna , Sistema de Registros , Neoplasias Uterinas/epidemiologia , Feminino , Humanos , Mola Hidatiforme/tratamento farmacológico , Incidência , Gravidez , Resultado da Gravidez , Medição de Risco , Reino Unido/epidemiologia , Neoplasias Uterinas/tratamento farmacológico
17.
Placenta ; 34(1): 50-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23201303

RESUMO

OBJECTIVES: Molar pregnancies, characterized by hydropic change and trophoblast hyperplasia of chorionic villi, are usually sporadic. Second and third molar pregnancies can occur by chance but may be associated with a rare autosomal recessive condition, familial recurrent hydatidiform mole (FRHM). This condition, in which affected women have a predisposition to complete hydatidiform moles (CHM), is not usually diagnosed until women have experienced several CHM when a differential diagnosis is made by demonstrating the CHM are diploid and biparental (BiCHM) in contrast to sporadic CHM which are androgenetic (AnCHM). Our objective was to investigate whether these genetic differences might be reflected in identifiable phenotypic differences between BiCHM and AnCHM that could enable earlier diagnosis of FRHM. STUDY DESIGN: Histopathological features were compared between 27 AnCHM from 17 individuals and 51 BiCHM from 20 families in whom a diagnosis of FRHM was confirmed by the presence of biallelic NLRP7 mutations or pathological variants. RESULTS: A spectrum of morphological features was observed in BiCHM. As a group they show subtle, but consistent, histological differences from typical sporadic AnCHM, with less marked villous trophoblast hyperplasia, extravillous trophoblast fragments, stromal apoptotic debris, budding architecture, cisterns and trophoblastic inclusions. While there are some BiCHM that individually show atypical histological features, the majority are indistinguishable from typical sporadic AnCHM. CONCLUSION: The majority of cases of FRHM cannot be distinguished from sporadic AnCHM on the basis of histopathological features alone. In a minority of cases CHM may demonstrate 'atypical' features that raise the possibility of underlying BiCHM requiring further investigation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mola Hidatiforme/genética , Mola Hidatiforme/patologia , Mutação , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Estudos de Coortes , Família , Feminino , Idade Gestacional , Homozigoto , Humanos , Padrões de Herança , Mutação/fisiologia , Pais , Gravidez
18.
Am J Transplant ; 12(11): 2997-3007, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22994906

RESUMO

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/mortalidade , Transplante de Fígado/métodos , Recidiva Local de Neoplasia/patologia , Adulto , Cadáver , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
20.
Br J Cancer ; 106(6): 1089-94, 2012 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-22374461

RESUMO

BACKGROUND: Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R). METHODS: 286 LR-GTN patients (Charing Cross Hospital (CXH) score 0-8, or FIGO score 0-6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI. RESULTS: 239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI≤1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI≤1 was 100% vs 20% in patients with UAPI>1 (χ(2) P<0.0001). CONCLUSION: UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ≤1 might be upstaged and offered combination chemotherapy rather than MTX.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Doença Trofoblástica Gestacional/irrigação sanguínea , Metotrexato/farmacologia , Fluxo Pulsátil , Artéria Uterina/fisiopatologia , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Velocidade do Fluxo Sanguíneo , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Humanos , Modelos Logísticos , Metotrexato/uso terapêutico , Análise Multivariada , Gravidez , Fatores de Risco , Estatísticas não Paramétricas
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