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High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400-TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion of SRCAP, P400, and VPS72 (YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.
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Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Histonas , Melanoma , Humanos , Melanoma/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Histonas/metabolismo , Histonas/genética , Acetilação , Apoptose/genética , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genéticaRESUMO
Long noncoding RNAs (lncRNAs) are involved in diverse cellular processes through multiple mechanisms. Here, we describe a previously uncharacterized human lncRNA, CONCR (cohesion regulator noncoding RNA), that is transcriptionally activated by MYC and is upregulated in multiple cancer types. The expression of CONCR is cell cycle regulated, and it is required for cell-cycle progression and DNA replication. Moreover, cells depleted of CONCR show severe defects in sister chromatid cohesion, suggesting an essential role for CONCR in cohesion establishment during cell division. CONCR interacts with and regulates the activity of DDX11, a DNA-dependent ATPase and helicase involved in DNA replication and sister chromatid cohesion. These findings unveil a direct role for an lncRNA in the establishment of sister chromatid cohesion by modulating DDX11 enzymatic activity.
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Cromátides/metabolismo , Replicação do DNA , DNA de Neoplasias/biossíntese , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , Células A549 , Animais , Apoptose , Proliferação de Células , Cromátides/genética , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , DNA de Neoplasias/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , Fatores de Tempo , Transcrição Gênica , Ativação Transcricional , Transfecção , Carga Tumoral , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The COVID-19 pandemic is a global traumatic experience for citizens, especially during sensitive time windows of heightened plasticity such as pregnancy and neonatal life. Pandemic-related stress experienced by mothers during pregnancy may act as an early risk factor for infants' regulatory capacity development by altering maternal psychosocial well-being (e.g., increased anxiety, reduced social support) and caregiving environment (e.g., greater parenting stress, impaired mother-infant bonding). The aim of the present longitudinal study was to assess the consequences of pandemic-related prenatal stress on infants' regulatory capacity. A sample of 163 mother-infant dyads was enrolled at eight maternity units in northern Italy. They provided complete data about prenatal stress, perceived social support, postnatal anxiety symptoms, parenting stress, mother-infant bonding, and infants' regulatory capacity at 3 months of age. Women who experienced emotional stress and received partial social support during pregnancy reported higher anxious symptoms. Moreover, maternal postnatal anxiety was indirectly linked to the infants' regulatory capacity at 3 months, mediated by parenting stress and mother-infant bonding. Dedicated preventive interventions should be delivered to mothers and should be focused on protecting the mother-infant dyad from the detrimental effects of pandemic-related stress during the COVID-19 healthcare emergency.
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COVID-19 , Relações Mãe-Filho , Recém-Nascido , Feminino , Lactente , Humanos , Gravidez , Estudos Longitudinais , Relações Mãe-Filho/psicologia , Pandemias , COVID-19/epidemiologia , Mães/psicologiaRESUMO
OBJECTIVE: Children exposed to chemotherapy in the prenatal period demonstrate normal neurocognitive development at 3 years but concerns regarding fetal brain growth remain high considering its vulnerability to external stimuli. Our aim was to evaluate the impact of in-utero chemotherapy exposure on brain growth and its effects on neurodevelopmental outcome. METHODS: The protocol was approved by the local ethics committee. Brain regional volumes at term postmenstrual age were measured by MRI in children exposed to in-utero chemotherapy and compared with normal MRI controls. Brain segmentation was performed by Advanced Normalization Tools (ANTs)-based transformations of the Neonatal Brain Atlas (ALBERT). Neurodevelopmental assessment (Bayley-III scales) was performed at 18 months corrected age in both exposed infants and in a group of healthy controls. Multiple linear regressions and false discovery rate correction for multiple comparisons were performed. RESULTS: Twenty-one newborns prenatally exposed to chemotherapy (epirubicin administered in 81% of mothers) were enrolled in the study: the mean gestational age was 36.4±2.4 weeks and the mean birthweight was 2,753±622 g. Brain MRI was performed at mean postmenstrual age of 41.1±1.4 weeks. No statistically significant differences were identified between the children exposed to chemotherapy and controls in both the total (398±55 cm3 vs 427±56 cm3, respectively) and regional brain volumes. Exposed children showed normal Bayley-III scores (cognitive 110.2±14.5, language 99.1±11.3, and motor 102.6±7.3), and no significant correlation was identified between the brain volumes and neurodevelopmental outcome. CONCLUSION: Prenatal exposure to anthracycline/cyclophosphamide-based chemotherapy does not impact fetal brain growth, thus supporting the idea that oncological treatment in pregnant women seems to be feasible and safe for the fetus.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Desenvolvimento Fetal/efeitos dos fármacos , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Neoplasias/tratamento farmacológico , GravidezRESUMO
Long noncoding RNAs (lncRNAs) are rapidly emerging as important regulators of gene expression in a wide variety of physiological and pathological cellular processes. In particular, a number of studies revealed that some lncRNAs participate in the p53 pathway, the unquestioned protagonist of tumor suppressor response. Indeed, several lncRNAs are not only part of the large pool of genes coordinated by p53 transcription factor, but are also required by p53 to fine-tune its response and to fully accomplish its tumor suppressor program. In this review we will discuss the current and fast growing knowledge about the contribution of lncRNAs to the complexity of the p53 network, the different mechanisms by which they affect gene regulation in this context, and their involvement in cancer. The incipient impact of lncRNAs in the p53 biological response may encourage the development of therapies and diagnostic methods focused on these noncoding molecules. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.
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Redes Reguladoras de Genes , Neoplasias/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/patologia , RNA Longo não Codificante/biossíntese , Transdução de Sinais , Proteína Supressora de Tumor p53/biossínteseRESUMO
Recent small RNA sequencing data has uncovered 3' end modification of mature microRNAs (miRNAs). This non-templated nucleotide addition can impact miRNA gene regulatory networks through the control of miRNA stability or by interfering with the repression of target mRNAs. The miRNA modifying enzymes responsible for this regulation remain largely uncharacterized. Here we describe the ability for two related terminal uridyl transferases (TUTases), Zcchc6 (TUT7) and Zcchc11 (TUT4), to 3' mono-uridylate a specific subset of miRNAs involved in cell differentiation and Homeobox (Hox) gene control. Zcchc6/11 selectively uridylates these miRNAs in vitro, and we biochemically define a bipartite sequence motif that is necessary and sufficient to confer Zcchc6/11 catalyzed uridylation. Depletion of these TUTases in cultured cells causes the selective loss of 3' mono-uridylation of many of the same miRNAs. Upon TUTase-dependent loss of uridylation, we observe a concomitant increase in non-templated 3' mono-adenylation. Furthermore, TUTase inhibition in Zebrafish embryos causes developmental defects and aberrant Hox expression. Our results uncover the molecular basis for selective miRNA mono-uridylation by Zcchc6/11, highlight the precise control of different 3' miRNA modifications in cells and have implications for miRNA and Hox gene regulation during development.
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Proteínas de Ligação a DNA/metabolismo , MicroRNAs/metabolismo , RNA Nucleotidiltransferases/metabolismo , Uridina/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Humanos , MicroRNAs/química , Motivos de Nucleotídeos , RNA Nucleotidiltransferases/antagonistas & inibidores , RNA Nucleotidiltransferases/genética , Peixe-Zebra/genéticaRESUMO
Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro-inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.
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BACKGROUND: Pregnancy associated breast cancer is the most common cancer diagnosed during pregnancy. When chemotherapy is indicated, although it is more common to use anthracycline-based chemotherapy as a first treatment, we suggest weekly paclitaxel as a valid alternative both in the adjuvant and neoadjuvant setting, as this allows for weekly assessment of maternal-fetal well-being and a quicker maternal and fetal bone marrow recovery in cases of unexpected preterm delivery. PATIENTS AND METHODS: We present a case series of pregnant breast cancer patients treated with weekly paclitaxel between 2016 and 2022. Patient demographics and tumor characteristics, data on management, delivery, and maternal-neonatal outcomes were extrapolated from institutional electronic databases. RESULTS: Eighteen patients underwent weekly paclitaxel for breast cancer during pregnancy (PrBC); 17 were primary diagnoses and 1 was a recurrence. None of the patients had severe adverse reactions to CT. Two cases of preterm prelabour rupture of membranes were reported while in 1 case treatment was stopped due to threatened preterm birth. Two babies were born large for gestational age, 2 were small for gestational age and 2 babies were growth restricted at birth. At a mean follow up of 42.9 months, 1 patient died, 1 patient was diagnosed with disease recurrence and another patient was diagnosed with disease progression. CONCLUSION: Weekly paclitaxel can be safely administered during pregnancy and should be included in the current therapeutic options for PrBC.
Assuntos
Neoplasias da Mama , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Gravidez , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/induzido quimicamente , Paclitaxel , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/tratamento farmacológicoRESUMO
OBJECTIVE: This study aimed to analyze long-term survival of clear cells (CCs) and endometrioid (E) ovarian cancer cases according to presence of endometriosis in the pathologic report. METHODS: This is a retrospective analysis of 47 CC and 66 E ovarian cancer cases observed consecutively at our center between 1990 and 2010.All cases had first surgery at our center or were referred to it for treatment and follow-up.Cases were identified according to the original diagnosis reported in clinical records.All pathologic reports were reviewed, and cases were classified with or without pathologic evidence of endometriosis on the basis of the pathologic report.Follow-up was updated in March 2011. The follow-up median was 147 months (range, 116-171). RESULTS: Endometriosis-associated ovarian cancer cases were more frequently diagnosed at stage I to II than cases without endometriosis: among the 36 endometriosis-associated ovarian cancer cases, 25 (69%) were at stage I or II, and the corresponding value was 35 (46%) of 77 among cases without endometriosis (P = 0.0173).The presence of endometriosis tended to be associated with a higher 10-year survival rate: after taking the potential confounding effect of stage into account, the finding was not statistically significant (hazards ratio, 0.7; 95% confidence interval, 0.3-1.5). CONCLUSIONS: This analysis shows that EA CCs and E ovarian cases are diagnosed at an earlier stage than cases without endometriosis. No clear association emerged between presence of endometriosis and survival.
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Adenocarcinoma de Células Claras/mortalidade , Carcinoma Endometrioide/mortalidade , Endometriose/mortalidade , Doenças Ovarianas/mortalidade , Neoplasias Ovarianas/mortalidade , Adenocarcinoma de Células Claras/complicações , Adenocarcinoma de Células Claras/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/complicações , Carcinoma Endometrioide/etiologia , Endometriose/complicações , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Doenças Ovarianas/complicações , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/etiologia , Estudos Retrospectivos , Análise de Sobrevida , Sobreviventes/estatística & dados numéricosRESUMO
ARID2 is the most recurrently mutated SWI/SNF complex member in melanoma; however, its tumor-suppressive mechanisms in the context of the chromatin landscape remain to be elucidated. Here, we model ARID2 deficiency in melanoma cells, which results in defective PBAF complex assembly with a concomitant genomic redistribution of the BAF complex. Upon ARID2 depletion, a subset of PBAF and shared BAF-PBAF-occupied regions displays diminished chromatin accessibility and associated gene expression, while BAF-occupied enhancers gain chromatin accessibility and expression of genes linked to the process of invasion. As a function of altered accessibility, the genomic occupancy of melanoma-relevant transcription factors is affected and significantly correlates with the observed transcriptional changes. We further demonstrate that ARID2-deficient cells acquire the ability to colonize distal organs in multiple animal models. Taken together, our results reveal a role for ARID2 in mediating BAF and PBAF subcomplex chromatin dynamics with consequences for melanoma metastasis.
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Proteínas Cromossômicas não Histona , Melanoma , Fatores de Transcrição , Animais , Cromatina , Montagem e Desmontagem da Cromatina , Regulação da Expressão Gênica , Humanos , Melanoma/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND AND AIM: Sars-CoV-2 infection has rapidly spread worldwide following the first cases reported in China. Piacenza is one of the most affected cities in Italy. Many infections occurred in the hospital due to the high frequency of patients and healthcare professionals interaction. The aim of the work is to evaluate advantages of universal screening for Sars-Cov-2 in pregnant women admitted to a hospital setting and calculate frequency of infection in an obstetrical population. Methods: all pregnant women attending Guglielmo da Saliceto Hospital in Piacenza from 22nd April to 18th June 2020 were screened for Sars-Cov-2 using a nasopharyngeal swab. Results: 240 pregnant women were tested upon admission: all twelve (5%) testing positive were asymptomatic. None of the positive asymptomatic women developed COVID-19 symptoms or adverse perinatal outcomes. CONCLUSIONS: the diagnosis of asymptomatic pregnant women through universal screening provides the opportunity to protect mothers, babies and heath care workers. In accordance with other studies, our findings add to the growing body of evidence showing high rates of asymptomatic infection in the healthcare setting and highlight a critical need for universal screening of pregnant women.
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Teste para COVID-19 , COVID-19/diagnóstico , Gestantes , China/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Pandemias , Gravidez , SARS-CoV-2/isolamento & purificaçãoRESUMO
The COVID-19 pandemic is a collective trauma that is threatening citizens' mental health resulting in increased emotional stress, reduced social support, and heightened risk for affective symptoms. The present study aimed to investigate the effects of antenatal pandemic-related emotional stress and perceived social support on the symptoms of depression and anxiety of mothers who were pregnant during the initial COVID-19 outbreak in northern Italy. A sample of 281 mothers was enrolled at eight maternity units in the first hotspot region of the COVID-19 outbreak in northern Italy. Participants filled out online questionnaires assessing the direct or indirect exposure to the SARS-CoV-2 virus, pandemic-related stress, perceived social support, as well as symptoms of depression and anxiety. Depressive and anxious symptomatology was above clinical concern, respectively, in 26 and 32% of the respondents. Mothers who reported no exposure to SARS-CoV-2 during pregnancy and those who reported at least one direct or indirect exposure did not differ in terms of affective symptoms. Continuous scores and risk for severe depression and anxiety were positively associated with prenatal pandemic-related emotional stress and negatively linked with perceived social support during pregnancy. Women who become mothers during the COVID-19 emergency may be at high risk for affective problems. Dedicated preventive programs are needed to provide adequate preventive support and care for maternal mental health during and after the COVID-19 pandemic.
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Oral consumption of probiotics is practical and can be an effective solution to preserve vaginal eubiosis. Here, we studied the ability of orally administered Lactobacillus paracasei LPC-S01 (DSM 26760) to affect the composition of the vaginal microbiota and colonize the vaginal mucosa in nondiseased adult women. A total of 40 volunteers took oral probiotic (24 billion CFU) or placebo capsules daily for 4 weeks, and after a 4-week washout, they switched to placebo or probiotic capsules according to the crossover design. A total of 23 volunteers completed the study according to the protocol. Before and after capsule ingestion, vaginal swabs were collected for qPCR quantification to detect L. paracasei LPC-S01 and for 16S rRNA gene sequencing. Vaginal swabs were grouped according to their bacterial taxonomic structure into nine community state types (CSTs), four of which were dominated by lactobacilli. Lactobacillus paracasei LPC-S01 was detected in the vagina of two participants. Statistical modeling (including linear mixed-effects model analysis) demonstrated that daily intake of probiotic capsules reduced the relative abundance of Gardnerella spp. Quantitative PCR with Gardnerella vaginalis primers confirmed this result. Considering the pathogenic nature of G. vaginalis, these results suggest a potential positive effect of this probiotic capsule on the vaginal microbial ecosystem.
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Lacticaseibacillus paracasei , Microbiota , Probióticos , Vaginose Bacteriana , Adulto , Cápsulas , Estudos Cross-Over , Feminino , Humanos , RNA Ribossômico 16S/genéticaRESUMO
LncRNAs have been shown to be direct players in chromatin regulation, but little is known about their role at active genomic loci. We investigate the role of lncRNAs in gene activation by profiling the RNA interactome of SMARCB1-containing SWI/SNF complexes in proliferating and senescent conditions. The isolation of SMARCB1-associated transcripts, together with chromatin profiling, shows prevalent association to active regions where SMARCB1 differentially binds locally transcribed RNAs. We identify SWINGN, a lncRNA interacting with SMARCB1 exclusively in proliferating conditions, exerting a pro-oncogenic role in some tumor types. SWINGN is transcribed from an enhancer and modulates the activation of GAS6 oncogene as part of a topologically organized region, as well as a larger network of pro-oncogenic genes by favoring SMARCB1 binding. Our results indicate that SWINGN influences the ability of the SWI/SNF complexes to drive epigenetic activation of specific promoters, suggesting a SWI/SNF-RNA cooperation to achieve optimal transcriptional activation.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/metabolismo , Proteína SMARCB1/metabolismo , Animais , Apoptose/genética , Carcinogênese , Proliferação de Células/genética , Conjuntos de Dados como Assunto , Feminino , Redes Reguladoras de Genes , Células HCT116 , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Neoplasias/patologia , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , RNA-Seq , Ativação Transcricional , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To evaluate histological alterations in placentas of women affected by breast cancer and treated with chemotherapy during pregnancy. STUDY DESIGN: We retrospectively reviewed histological slides of 23 placentas of patients affected by breast cancer and treated with chemotherapy during pregnancy and 23 control placentas of women without breast cancer and with physiological pregnancies of the same gestational age. RESULTS: All the patients had breast ductal infiltrating carcinoma, 19 of 23 cases had a G3 cancer. All patients were treated with 2-6 cycles of chemotherapy starting after 16 weeks of gestation, with different protocols. No hypertensive complications and no pre-eclampsia episodes were observed; birth weight was consistent with gestational age in all babies in both group with no uneventful outcomes and no perinatal mortality or fetal malformations. Twenty out of 23 cases (86 %) showed hypoxia-induced villous alterations, including increased syncytial knotting (Tenney-Parker changes), perivillar fibrin deposits, distal villous hypoplasia or accelerated maturation and focal villous chorangiosis. These alterations were found in 19 out of 23 controls (83 %), with no statistically significant difference between the two groups. CONCLUSIONS: These results shows that chemotherapy in the second and third trimester of pregnancy may lead to non-specific alterations in placental vasculature and morphology.
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Neoplasias da Mama , Doenças Placentárias , Neoplasias da Mama/tratamento farmacológico , Vilosidades Coriônicas , Feminino , Humanos , Placenta , Gravidez , Estudos RetrospectivosRESUMO
Magnesium (Mg) and calcium (Ca) are essential cations for women's preconception health. It is well known that, in blood, the concentration of ionized form of these two cations is temporally altered during menstrual cycle, suggesting a correlation between sex steroid hormones and serum calcium and magnesium levels. Evidence from literature suggests that in assisted reproductive technology increasing estrogens during ovarian hyperstimulation may also modulate serum magnesium and calcium levels. Therefore, we first examined total serum magnesium and calcium levels during follicular phase in a large population of infertile patients who underwent intrauterine insemination (IUI). The results were compared to a group of fertile women. Successively, we studied the total serum magnesium and calcium concentrations in infertile patients before and after ovarian hyperstimulation for in vitro fertilization (IVF). Results highlight that total serum concentration of magnesium and calcium does not seem altered in infertile women. During stimulation with gonadotropins, the values of the two cations do not change significantly in ovarian-stimulated women. However, we found a downward trend in the total magnesium and calcium levels in relation to the rising estrogens.
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Cálcio/sangue , Infertilidade Feminina/sangue , Magnésio/sangue , Técnicas de Reprodução Assistida , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Indução da Ovulação , Valores de Referência , Adulto JovemRESUMO
BACKGROUND: It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cell transformation. However, the underlying mechanisms remain poorly understood and it is unknown how the sequences of lncRNA dictate their function. RESULTS: Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1. CONCLUSIONS: Our findings support a conserved functional co-dependence between LINC-PINT and PRC2 and lead us to propose a new mechanism where the lncRNA regulates the availability of free PRC2 at the proximity of co-regulated genomic loci.
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Invasividade Neoplásica , RNA Longo não Codificante/química , RNA Longo não Codificante/fisiologia , Animais , Sequência de Bases , Movimento Celular , Sequência Conservada , Regulação para Baixo , Inativação Gênica , Humanos , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Complexo Repressor Polycomb 2/metabolismoRESUMO
OBJECTIVE: To evaluate the efficacy of 2 different regimens for labor induction in patients with unfavorable cervix not responsive to a first dose of dinoprostone vaginal insert. METHODS: Between November, 2011 and June, 2014, 338 patients underwent induction of labor. After standard 24 hours treatment, 94 singleton term pregnancies remained with a Bishop score ≤6 and were randomized into 2 different regimens: repeated vaginal dinoprostone (group A, n = 47) or intravenous oxytocin (group B, n = 47). Primary outcome was vaginal delivery, and the secondary outcomes were interval between labor induction and delivery and operative delivery rates. RESULTS: Vaginal deliveries were significantly higher (group A: 26/47 (55.3%) and group B 16/47 (34.0%), P < .05), and cesarean sections were significantly lower (group A 21/47 (44.7%) and group B 31/47 (66%), P < .05) in patients who received a double dose of dinoprostone. The intervals between labor induction and onset of labor and between labor induction and delivery were lower in the group treated with oxytocin. Neonatal outcomes were similar in the 2 groups. CONCLUSION: A second dinoprostone vaginal insert is an effective and safe choice for patients with unfavorable cervix not responsive to a first 24 hours administration of dinoprostone for cervical ripening, and its use is associated with lower cesarean section rates.
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Maturidade Cervical/efeitos dos fármacos , Dinoprostona/administração & dosagem , Trabalho de Parto Induzido , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Resultado da Gravidez , Administração Intravaginal , Administração Intravenosa , Adulto , Cesárea , Feminino , Humanos , Gravidez , Estudos ProspectivosRESUMO
TDP-43 (TAR DNA-binding protein 43) is an RNA-binding protein implicated in RNA metabolism at several levels. Even if ubiquitously expressed, it is considered as a neuronal activity-responsive factor and a major signature for neurological pathologies, making the comprehension of its activity in the nervous system a very challenging issue. TDP-43 has also been described as an accessory component of the Drosha-DGCR8 (DiGeorge syndrome critical region gene 8) microprocessor complex, which is crucially involved in basal and tissue-specific RNA processing events. In the present study, we exploited in vitro neuronal differentiation systems to investigate the TDP-43 demand for the microprocessor function, focusing on both its canonical microRNA biosynthetic activity and its alternative role as a post-transcriptional regulator of gene expression. Our findings reveal a novel role for TDP-43 as an essential factor that controls the stability of Drosha protein during neuronal differentiation, thus globally affecting the production of microRNAs. We also demonstrate that TDP-43 is required for the Drosha-mediated regulation of Neurogenin 2, a master gene orchestrating neurogenesis, whereas post-transcriptional control of Dgcr8, another Drosha target, resulted to be TDP-43-independent. These results implicate a previously uncovered contribution of TDP-43 in regulating the abundance and the substrate specificity of the microprocessor complex and provide new insights into TDP-43 as a key player in neuronal differentiation.