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1.
J Hematol Oncol ; 14(1): 30, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596982

RESUMO

Histone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

2.
Chem Commun (Camb) ; 56(80): 12013-12016, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-32901620

RESUMO

A palladium-catalyzed arylation/aza-Michael addition cascade reaction of ß-substituted cyclic enones and 2-haloanilines has been reported. Using 1 mol% Pd(PPh3)4 as a catalyst, C2-spiroindolines are accessed via an intermolecular vinylogous arylation of ß-alkyl cyclic enones and 2-haloanilines followed by an intramolecular aza-Michael addition. The functional group tolerance of this transformation is examined by 18 examples in up to 93% yield. In the second part, we developed an α'-arylation/aza-Michael addition cascade strategy to construct azabicyclo[3.2.2]nonanones catalyzed by Pd(MeCN)2Cl2·PPh3. This study provides a quick route to complex and useful spiro- and bridged-heterocycles from readily available starting materials in good yields with high regioselectivity.

3.
Chem Commun (Camb) ; 55(95): 14383-14386, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31723947

RESUMO

An AgI-promoted regioselective [4+2] annulation reaction of indoles with alkenes has been established. During the transformation, N-centered radicals are generated by the oxidation of the N-H bond of N-alkoxyamides. Control experiments and DFT calculations reveal a plausible mechanism. This synergistic process achieves the direct construction of new C-C and C-N bonds under relatively mild conditions with broad substrate scope, high atom economy, and easy-to-handle nature.

4.
Anal Chem ; 91(19): 12468-12475, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475538

RESUMO

In this work, hydrazine-functionalized perylene diimide derivative supramolecular (HPDS), a novel self-enhanced donor-acceptor-donor (D-A-D) type aggregates with excellent photoelectric activity, was synthesized by a facile one-pot green route and further applied in construction of coreactant-free photoelectrochemical (PEC) biosensor for ultrasensitive DNA assay. Impressively, the HPDS formed by D-A-D units not only possessed effectively shorted electron-transfer path between donor and acceptor, but also presented a desiring aggregate state via the π-π stacking of perylene core and hydrogen bonding of the terminal moiety, thereby acquiring a high density electron flow for generating the extremely high PEC signal. Experimental data showed that the well film-formed HPDS aggregate could produce an exciting photocurrent intensity about 6-fold stronger than that of precursor perylene dianhydride with donor N2H4 in detection buffer and even 12-fold than that of perylene dianhydride only. In this respect, the resultant HPDS aggregate as a novel self-enhanced PEC signal tag was adopted to fabricate the coreactant-free PEC biosensor with the help of target dual-recycling-induced bipedal DNA walker cascade amplification strategy for ultrasensitive DNA (a fragment of TP53 gene) assay. The proposed biosensor showed a high sensitivity with a low detection limit down to femtomole level, providing a new avenue for sensitive bioanalysis and clinical diagnosis.


Assuntos
Técnicas Biossensoriais/métodos , DNA/análise , Imidas/química , Limite de Detecção , Perileno/análogos & derivados , Processos Fotoquímicos , Eletroquímica , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Modelos Moleculares , Conformação Molecular , Nanopartículas/química , Perileno/química , Dióxido de Silício/química
5.
Org Lett ; 21(17): 7073-7077, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31441310

RESUMO

An efficient strategy for N/O-(deutero)alkylation of indoles and phenols with alkoxides/alcohols as the alkylation reagents is described. The consecutive detosylation/alkylation transformations feature mild reaction conditions, high ipso-selectivity, and good functional group tolerance (>50 examples). A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized. The application of this method is demonstrated by the introduction of isotope-labeled (CD3 and 13CH3) groups using the readily accessible labeled alcohols and the synthesis of pharmaceuticals.

7.
Org Lett ; 21(6): 1654-1658, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30821152

RESUMO

An unprecedented synthesis of valuable benzofuran-3(2 H)-one scaffolds with a quaternary center was developed via Rh/Co relay catalyzed C-H functionalization/annulation of N-aryloxyacetamides with propiolic acids in moderate to good yields. The reaction features the simultaneous construction of the benzofuran motif containing a C2 quaternary center and a C3 carbonyl group. The preliminary mechanism study verified that the O atom of C3 carbonyl group originates from molecular oxygen.

8.
J Am Chem Soc ; 140(35): 10970-10974, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30075628

RESUMO

Herein we describe a general, mild and scalable method for deuterium incorporation by potassium methoxide/hexamethyldisilane-mediated dehalogenation of arylhalides. With CD3CN as a deuterium source, a wide array of heteroarenes prevalent in pharmaceuticals and bearing diverse functional groups are labeled with excellent deuterium incorporation (>60 examples). The ipso-selectivity of this method provides precise access to libraries of deuterated indoles and quinolines. The synthetic utility of our method has been demonstrated by the incorporation of deuterium into complex natural and drug-like compounds.

10.
World J Gastroenterol ; 21(13): 3978-82, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25852284

RESUMO

AIM: To evaluate the technique of transpancreatic septotomy (TS) for cannulating inaccessible common bile ducts in endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Between May 2012 and April 2013, 1074 patients were referred to our department for ERCP. We excluded 15 patients with previous Billroth II gastrectomy, Roux-en-Y anastomosis, duodenal stenosis, or duodenal papilla tumor. Among 1059 patients who underwent ERCP, there were 163 patients with difficult bile duct cannulation. Pancreatic guidewire or pancreatic duct plastic stent assistance allowed for successful ERCP completion in 94 patients. We retrospectively analyzed clinical data from 69 failed patients (36 transpancreatic septotomies and 33 needle-knife sphincterotomies). RESULTS: Of the 69 patients who underwent precut papillotomy, common bile duct cannulation was successfully achieved in 67. The success rates in the TS and needle knife sphincterotomy (NKS) groups were 97.2% (35/36) and 96.9% (32/33), respectively, which were not significantly different (P > 0.05). Complications occurred in 11 cases, including acute pancreatitis (n = 6), bleeding (n = 2), and cholangitis (n = 3). The total frequency of complications in the TS group was lower than that in the NKS group (8.3% vs 24.2%, P < 0.05). CONCLUSION: Pancreatic guidewire or pancreatic duct plastic stent assistance improves the success rate of selective bile duct cannulation in ERCP. TS and NKS markedly improve the success rate of selective bile duct cannulation in ERCP. TS precut is safer as compared with NKS.


Assuntos
Cateterismo/métodos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Ducto Colédoco/cirurgia , Esfinterotomia Endoscópica/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo/efeitos adversos , Cateterismo/instrumentação , Cateteres , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/instrumentação , Ducto Colédoco/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Esfinterotomia Endoscópica/efeitos adversos , Stents , Resultado do Tratamento , Adulto Jovem
11.
World J Gastroenterol ; 21(3): 1032-5, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25624743

RESUMO

A 67-year-old man had a sev-ere cough and pulmonary infection for 1 wk before seeking evaluation at our hospital. He had undergone esophagectomy with gastric pull-up and radiotherapy for esophageal cancer 3 years previously. After admission to our hospital, gastroscopy and bronchoscopy revealed a fistulous communication between the posterior tracheal wall near the carina and the upper residual stomach. We measured the diameter of the trachea and bronchus and determined the site and size of the fistula using multislice computed tomography and gastroscopy. A covered self-expanding Y-shaped metallic stent was implanted into the trachea and bronchus. Subsequently, the fistula was closed completely. The patient tolerated the stent well and had good palliation of his symptoms.


Assuntos
Broncoscopia/instrumentação , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Fístula Gástrica/terapia , Metais , Fístula do Sistema Respiratório/terapia , Stents , Doenças da Traqueia/terapia , Idoso , Evolução Fatal , Fístula Gástrica/diagnóstico , Fístula Gástrica/etiologia , Gastroscopia , Humanos , Masculino , Tomografia Computadorizada Multidetectores , Cuidados Paliativos , Desenho de Prótese , Fístula do Sistema Respiratório/diagnóstico , Fatores de Tempo , Doenças da Traqueia/diagnóstico , Doenças da Traqueia/etiologia , Resultado do Tratamento
12.
J Huazhong Univ Sci Technolog Med Sci ; 34(6): 942-949, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25480595

RESUMO

There is continuous debate regarding the effectiveness of thymectomy in the treatment of non-thymomatous myasthenia gravis (MG). This systematic review was undertaken to determine whether thymectomy was effective in non-thymomatous MG. We retrieved articles published between January 1980 and September 2013. Sixteen cohort studies were included. Given the considerable heterogeneity, we used a descriptive method instead of statistical synthesis. The median relative rates (RRs) and their interquartile ranges were used to estimate the magnitude of benefit. Compared to conservatively treated MG patients, thymectomized patients had higher survival, clinical remission, pharmacologic remission and improvement rates, and RRs were 1.07 (1.01-1.17), 1.83 (0.82-2.99), 1.55 (1.22-1.95) and 1 (1.00-1.09), respectively. Subgroup analyses showed that patients with moderate to severe generalized MG benefited more from thymectomy, with RRs of survival and pharmacologic remission increasing to 1.35 (1.24-1.49) and 2.68 (1.73-4.17), respectively. These results suggested that thymectomy might be an effective procedure in non-thymomatous MG patients. The patients with moderate to severe generalized MG might benefit more. Taking into account the poor methodological quality of present studies, more well-designed prospective randomized controlled trials (RCTs) are still required to reach unequivocal conclusion.


Assuntos
Miastenia Gravis/mortalidade , Miastenia Gravis/cirurgia , Timectomia , Intervalo Livre de Doença , Humanos , Taxa de Sobrevida
13.
Asian Pac J Cancer Prev ; 15(18): 7645-52, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25292042

RESUMO

Neuroblastoma (NB), the most common extracranial solid tumor, accounts for 10% of childhood cancer. To date, scientists have gained quite a lot of knowledge about microRNAs (miRNAs) and their genes in NB. Discovering inner regulation networks, however, still presents problems. Our study was focused on determining differentially-expressed miRNAs, their target genes and transcription factors (TFs) which exert profound influence on the pathogenesis of NB. Here we constructed three regulatory networks: differentially-expressed, related and global. We compared and analyzed the differences between the three networks to distinguish key pathways and significant nodes. Certain pathways demonstrated specific features. The differentially-expressed network consists of already identified differentially-expressed genes, miRNAs and their host genes. With this network, we can clearly see how pathways of differentially expressed genes, differentially expressed miRNAs and TFs affect on the progression of NB. MYCN, for example, which is a mutated gene of NB, is targeted by hsa-miR-29a and hsa-miR-34a, and regulates another eight differentially-expressed miRNAs that target genes VEGFA, BCL2, REL2 and so on. Further related genes and miRNAs were obtained to construct the related network and it was observed that a miRNA and its target gene exhibit special features. Hsa-miR-34a, for example, targets gene MYC, which regulates hsa-miR-34a in turn. This forms a self-adaption association. TFs like MYC and PTEN having six types of adjacent nodes and other classes of TFs investigated really can help to demonstrate that TFs affect pathways through expressions of significant miRNAs involved in the pathogenesis of NB. The present study providing comprehensive data partially reveals the mechanism of NB and should facilitate future studies to gain more significant and related data results for NB.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genes Neoplásicos/genética , MicroRNAs/genética , Neuroblastoma/genética , Perfilação da Expressão Gênica , Humanos
14.
Med Sci Monit ; 20: 1728-34, 2014 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-25256693

RESUMO

BACKGROUND: The complexity of multiple-item criteria in acute respiratory distress syndrome (ARDS) often causes inconvenience for physicians in the management of patients with severe acute pancreatitis (SAP). We evaluated whether serum SP-A levels in the presence of diffuse alveolar damage (DAD) can be qualitatively assessed for diagnosis of SAP-induced ARDS. MATERIAL AND METHODS: Eighty rats were randomly divided into 2 groups (n=40 each) - the sham-operated (SO) group and the SAP group - and then randomly subdivided into 4 subgroups in a time-course manner. Furthermore, rats in the SAP group were subdivided into the SAP induced-ARDS group (ARDS group) and the SAP without ARDS group (non-ARDS group) according to the diagnostic standard of ARDS. The diagnostic cut-off values of SP-A for SAP-induced ARDS were determined by the receiver operating characteristic curve (ROC). RESULTS: Serum SP-A levels in Baseline, SO group, SAP group, ARDS group, and non-ARDS group were 43.15±14.29, 51.91±16.99, 193.4±35.37, 198.0+29.73, and 185.7±43.21 ug/ml, respectively. The best cut-off value for the serum SP-A level for the diagnosis of SAP-induced ARDS was 150 ug/ml and the area under the ROC curve of SP-A was 0.88. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of SP-A in the diagnosis of SAP-induced ARDS were 100.0%, 81.8%, 71.4%, 100.0%, and 87.5%, respectively. CONCLUSIONS: Serum SP-A levels may allow the detection of SAP-induced ARDS and may help to support the clinical diagnosis of ARDS. The optimal serum SP-A cut-off value to discriminate SAP-induced ARDS and other groups (SO group and non-ARDS group) is around 150 ug/ml.


Assuntos
Pancreatite/complicações , Proteína A Associada a Surfactante Pulmonar , /etiologia , Animais , Pulmão/patologia , Masculino , Pâncreas/patologia , Pancreatite/sangue , Proteína A Associada a Surfactante Pulmonar/sangue , Curva ROC , Ratos Wistar , /sangue
15.
Zhonghua Xin Xue Guan Bing Za Zhi ; 39(7): 642-6, 2011 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-22088246

RESUMO

OBJECTIVE: To analyze the clinical and angiographic characteristics of patients with slow coronary flow (SCF). METHODS: In this retrospective study, 140 patients with SCF and 140 control subjects without SCF were included. SCF were diagnosed by the combination of TIMI flow grade method and TIMI frame count method. All subjects had angiographically normal coronary arteries. The clinical and laboratory data were obtained from medical records at admission. RESULTS: Compared to control group, patients with SCF were younger [(57.8 +/- 10.7) years vs. (59.8 +/- 8.2) years], rate of smokers (59.3% vs. 46.4%) and diabetes mellitus (49.3% vs. 30.7%), fasting blood glucose (FBG) level [(7.8 +/- 2.8) mmol/L vs. (6.2 +/- 2.0) mmol/L, P < 0.05] and triglyceride (TG) level [(2.11 +/- 1.93) mmol/L vs. (1.67 +/- 1.01) mmol/L, P < 0.05] were higher, while high density lipoprotein cholesterol (HDL-C) level [(1.05 +/- 0.35) mmol/L vs. (1.42 +/- 0.74) mmol/L, P < 0.01] and apolipoprotein A1 (apoA1) level [(1.10 +/- 0.19) mmol/L vs. (1.31 +/- 0.31) mmol/L, P < 0.01] were lower. Among the 140 SCF patients, left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA) were involved at the same time in 92 patients. Among the three vessels, RCA is the most frequent involved vessel (n = 119). After adjusting for other risk factors, current smoking (OR = 1.92, 95% CI: 1.04 - 3.57, P < 0.05), DM history (OR = 2.44, 95% CI:1.32-4.76, P < 0.01), FBG (OR = 2.13, 95% CI:1.16-3.98, P < 0.05), TG (OR = 1.47, 95% CI:1.03-2.13, P < 0.05), HDL-C (OR = 0.47, 95% CI:0.24-0.85, P < 0.05) and apoA1 (OR = 0.55, 95% CI:0.40 - 0.75, P < 0.01) were independent factors for SCF (all P < 0.05). CONCLUSIONS: Our results demonstrated that patients with SCF were prone to have a significant metabolic disorder compared to the control group. Patients with high levels of FBG, TG and low levels of HDL-C were more likely to suffer from SCF, which maybe explained by the development of coronary endothelium and microvascular dysfunction.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Idoso , Estudos de Casos e Controles , Angiografia Coronária , Circulação Coronária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Mol Biol Rep ; 38(2): 777-84, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20393883

RESUMO

The Msx2-interacting nuclear target protein (MINT) is a nuclear matrix protein that regulates the development of many tissues. However, little is known regarding the role of MINT in tooth development. In this study, we prepared polyclonal antibodies against MINT, and found that that MINT was expressed in different cells at each stage of tooth germ development by immunohistochemistry. The role of MINT in tooth development was further illustrated by the misshapen and severely hypoplastic tooth organ in the cultured mandibular explants of MINT deficient mice. From the initiation to cap stage, the differences between mutants and wild-type molars were more and more distinguished histologically. In the MINT-deficient mandibular explants, the tooth germ was reduced in the overall size and lacked enamel knot, with abnormal dental lamina and collapsed stellate reticulum. Furthermore, the BrdU incorporation experiment showed that the proliferation activity was significantly reduced in MINT-deficient dental epithelium. Our results suggest that MINT plays an important role in tooth development, in particular, epithelial morphogenesis.


Assuntos
Mandíbula/citologia , Proteínas Nucleares/genética , Germe de Dente/citologia , Germe de Dente/embriologia , Dente/embriologia , Animais , Bromodesoxiuridina/farmacologia , Proliferação de Células , Proteínas de Ligação a DNA , Células Epiteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/citologia , Camundongos , Camundongos Knockout , Proteínas Nucleares/metabolismo , Técnicas de Cultura de Órgãos , Proteínas de Ligação a RNA , Dente/metabolismo
17.
Chin Med J (Engl) ; 123(7): 857-63, 2010 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-20497678

RESUMO

BACKGROUND: The success rate of antegrade approach for chronic total occlusions (CTO) recanalization has not dramatically increased, especially in complex CTO subset. The retrograde technique may hold great promise. This report aimed to describe our experience of retrograde recanalization for CTO, focusing on its safety and feasibility. METHODS: We identified 42 patients who underwent revascularization in CTO with retrograde approach from July 2005 to November 2009 in our center. RESULTS: Three kinds of strategy were applied: retrograde as primary strategy (50.0%), retrograde immediately after antegrade failure (26.2%) and repeat procedure after previous antegrade failure (23.8%). Septal collaterals were more frequently used as the retrograde access route (92.9%). Overall success rate was 88.1%. In patients with successful retrograde wire crossing collateral channel to the distal cap of CTO, the success rate of recanalization was 94.1%. In patient with failure to cross the collaterals, the success rate was 62.5%. Eight different kinds of retrograde techniques were used: kissing wire technique (35.3%), wire trapped and reverse wire trapped technique (17.6%), back-end balloon and microcatheter reversal technique (14.7%), controlled antegrade and retrograde subintimal tracking (CART) technique (8.8%), reverse CART and modified reverse CART technique (8.8%), retrograde wire crossing technique (2.9%). There were 4 complications occurred without in-hospital major adverse cardiac events (MACE). In-hospital MACE was 7.7%. All of them were non-Q wave myocardial infarction. There were no cases of death or target vessel revascularization, either surgery or percutaneous. CONCLUSIONS: The retrograde approach can be an effective tool for increasing the success rate of recanalization in the very complex CTO. To ensure the success and safety of the approach, careful case selection and device handling by experienced operators is essential.


Assuntos
Angioplastia Coronária com Balão/métodos , Oclusão Coronária/terapia , Idoso , Doença Crônica , Angiografia Coronária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Resultado do Tratamento
18.
Zhonghua Yi Xue Za Zhi ; 83(10): 813-8, 2003 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-12895329

RESUMO

OBJECTIVE: To compare the effects of mifepristone of different doses on emergency contraception. METHODS: 3,052 healthy women with regular menstrual cycle who visited the 10 family planning institutes and hospitals in Beijing, Shanghai, Shangdong, Sichuan, Tianjin, Guangdong, and Liaoning for emergency contraception within the period of 120 hours after a single act of unprotected sex were given a single dose of 10 mg or 25 mg mifepristone randomly and double-blindly. They were asked to record the vaginal hemorrhage that would occur and not to have unprotected sex until the next menstrual onset when they were followed up. The trial for a specific subject ended when she menstruated. If the menstruation was irregular or a specific subject failed to menstruate on time a blood or urine human chorionic gonadotropin (hCG) test was made. If the hCG test was negative, an appointment was made to follow up once one week later. If the hCG test was positive ultrasound examination was made to detect pregnancy. If the subject still failed to menstruate and the hCG test was still negative follow-up for this subject could be finished. RESULTS: Twenty-two of the 3,052 subjects were lost to follow up. Among the remaining 3,030 women 1,516 were in the 10 mg group and 1 514 in the 25 mg group. Seventeen pregnancies occurred in each group, with a pregnancy rate of 1.1% for both groups. The relative risk of pregnancy of treatment of 25 mg mifepristone in comparison with treatment of 10 mg mifepristone was 1.0 (95% CI: 0.51-1.95). Both doses prevented about 85% approximately 86% of the anticipated pregnancy if no measure had been adopted. The pregnancy rate nearly doubled in the women who had unprotected sex after treatment of mifepristone. The efficacy of mifepristone decreased along with the delay of mifepristone administration. Side effects were uncommon and mild. Delay of 7 days or more in the onset of next menstruation occurred in 9%-10% of the women. CONCLUSION: Mifepristone of the dose of 10 mg is safe and effective for emergency contraception. Earlier administration is preferable, although the method can be used effectively up to five days after the unprotected sex.


Assuntos
Anticoncepção/métodos , Anticoncepcionais Sintéticos Pós-Coito/administração & dosagem , Mifepristona/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Emergências , Feminino , Humanos , Gravidez
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