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1.
Front Endocrinol (Lausanne) ; 13: 849534, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35399940

RESUMO

Recent studies have suggested that sperm mitochondrial DNA copy number (mtDNA-CN), DNA fragmentation index (DFI), and reactive oxygen species (ROS) content are crucial to sperm function. However, the associations between these measurements and embryo development and pregnancy outcomes in assisted reproductive technology (ART) remain unclear. Semen samples were collected from 401 participants, and seminal quality, parameters of sperm concentration, motility, and morphology were analyzed by a computer-assisted sperm analysis system. DFI, mtDNA-CN, and ROS levels were measured using sperm chromatin structure assay, real-time quantitative polymerase chain reaction, and ROS assay, respectively. Among the participants, 126 couples underwent ART treatments, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and 79 of the couples had embryos transferred. In 401 semen samples, elevated mtDNA-CN and DFI were associated with poor seminal quality. In 126 ART couples, only mtDNA-CN was negatively correlated with the fertilization rate, but this correlation was not significant after adjusting for male age, female age, seminal quality, ART strategy, number of retrieved oocytes, controlled stimulation protocols, and cycle rank. Regarding pregnancy outcomes, sperm mtDNA-CN, ROS, and DFI were not associated with the clinical pregnancy rate or live birth rate in 79 transferred cases. In conclusion, increased mtDNA-CN and DFI in sperm jointly contributed to poor seminal quality, but sperm mtDNA-CN, ROS, and DFI were not associated with clinical outcomes in ART.


Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial , Fragmentação do DNA , DNA Mitocondrial/genética , Feminino , Humanos , Masculino , Gravidez , Espécies Reativas de Oxigênio , Técnicas de Reprodução Assistida , Espermatozoides/fisiologia
2.
Ann Transl Med ; 10(4): 171, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35280386

RESUMO

Background: The aim of this non-randomized single-center phase II trial was to prospectively assess the clinical efficacy of triplet chemotherapy with modified 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (mFOLFOXIRI) plus bevacizumab as conversion therapy for initially unresectable rat sarcoma viral oncogene homolog (RAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/phosphatidylinositol-3 kinase catalytic alpha (PIK3CA) mutant colorectal liver-limited metastases (CRLMs). Methods: Patients with RAS/BRAF/PIK3CA mutant initially unresectable CRLMs were recruited at a ratio of 2:1 to receive mFOLFOXIRI plus bevacizumab (experimental group) or mFOLFOXIRI alone (control group). The rate of patients attaining no evidence of disease (NED) was the primary endpoint. The secondary endpoints included objective response rate (ORR), depth of tumor response (DpR), secondary resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: The rate of NED achieved was 40.7% and 30.8%, respectively, in the experimental (n=54) and control groups (n=26); the adjusted odds ratio was 4.519 [95% confidence interval (CI): 1.247-16.375, P=0.022]. The ORR was 77.4% in the experimental group and 60.0% in the control group (P=0.112). The median DpR was significantly greater in the experimental group (45.6% vs. 34.9%, P=0.041). The median PFS was 12.6 months in the experimental group and 9.1 months in the control group [adjusted hazard ratio (HR): 0.584, 95% CI: 0.304-1.121, P=0.106]. Median OS was prolonged in the experimental group compared with the control group (42.6 vs. 35.3 months, adjusted HR: 0.443, 95% CI: 0.195-1.006, P=0.052). Thirty patients (55.6%) in the experimental group and 16 (61.5%) in the control group experienced grade 3/4 adverse events. Conclusions: We observed that the combination of mFOLFOXIRI and bevacizumab increased the rate of clinical NED and showed a trend toward improved survival compared with mFOLFOXIRI alone. This could represent a conversion therapy option for fit patients with initially unresectable RAS/BRAF/PIK3CA mutant CRLMs.

3.
Front Genet ; 13: 823728, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35356430

RESUMO

Although many prognostic models have been developed to help determine personalized prognoses and treatments, the predictive efficiency of these prognostic models in hepatocellular carcinoma (HCC), which is a highly heterogeneous malignancy, is less than ideal. Recently, aberrant glycosylation has been demonstrated to universally participate in tumour initiation and progression, suggesting that dysregulation of glycosyltransferases can serve as novel cancer biomarkers. In this study, a total of 568 RNA-sequencing datasets of HCC from the TCGA database and ICGC database were analysed and integrated via bioinformatic methods. LASSO regression analysis was applied to construct a prognostic signature. Kaplan-Meier survival, ROC curve, nomogram, and univariate and multivariate Cox regression analyses were performed to assess the predictive efficiency of the prognostic signature. GSEA and the "CIBERSORT" R package were utilized to further discover the potential biological mechanism of the prognostic signature. Meanwhile, the differential expression of the prognostic signature was verified by western blot, qRT-PCR and immunohistochemical staining derived from the HPA. Ultimately, we constructed a prognostic signature in HCC based on a combination of six glycosyltransferases, whose prognostic value was evaluated and validated successfully in the testing cohort and the validation cohort. The prognostic signature was identified as an independent unfavourable prognostic factor for OS, and a nomogram including the risk score was established and showed the good performance in predicting OS. Further analysis of the underlying mechanism revealed that the prognostic signature may be potentially associated with metabolic disorders and tumour-infiltrating immune cells.

4.
Reprod Sci ; 29(4): 1124-1135, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34988918

RESUMO

Over the past decades, the investigation of innate lymphoid cells (ILCs) has revealed their significance in successful pregnancy. Sex hormones, such as estradiol and progesterone, show specific changes during pregnancy and modulate both adaptive and innate immune systems. ILC subset distribution in peripheral blood of pregnant women and its potential association with sex hormone levels have not been well revealed. Peripheral blood was obtained from healthy non-pregnant, early-pregnant, and late-pregnant women. Radioimmunoassay was performed to measure plasma estradiol and progesterone levels. The levels of type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), type 3 ILCs (ILC3s), and total ILCs as well as estrogen and progesterone receptors of ILC2s in peripheral blood were analyzed using flow cytometry. The proportion of total ILCs and distribution of ILC subsets in peripheral blood changed dynamically during pregnancy. Compared to non-pregnant women, late-pregnant women displayed significantly higher proportion of circulating ILCs, among which ILC2s accounted for the majority in late-pregnant women while a smaller part in others, and ILC3s displayed the opposite. Plasma estradiol and progesterone levels elevated while pregnancy proceeded and the expression of their receptors in ILC2s increased consisted with the proportion of circulating ILC2s. Our work first observed the existence of progesterone receptors in human circulating ILC2s and revealed the distribution pattern of circulating ILC subsets and their interrelation with plasma sex hormone levels during pregnancy. Our results suggested that the estradiol and progesterone levels might partly influence the distribution of circulating ILC subsets and implied the interplay between circulating ILCs and pregnancy.


Assuntos
Imunidade Inata , Progesterona , Estradiol/metabolismo , Feminino , Humanos , Linfócitos/metabolismo , Gravidez , Progesterona/metabolismo , Receptores de Progesterona/metabolismo
5.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34647995

RESUMO

Seminal plasma contains a high concentration of extracellular vesicles (EVs). The heterogeneity of small EVs or the presence of nonvesicular extracellular matter (NV) pose major obstacles in understanding the composition and function of seminal EVs. In this study, we employed high-resolution density gradient fractionation to accurately characterize the composition and function of seminal EVs and NV. We found that the seminal EVs could be divided into 3 different subtypes-namely, high-density EV (EV-H), medium-density EV (EV-M), and low-density EV (EV-L)-after purification using iodixanol, while NV was successfully isolated. EVs and NV display different features in size, shape, and expression of some classic exosome markers. Both EV-H and NV could markedly promote sperm motility and capacitation compared with EV-M and EV-L, whereas only the NV fraction induced sperm acrosome reaction. Proteomic analysis results showed that EV-H, EV-M, EV-L, and NV had different protein components and were involved in different physiological functions. Further study showed that EV-M might reduce the production of sperm intrinsic reactive oxygen species through glutathione S-transferase mu 2. This study provides novel insights into important aspects of seminal EVs constituents and sounder footing to explore their functional properties in male fertility.


Assuntos
Vesículas Extracelulares/metabolismo , Proteômica/métodos , Sêmen/metabolismo , Motilidade Espermática , Reação Acrossômica , Biomarcadores/metabolismo , Biotinilação , Biologia Computacional , Exossomos/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Masculino , Fosforilação , Proteínas Tirosina Fosfatases/química , Proteoma , Espécies Reativas de Oxigênio , Espermatozoides/metabolismo , Espermatozoides/fisiologia , Ácidos Tri-Iodobenzoicos/farmacologia
6.
Reproduction ; 162(6): 437-448, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34605773

RESUMO

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.


Assuntos
Depressão , Fosfatidilinositol 3-Quinases , Animais , Ansiedade/etiologia , Depressão/etiologia , Fertilização In Vitro/efeitos adversos , Masculino , Camundongos , Técnicas de Reprodução Assistida/efeitos adversos , Estudos Retrospectivos
7.
J Clin Med ; 10(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34501345

RESUMO

BACKGROUND: Preimplantation genetic testing for aneuploidies (PGT-A) is widely used in women of advanced maternal age (AMA). However, the effectiveness remains controversial. METHOD: We conducted a comprehensive literature review comparing outcomes of IVF with or without PGT-A in women of AMA in PubMed, Embase, and the Cochrane Central Register of Controlled Trials in January 2021. All included trials met the criteria that constituted a randomized controlled trial for PGT-A involving women of AMA (≥35 years). Reviews, conference abstracts, and observational studies were excluded. The primary outcome was the live birth rate in included random control trials (RCTs). RESULTS: Nine randomized controlled trials met our inclusion criteria. For techniques of genetic analysis, three trials (270 events) performed with comprehensive chromosomal screening showed that the live birth rate was significantly higher in the women randomized to IVF/ICSI with PGT-A (RR = 1.30, 95% CI 1.03-1.65), which was not observed in six trials used with FISH as well as all nine trials. For different stages of embryo biopsy, only the subgroup of blastocyst biopsy showed a higher live birth rate in women with PGT-A (RR = 1.36, 95% CI 1.04-1.79). CONCLUSION: The application of comprehensive chromosome screening showed a beneficial effect of PGT-A in women of AMA compared with FISH. Moreover, blastocyst biopsy seemed to be associated with a better outcome than polar body biopsy and cleavage-stage biopsy.

8.
Sci Rep ; 11(1): 18366, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526571

RESUMO

Alterations of mitogen-activated protein kinase kinase 1 (MEK1) are commonly associated with tumorigenesis, and MEK1 is thought to be a suitable targeted therapy for various cancers. However, abnormal MEK1 alterations and their relevant clinical implications are unknown. Our research comprehensively analyzed the MEK1 alteration spectrum and provided novel insight for targeted therapies. There were 7694 samples covering 32 types of cancer from The Cancer Genome Atlas (TCGA) database. They were used to conduct an integrative analysis of MEK1 expression, alterations, functional impacts and clinical significance. There was a dramatic difference in the alteration frequency and distribution and clinical implications in 32 types of cancer from the TCGA. Skin cutaneous melanoma (SKCM) has the most alterations and has therapeutic targets located in the protein kinase domain, and the growing expression of SKCM is positively related to patient prognosis. MEK1 expression in lung adenocarcinoma (LUAD), kidney renal papillary cell carcinoma (KIRP), esophageal carcinoma (ESCA) and liver hepatocellular carcinoma (LIHC) is decreased, which is associated with better prognosis, while MEK1 expression in thymoma (THYM), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), testicular germ cell tumors (TGCTs) and head and neck squamous cell carcinoma (HNSC) is increased, which is associated with better prognosis. Mesothelioma (MESO) has the second highest alterations but has no therapy targets. This study provided a great and detailed interpretation of MEK1 expression, alterations and clinical implications in 32 types of cancer and reminded us to fill the gap in MEK1 research from a new perspective.


Assuntos
MAP Quinase Quinase 1/genética , Mutação , Neoplasias/genética , Bases de Dados Genéticas , Humanos , MAP Quinase Quinase 1/química , MAP Quinase Quinase 1/metabolismo , Neoplasias/patologia , Domínios Proteicos
9.
Mol Ther Oncolytics ; 21: 62-73, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-33869743

RESUMO

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer. This study investigated the molecular mechanism and influences of MIR503HG, miR-224-5p, and homeobox A9 (HOXA9) on TNBC cell growth and migration. Dual-luciferase reporter gene and RNA immunoprecipitation were performed to examine the regulation of MIR503HG, miR-224-5p, and HOXA9. Cell proliferation, apoptosis, migration, and invasion were evaluated by colony formation, flow cytometry, and Transwell assays. Finally, nude mice were employed to investigate the influence of MIR503HG on TNBC tumor growth. HOXA9 protein levels were detected by immunohistochemical staining. MIR503HG and HOXA9 expression were reduced in TNBC, while miR-224-5p was increased. Overexpression of MIR503HG or HOXA9 reduced the cell migration ability and proliferation and promoted apoptosis, and knockdown of MIR503HG or overexpression of miR-224-5p exhibited the opposite effects. Furthermore, MIR503HG promoted HOXA9 expression by inhibiting miR-224-5p. Overexpression of miR-224-5p reversed the effects of MIR503HG overexpression on TNBC cells, while overexpression of HOXA9 reversed the effect of MIR503HG knockdown. Additionally, an in vivo study proved that MIR503HG inhibited TNBC tumor growth via the miR-224-5p/HOXA9 axis. MIR503HG inhibited cell proliferation and promoted the apoptosis of TNBC cells via the miR-224-5p/HOXA9 axis, which may function as a novel target for the treatment of TNBC.

10.
J Assist Reprod Genet ; 38(5): 1231-1237, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33594624

RESUMO

PURPOSE: Pentraxin 3 (PTX3) plays a crucial role in cumulus expansion and fertilization. The ovarian PTX3 level in polycystic ovary syndrome (PCOS) remains uncertain. In the present study, we investigated the follicular PTX3 levels and found the influence of reproductive hormones on ovarian PTX3 concentration. METHODS: This study was based on 204 healthy-weight women (102 PCOS and 102 normal ovulating subjects) undergoing in vitro fertilization (IVF). Follicular fluid (FF) was collected during oocyte retrieval. The PTX3 levels and other hormone levels in FF samples were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The PTX3 level in the follicle was significantly higher in the healthy-weight PCOS women than controls. Positive correlations were found between ovarian PTX3 level and the existence of PCOS, cycle length, basal LH to FSH ratio and TT in serum, antral follicle count, and ovarian insulin and androgen level, and inverse correlations with the basal serum PRL and ovarian SHBG. In multivariant linear regression analysis, the presence of PCOS diagnosis, participants' basal LH to FSH ratio, and ovarian androstenedione level were the main predictors of ovarian PTX3 level among the enrolled subjects. CONCLUSION: Elevated ovarian PTX3 level supports the low-grade chronic inflammatory state in the follicles of PCOS. The existence of PCOS, disturbed pituitary gland, and ovarian hyperandrogenism might also be related to this state of low-grade chronic inflammation and could be a subject of further study.


Assuntos
Hormônio Antimülleriano/genética , Proteína C-Reativa/genética , Folículo Ovariano/metabolismo , Síndrome do Ovário Policístico/genética , Componente Amiloide P Sérico/genética , Adulto , Androgênios/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Fertilização In Vitro , Hormônio Foliculoestimulante/genética , Humanos , Hormônio Luteinizante/genética , Recuperação de Oócitos , Folículo Ovariano/crescimento & desenvolvimento , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia
11.
Clin Epidemiol ; 13: 103-112, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33623437

RESUMO

OBJECTIVE: The purpose of the present study was to evaluate the associations between seven tagging single nucleotide polymorphisms (tSNPs) and risk of breast cancer assessed by tumor pathological characteristics and body mass index (BMI). METHODS: Seven tSNPs of four breast cancer susceptibility genes were analyzed in 734 Chinese women with breast cancer and 672 age-matched healthy controls; then, the association with clinicopathological characteristics, BMI, molecular subtype, TNM (T, tumor; N, lymph node; M, metastasis) staging and lymph node status was determined by unconditional logistic regression. RESULTS: Rs12951053 in TP53 and rs16945628 in BRIP1, displayed increased risk of breast cancer in the BMI ≧ 25 kg/m2 group (OR=1.50, 95% CI: 1.02-2.21, P=0.041 and OR=1.92, 95% CI: 1.13-3.26, P=0.015, respectively). The other five tSNPs (rs1805812, rs2735385 and rs6999227 in NBS1, rs7220719 in BRIP1 and rs2299941 in PTEN) displayed a decreased risk of breast cancer in the 18.5≤BMI<25 kg/m2 group. Rs12951053 in TP53 and rs7220719 in BRIP1 exhibited an increased risk of triple-negative breast cancer (OR=1.50, 95% CI: 1.05-2.15, P=0.026 and OR=2.13, 95% CI: 1.05-4.29, P=0.032, respectively), but three tSNPs in NBS1 (rs1805812, rs2735385 and rs6999227) all displayed a negative association with both luminal B and triple-negative breast cancer. The tSNP rs2299941 in PTEN also exhibited a negative association with each molecular subtype, except triple-negative breast cancer. The majority of tSNPs displayed a negative association with stage II or III breast cancer. Most tSNPs showed a negative association with breast cancer that was lymph node negative or with 1-3 positive nodes. Only rs12951053 in TP53 displayed a positive association with lymph node-negative breast cancer (OR=1.43, 95% CI: 1.08-1.91, P=0.013). CONCLUSION: The majority of tSNPs displayed a negative association with breast cancer and only a few tSNPs (rs12951053 in TP53, rs16945628 and rs7220719 in BRIP1) showed an increased risk of breast cancer as defined by clinicopathological characteristics.

12.
World J Pediatr ; 17(2): 197-204, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33625695

RESUMO

BACKGROUND: Previous studies investigated the association between gestational anemia and neonatal outcomes. However, few studies explored whether the effects of gestational anemia could be eliminated by subsequent correction of anemia in the later stages of pregnancy. This study aimed to investigate the relationship between anemia in different trimesters and neonatal outcomes. METHODS: The study was conducted in Shanghai, China, with a sample of 46,578 pregnant women who delivered between January 1, 2016 and July 1, 2019. A multivariable logistic regression model was adopted to analyse the associations between maternal anemia and neonatal outcomes. RESULTS: The incidence of gestational anemia was 30.2%, including 4.4% in the first trimester, 9.6% in the second trimester, and 16.2% in the third trimester. Only 24.5% (507/2066) of anemia that occurred in the first trimester and 29.6% (1320/4457) that occurred in the second trimester could be corrected in the later stages of pregnancy. Anemia occurring in the first trimester was associated with small for gestational age [odds ratio (OR) 1.46; 95% confidence interval (CI) 1.20-1.78] and with fetal distress (OR 1.23; 95% CI 1.08-1.40). Anemia corrected in the first trimester also was associated with a higher risk of small for gestational age. CONCLUSIONS: Gestational anemia is a public health problem in China impacting neonatal health. Anemia in pregnancy could be corrected in only about a quarter of the women. Anemia in the first trimester, whether corrected or not, still led to lower birth weight; therefore, the prevention of anemia prior to pregnancy is important.


Assuntos
Anemia/epidemiologia , Resultado da Gravidez , Adulto , China/epidemiologia , Feminino , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Estudos Longitudinais , Gravidez , Estudos Retrospectivos
13.
Front Genet ; 12: 633003, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33633790

RESUMO

BACKGROUND: Alport syndrome, a monogenic kidney disease, is characterized by progressive hemorrhagic nephritis, sensorineural hearing loss, and ocular abnormalities. Mutations in COL4A5 at Xq22 accounts for 80-85% of X-linked Alport syndrome patients. Three couples were referred to our reproductive genetics clinic for prenatal or preconception counseling. METHODS: Prenatal diagnoses were performed by amplifying targeted regions of COL4A5. Targeted next-generation sequencing (NGS)-based haplotype analysis or karyomapping was performed in two patients. Pregnancy outcomes in the three patients were collected and analyzed. Published Alport syndrome cases were searched in Pubmed and Embase. RESULTS: Prenatal diagnoses in two cases showed one fetus harbored the same pathogenic mutation as the proband and the other was healthy. The couple with an affected fetus and the patient with a family history of Alport syndrome chose to take the preimplantation genetic testing (PGT) procedure. One unaffected embryo was transferred to the uterus, and a singleton pregnancy was achieved, respectively. Two patients presented non-nephrotic range proteinuria (<3 g/24 h) during pregnancy and the three cases all delivered at full-term. However, published Alport cases with chronic kidney disease or proteinuria during pregnancy were came with a high rate (75%) of adverse maternal and fetal outcomes. CONCLUSION: The PGT procedure performed in this study was proven to be practicable and might be expanded to be applied in other monogenic diseases. Moderate or severe renal impairments in Alport syndrome were strongly associated with adverse maternal and fetal outcomes, and baseline proteinuria was a potential predictor for pregnancy outcomes of Alport syndrome as other kidney diseases.

14.
Front Cell Dev Biol ; 9: 637781, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33634140

RESUMO

Frozen and thawed embryo transfer (FET) is currently widely applied in routine assisted reproductive technology (ART) procedure. It is of great necessity to assess the safety of FET and investigate the long-term effect including glucose metabolism on FET-conceived offspring. The mouse model is a highly efficient method to figure out the relationship between the process of FET and offspring health. In this study, we obtained mouse offspring of natural conception (NC), in vitro fertilization (IVF), and FET. Glucose and insulin tolerance test (GTT/ITT) were performed on both chow fed or high fat diet (HFD) fed offspring to examine the glucose metabolism status. We detected hepatic PI3K/AKT pathway by western blotting and transcriptome status by RNA-sequencing. Impaired glucose tolerance (IGT) and decreased insulin tolerance were occurred in FET conceived male offspring. After challenged with the HFD-fed, male offspring in FET group performed earlier and severer IGT than IVF group. Furthermore, higher HOMA-IR index and higher serum insulin level post glucose injected in FET-chow group suggested the insulin resistance status. The PI3K/AKT signaling pathway, the major pathway of insulin in the liver, were also disrupted in FET group. Transcriptomics of the liver reveals significantly downregulated in glucose metabolic process and insulin resistance in the FET-chow group. In our study, FET-conceived male mouse offspring presented glucose metabolism dysfunction mainly manifesting insulin resistance. The hepatic insulin signaling pathway were in concordance with reduced glycogen synthesis, increased glycolysis and enhanced gluconeogenesis status in FET-conceived male offspring.

15.
Oncologist ; 26(1): e90-e98, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33400355

RESUMO

PURPOSE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. PATIENTS AND METHODS: Patients were enrolled to receive cetuximab (500 mg/m2 ) plus mFOLFOXIRI (oxaliplatin 85 mg/m2 , irinotecan 165 mg/m2 , folinic acid 400 mg/m2 , 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. RESULTS: Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%-48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%-36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. CONCLUSION: Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. IMPLICATIONS FOR PRACTICE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Cetuximab/uso terapêutico , China , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organoplatínicos , Proteínas Proto-Oncogênicas B-raf/genética
16.
Surg Endosc ; 35(5): 2134-2143, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32410082

RESUMO

AIM: The impact of pelvis on the development of anastomotic leak (AL) in rectal cancer (RC) patients who underwent anterior resection (AR) remains unclear. The aim of this study was to evaluate the impact of pelvic dimensions on the risk of AL. METHODS: A total of 1058 RC patients undergoing AR from January 2013 to January 2016 were enrolled. Pelvimetric parameters were obtained using abdominopelvic computed tomography scans. RESULTS: Univariate analyses showed that pelvic inlet, pelvic outlet, interspinous distance, and intertuberous distance were significantly associated with the risk for AL (P < 0.05). Multivariate analysis confirmed that pelvic inlet and intertuberous distance were independent risk factors for AL (P < 0.05). Significant factors from multivariate analysis were assembled into the nomogram A (without pelvic dimensions) and nomogram B (with pelvic dimensions). The area under curve (AUC) of nomogram B was 0.72 (95% CI 0.67-0.77), which was better than the AUC of nomogram A (0.69, [95% CI 0.65-0.74]), but didn't reach a statistical significance (P = 0.199). Decision curve supported that nomogram B was better than nomogram A. CONCLUSION: Pelvic dimensions, specifically pelvic inlet and intertuberous distance, seemed to be independent predictors for postoperative AL in RC patients. Pelvic inlet and intertuberous distance incorporated with preoperative radiotherapy, preoperative albumin, conversion, and tumor diameter in the nomogram might provide a clinical tool for predicting AL.


Assuntos
Fístula Anastomótica/etiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Pelve/anatomia & histologia , Neoplasias Retais/cirurgia , Idoso , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nomogramas , Pelvimetria/métodos , Pelve/diagnóstico por imagem , Fatores de Risco , Tomografia Computadorizada por Raios X
17.
Eur J Radiol ; 133: 109368, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33207287

RESUMO

OBJECTIVES: To explore the ability of liver acquisition with volume acceleration contrast-enhanced sequence (LAVA-ce) to improve the accuracy of reassessing adjacent organ involvement by rectal mucinous adenocarcinoma (MC) after neoadjuvant therapy (NAT). METHODS: This study retrospectively enrolled twenty-five patients with MC who underwent pre- and post-NAT MRI, were staged as T4b using pre-NAT T2 weighted imaging, received NAT and underwent radical resection. All MR images were divided into two schemes, T2 weighted plus diffusion weighted imaging (T2Dw protocol) and plus LAVA-ce (T2DwLce protocol). All patients were scored on a 0-4 scale to reassess organ-invasive mucus components. Postoperative pathology was used to identify the involvement of surrounding organs (ypT4b). The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the consistency of the results with pathology after adding fs-CE sequence. RESULTS: Among 25 MC patients (15 males and 10 females, aged 21-89 years), 21 were restaged as yT4b after NAT by using T2Dw, with an accuracy of 44.0 % (11/25), which was lower than the accuracy of staging patients with non-mucinous rectal adenocarcinoma (94.1 %, 96/102). The accuracy of MC restaging was improved by using T2DwLce (23/25). The AUC of T2DwLce was 0.857 (95 % CI, 0.660∼0.964), which was higher than that of T2Dw (AUC, 0.611 [95 % CI, 0.397∼0.798]) (P = 0.019). CONCLUSION: The LAVA-ce sequence can improve the accuracy of reevaluation and should be included in the MRI protocol for MC patients.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias Retais , Aceleração , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
18.
Cancer Cell Int ; 20: 508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088216

RESUMO

BACKGROUND: As an aggressive subtype of breast cancer with a high risk of recurrence, triple-negative breast cancer (TNBC) lacks available treatment targets. LncRNA MIR100HG promotes cell proliferation in TNBC. However, few studies have investigated the molecular mechanism of MIR100HG in TNBC. Thus, additional in-depth investigations are needed to unravel its associated regulatory mechanism. METHODS: MIR100HG and miR-5590-3p expression in TNBC tissue samples and cell lines was detected by RT-qPCR. Flow cytometry, transwell, wound-healing, CCK8 and colony formation assays were performed to analyse cell apoptosis, cell cycle, invasion, migration and proliferation. The protein expression of orthodenticle homeobox 1 (OTX1) and proteins in the ERK/MAPK signalling pathway were assessed by western blot analysis. Bioinformatics and luciferase assay were performed to predict and validate the interaction between MIR100HG and miR-5590-3p as well as OTX1 and miR-5590-3p. RNA immunoprecipitation (RIP) was used to detect the interaction between MIR100HG and miR-5590-3p. Subcutaneous tumour growth was observed in nude mice. Immunohistochemistry (IHC) analysis was used to assess OTX1 expression in tumour tissues. RESULTS: MIR100HG expression was upregulated, whereas that of miR-5590-3p was downregulated in TNBC. MIR100HG was shown to directly interact with miR-5590-3p. Furthermore, MIR100HG knockdown could promote TNBC cell apoptosis and cell cycle arrest in G0/G1 phase while inhibiting migration, invasion and proliferation. Furthermore, miR-5590-3p inhibition showed the opposite results and could reverse the effect of MIR100HG knockdown in TNBC cells. MiR-5590-3p downregulated the ERK/MAPK signalling pathway, suppressed the migration, invasion and proliferation of TNBC cells and promoted their apoptosis and cell cycle arrest in G0/G1 phase by targeting OTX1. In addition, MIR100HG knockdown inhibited OTX1 expression by upregulating miR-5590-3p in vivo, thereby inhibiting tumour growth. CONCLUSIONS: MIR100HG promotes the progression of TNBC by sponging miR-5590-3p, thereby upregulating OTX1, suggesting a new potential treatment target for TNBC.

19.
EBioMedicine ; 61: 103058, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33096483

RESUMO

BACKGROUND: Disordered folliculogenesis is a core characteristic of polycystic ovary syndrome (PCOS) and androgen receptors (ARs) are closely associated with hyperandrogenism and abnormalities in folliculogenesis in PCOS. However, whether the new AR binding partner phosphoglycerate kinase 1 (PGK1) in granulosa cells (GCs) plays a key role in the pathogenesis of PCOS remains unclear. METHODS: We identified the new AR binding partner PGK1 by co-IP (co-immunoprecipitation) in luteinized GCs, and reconfirmed by co-IP, co-localization and GST pull down assay, and checked PGK1 expression levels with qRT-PCR and western blotting. Pharmaceuticals rescue assays in mice, and metabolism assay, AR protein stability and RNA-seq of PGK1 targets in cells proved the function in PCOS. FINDINGS: PGK1 and AR are highly expressed in PCOS luteinized GCs and PCOS-like mouse ovarian tissues. PGK1 regulated glucose metabolism and deteriorated PCOS-like mouse metabolic disorder, and paclitaxel rescued the phenotype of PCOS-like mice and reduced ovarian PGK1 and AR protein levels. PGK1 inhibited AR ubiquitination levels and increased AR stability in an E3 ligase SKP2-dependent manner. Additionally, PGK1 promoted AR nuclear translocation, and RNA-seq data showed that critical ovulation-related genes were regulated by the PGK1-AR axis. INTERPRETATION: PGK1 regulated GCs metabolism and interacted with AR to regulate the expression of key ovulation genes, and also mediated cell proliferation and apoptosis, which resulted in the etiology of PCOS. This work highlights the pathogenic mechanism and represents a novel therapeutic target for PCOS. FUNDING: National Key Research and Development Program of China; National Natural Science Foundation of China grant.


Assuntos
Glucose/metabolismo , Células da Granulosa/metabolismo , Ovulação , Fosfoglicerato Quinase/metabolismo , Receptores Androgênicos/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Adulto , Animais , Apoptose/genética , Biomarcadores , Metabolismo dos Carboidratos , Linhagem Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos , Modelos Biológicos , Ovulação/genética , Fosfoglicerato Quinase/genética , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/metabolismo , Ligação Proteica , Estabilidade Proteica , Transporte Proteico , Proteínas Quinases Associadas a Fase S/genética
20.
Front Oncol ; 10: 1425, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32974154

RESUMO

Background and Aim: This work aims to study the relationship between MRI-defined mucin pool (MP) patterns prior to treatment and the efficacy of neoadjuvant therapy (NAT) in locally advanced rectal mucinous adenocarcinoma (RMAC). Methods: This retrospective study included 278 RMAC patients evaluated between January 2012 and January 2019. After having been trained by using 118 cases with postoperative pathological images, radiologists distinguished MRI-defined MP status as mixed type (MTMP) and separate type (STMP) in a NAT cohort (160 patients) in addition to tumor characteristics, invasion of mesorectal facia, and nodal status. Reader reproducibility was determined using the κ coefficient. The main outcome was the accuracy of MP dichotomy in predicting whether patients had tumor responsiveness or not. Results: Among 278 cases, MTMP and STMP accounted for 49.6 and 50.4% of MPs, respectively. A total of 72 patients received neoadjuvant chemoradiotherapy and 88 received chemotherapy. The tumor responsiveness rate in the chemoradiotherapy group was higher than that in the chemotherapy group (58.3 vs. 21.6%, P < 0.001). In the chemotherapy group, the tumor responsiveness rate in patients with MTMPs was lower than that in patients with STMPs (4.9 vs. 25.5%, P = 0.002). The baseline MRI-defined MTMP was associated with lower responsiveness rates after NAT in the chemotherapy group (odds ratio, 11.050, with 95% CI, 2.368-51.571, P = 0.002). Conclusions: MP dichotomy can be reliably evaluated by using MRI. In the chemotherapy group, MTMP may be a dependent predictor to indicate a lower likelihood of tumor responsiveness after NAT.

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