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1.
J Orthop Surg Res ; 16(1): 480, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34364374

RESUMO

INTRODUCTION: The role of open cerclage wiring in comminuted femoral shaft fracture treatment with intramedullary nails remains unclear. Here, we analyzed the effect of open cerclage wiring and the risk factors for nonunion after interlocking nailing in comminuted femoral shaft fracture treatment. We hypothesized that open cerclage wiring can be applied in patients with severe comminuted femoral shaft fractures without affecting bone healing. PATIENTS AND METHODS: This retrospective cohort study used data from consecutive patients who underwent interlocking nail fixation of a comminuted femoral shaft fracture between January 1, 2009, and December 31, 2016. First, eligible patients were divided into the wire and no wire groups according to the surgical technique used, and their union rate was recorded. The patients were then divided into the union and nonunion groups, and their perioperative data were analyzed. RESULTS: In total, 71 comminuted femoral shaft fractures treated with interlocking nail fixation were included: 38 fractures (53.5%) augmented with the open wiring technique and 33 reduced with closed or mini-open techniques without wiring. The wire group demonstrated significant improvements in fracture reduction compared with the no wire group, whereas no significant difference was observed in the union rate between the wire and no wire groups (p = 0.180). Moreover, 46 (65%) of 71 fractures achieved union smoothly, and no significant difference was observed in any perioperative data between the union and nonunion groups. DISCUSSION: Augmentation with open cerclage wiring is indicated for comminuted femoral shaft fractures treated with intramedullary nails, even when the fragments are large or greatly displaced. Thus, open cerclage wiring can be used for fracture treatment without decreasing the union rate.

2.
Sci Rep ; 11(1): 15709, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344965

RESUMO

Calcaneal quantitative ultrasonography (QUS) is a useful prescreening tool for osteoporosis, while the dual-energy X-ray absorptiometry (DXA) is the mainstream in clinical practice. We evaluated the correlation between QUS and DXA in a Taiwanese population. A total of 772 patients were enrolled and demographic data were recorded with the QUS and DXA T-score over the hip and spine. The correlation coefficient of QUS with the DXA-hip was 0.171. For DXA-spine, it was 0.135 overall, 0.237 in females, and 0.255 in males. The logistic regression model using DXA-spine as a dependent variable was established, and the classification table showed 66.2% accuracy. A receiver operating characteristic (ROC) analyses with Youden's Index revealed the optimal cut-off point of QUS for predicting osteoporosis to be 2.72. This study showed a meaningful correlation between QUS and DXA in a Taiwanese population. Thus, it is important to pre-screen for osteoporosis with calcaneus QUS.


Assuntos
Absorciometria de Fóton/métodos , Densidade Óssea , Calcâneo/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Ultrassonografia/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Taiwan
3.
Cancers (Basel) ; 13(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064004

RESUMO

This study is to identify potential multiomics biomarkers for the early detection of the prognostic recurrence of PC patients. A total of 494 prostate adenocarcinoma (PRAD) patients (60-recurrent included) from the Cancer Genome Atlas (TCGA) portal were analyzed using the autoencoder model and similarity network fusion. Then, multiomics panels were constructed according to the intersected omics biomarkers identified from the two models. Six intersected omics biomarkers, TELO2, ZMYND19, miR-143, miR-378a, cg00687383 (MED4), and cg02318866 (JMJD6; METTL23), were collected for multiomics panel construction. The difference between the Kaplan-Meier curves of high and low recurrence-risk groups generated from the multiomics panel achieved p-value = 5.33 × 10-9, which is better than the former study (p-value = 5 × 10-7). Additionally, when evaluating the selected multiomics biomarkers with clinical information (Gleason score, age, and cancer stage), a high-performance prediction model was generated with C-index = 0.713, p-value = 2.97 × 10-15, and AUC = 0.789. The risk score generated from the selected multiomics biomarkers worked as an effective indicator for the prediction of PRAD recurrence. This study helps us to understand the etiology and pathways of PRAD and further benefits both patients and physicians with potential prognostic biomarkers when making clinical decisions after surgical treatment.

4.
Int J Biol Macromol ; 163: 1106-1116, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679318

RESUMO

In order to efficiently promote loading efficiency and aqueous photostability of indocyanine green (ICG), an amphiphilic tricarbocyanine dye, the polysaccharide-based nanomicelles utilized as a vehicle for ICG were fabricated by self-assembly of the amphiphilic benzoic-imine-containing PEGylated chitosan/4-(dodecyloxy)benzaldehyde (DBA) conjugates in aqueous solution of pH 7.4. The resulting polymeric micelles were characterized to have a hydrophobic hybrid chitosan/DBA core surrounded by hydrophilic PEG shells. Importantly, the encapsulation of ICG into the hybrid chitosan/DBA core of polymeric micelles by the combined hydrophobic and electrostatic interactions not only promoted the ICG loading but also enhanced its aqueous photostability. With the pH of micelle suspension being reduced from 7.4 to 5.0, upon acid-triggered cleavage of benzoic-imine bonds between chitosan and DBA as well as the extending of the protonated chitosan segments from hybrid cores toward aqueous phase, the rather hydrophobic DBA-rich core was formed within micelles, thereby leading to shrinking of the polymeric micelles. The robust ICG-loaded polymeric micelles showed several superior properties including the inhibition of ICG leakage under the mimic physiological and acidic conditions, favorable biocompatibility and photo-activated hyperthermia effect. This work suggests that the pH-responsive ICG-carrying chitosan-based micelles display great potential in cancer theranostic.


Assuntos
Ácido Benzoico/química , Quitosana/química , Iminas/química , Polietilenoglicóis/química , Polímeros/química , Tensoativos/química , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Verde de Indocianina/química , Células MCF-7 , Micelas , Tamanho da Partícula
5.
BMC Pregnancy Childbirth ; 20(1): 336, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487027

RESUMO

BACKGROUND: A high incidence of posterior reversible encephalopathy syndrome (PRES) has been observed in women with eclampsia on imaging. However this association was documented mostly after convulsions occurred. This study aimed to detect the development of PRES using magnetic resonance imaging (MRI) in women with severe preeclampsia and headache, and evaluate the clinical and radiological findings in obstetric outcomes. METHODS: A prospective single-center cohort study comprising 20 pregnant women with severe pre-eclampsia related headache was conducted using Numeric Rating Scale (NRS) score of ≧4. Additionally, non-contrast brain MRI was used to detect PRES and related radiological central nervous system (CNS) abnormalities. RESULTS: Patients were enrolled at a mean gestational age of 32 weeks (range 29-38 weeks). Two women were unable to complete the scanning. Of the 18 MRI scans, 15 (83%) revealed abnormal findings. One patient developed an altered mental state and diffuse PRES, with the occipital, temporal, thalamus, and basal ganglia, the brain stem, and the cerebellum being affected. Two patients had abnormal susceptibility-weighted imaging (SWI) findings, indicating micro-hemorrhages. The majority (12 cases, 66%) of the patients had abnormal cortical hyperintensities in the occipital and temporal lobes. Only three patients had normal MRI pictures. None of the women had eclampsia occurred during the peripartum period, and only one unrelated neonatal death due to congenital anomalies. CONCLUSION: A high incidence of abnormal cortical hyperintensity changes at locations typical for PRES on MRI was noted in women with severe pre-eclampsia and headache. These early hypertensive neurological signs allowed prompt and efficient obstetrical management, to prevent the development of eclampsia and PRES.


Assuntos
Cefaleia/epidemiologia , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/epidemiologia , Pré-Eclâmpsia/epidemiologia , Índice de Gravidade de Doença , Adulto , Cesárea , Comorbidade , Eclampsia/prevenção & controle , Feminino , Seguimentos , Idade Gestacional , Humanos , Incidência , Imageamento por Ressonância Magnética , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Convulsões , Taiwan/epidemiologia
6.
Br J Cancer ; 123(2): 226-239, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32390005

RESUMO

BACKGROUND: Human urothelial carcinoma (UC) has a high tendency to recur and progress to life-threatening advanced diseases. Advanced therapeutic regimens are needed to control UC development and recurrence. METHODS: We pursued in vitro and in vivo studies to understand the ability of a triple combination of gemcitabine, romidepsin, and cisplatin (Gem+Rom+Cis) to modulate signalling pathways, cell death, drug resistance, and tumour development. RESULTS: Our studies verified the ability of Gem+Rom+Cis to synergistically induce apoptotic cell death and reduce drug resistance in various UC cells. The ERK pathway and reactive oxygen species (ROS) played essential roles in mediating Gem+Rom+Cis-induced caspase activation, DNA oxidation and damage, glutathione reduction, and unfolded protein response. Gem+Rom+Cis preferentially induced death and reduced drug resistance in oncogenic H-Ras-expressing UC vs. counterpart cells that was associated with transcriptomic profiles related to ROS, cell death, and drug resistance. Our studies also verified the efficacy and safety of the Gem plus Rom+Cis regimen in controlling UC cell-derived xenograft tumour development and resistance. CONCLUSIONS: More than 80% of UCs are associated with aberrant Ras-ERK pathway. Thus the compensatory combination of Rom with Gem and Cis should be seriously considered as an advanced regimen for treating advanced UCs, especially Ras-ERK-activated UCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células de Transição/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Depsipeptídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Recidiva Local de Neoplasia/patologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/efeitos dos fármacos , Urotélio/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Gene ; 738: 144461, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057927

RESUMO

Down syndrome is one of the most common chromosomal disorders and yet our understanding about the dysregulated genes in this disease is limited. Through this case study, we investigated the gene expression profile of primary amniotic fluid mesenchymal stem cells (AFMSCs) isolated from the amniotic sac of monozygotic twins discordant for trisomy 21 with one fetal hydrops at 17 weeks of gestation. AFMSCs were cultured to analyze the gene expression profiles for the human transcriptome array. Gene ontology was used to evaluate dysregulated gene functions. Total 25,799 genes were identified such that 65 were up-regulated (0.25%) and 111 were down-regulated (0.43%) with a log2 fold change trisomy 21/euploidy (log2 [FC]) > 1, p < 0.01). 16 genes were selected and verified by qRT-PCR, which showed compatible result with transcriptome array. At the chromosome level, chromosome 21 was found to carry the highest percentage of up-regulated genes (2.13%, 7/329 genes) with the highest mean log2 [FC] (0.23, p < 10-5), particularly on 21q22.3. There were eight segments with significant mean log2 [FC] on chromosomes 1, 6, 11, and 21 for upregulation, and on chromosomes 16, 17, and 19 for downregulation, indicating a pattern of dysregulated genes clustering in domains along the genome. Gene ontology showed the identified genes associated with extracellular matrix organization (11 genes, p = 5.1 × 10-6) and central nervous system development (8 genes, p = 6.0 × 10-5). Using transcriptome analysis of the AFMSCs of monozygotic twins discordant for trisomy 21, we report the dysregulated genes involved in Down syndrome, their predominance on chromosome 21, and the cluster pattern on the whole genome.


Assuntos
Síndrome de Down/genética , Perfilação da Expressão Gênica/métodos , Análise em Microsséries/métodos , Líquido Amniótico , Transtornos Cromossômicos/genética , Doenças em Gêmeos/genética , Feminino , Ontologia Genética , Genoma , Genótipo , Humanos , Células-Tronco Mesenquimais/fisiologia , Fenótipo , Gravidez , Transcriptoma/genética , Trissomia/genética , Gêmeos Monozigóticos/genética
8.
Brain Imaging Behav ; 14(6): 2647-2658, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31900889

RESUMO

This study used functional magnetic resonance imaging to explore the neural networks of pain during labor and its relief. It was hypothesized that epidural analgesia would affect the neural activities and the underlying network connectivity. Analysis using dynamic causal modelling and functional connectivity was performed to investigate the spatial activity and network connection of labor pain with and without epidural analgesia. This Institutional Review Board approved study acquired Magnetic Resonance Imaging from 15 healthy women of spontaneous normal delivery (with/without epidural analgesia = 7/8, aged 29.6 ± 2.3 and 29.3 ± 4.8 years old respectively) using a 1.5 Tesla scanner. Numerical rating score of pain was evaluated by a research nurse in the beginning of the first stage of labor and approximately 30 min after imaging examination. Six regions of interested from the activated clusters and literature were selected for dynamic causal modelling, which included primary and secondary somatosensory cortex, middle frontal gyrus, anterior cingulate cortex, insula and lentiform. Functional connectivity was calculated from selected sensory and affective regions. All analyses were performed by using software of statistical parametric mapping version 8 and CONN functional connectivity toolbox. The result showed that the experience of labor pain can lead to activations within a distributed brain network. The pain relief from epidural analgesia can be accompanied with altered functional connectivity, which was most evident in the cingulo-frontal system. The present study, therefore, provides an overview of a pain-related neural network that occur during labor and upon epidural analgesia.


Assuntos
Analgesia Epidural , Adulto , Analgesia Obstétrica , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Medição da Dor , Gravidez
9.
Acta Orthop Traumatol Turc ; 53(6): 408-413, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582200

RESUMO

OBJECTIVE: The aim of this study was to compare the clinical and radiographic outcomes of clavicular hook plate fixation with and without coracoclavicular (CC) tape augmentation for the treatment of acute unstable AC dislocation. METHODS: We treated 47 patients (31 men and 16 women; mean age: 47 years (range, 21-81)) with unstable acute AC dislocations (Rockwood III-V) and divided them into two groups according to the treatment modality, with hook plate fixation (hook plate group) or hook plate plus CC tape augmentation (combined group). We assessed radiologic findings, such as subacromial osteolysis and AC osteoarthritis. We also evaluated the clinical outcomes using a visual analogue scale (VAS) for pain, as well as the University of California at Los Angeles (UCLA) Shoulder Rating Scale and the American Shoulder and Elbow Surgeons (ASES) Shoulder Score. RESULTS: We found that the combined group had less subacromial osteolysis upon radiography, although the CC distance was similar in both groups (119 ± 29.7% of contralateral side CC distance in hook plate group versus 119 ± 34.8% in the combined group, p = 0.77). Compared with the hook plate group, the combined group had a lower VAS score (4.5 ± 2.3 in hook plate group versus 2.3 ± 1.4 in the combined group, p < 0.001), better UCLA scores (19.9 ± 4.9 in hook plate group versus 27.2 ± 4.0 in the combined group, p < 0.001) as well as better ASES scores (51.9 ± 17.8 in hook plate group versus 73.8 ± 13.1 in the combined group, p < 0.001) at 3 and 6 months after surgery. CONCLUSION: Hook plate fixation plus CC tape augmentation may prevent subacromial osteolysis and yield better short-term functional outcomes. LEVEL OF EVIDENCE: Level III, Therapeutic Study.


Assuntos
Articulação Acromioclavicular/cirurgia , Placas Ósseas , Luxações Articulares/cirurgia , Procedimentos Ortopédicos/métodos , Técnicas de Sutura/instrumentação , Suturas , Articulação Acromioclavicular/diagnóstico por imagem , Articulação Acromioclavicular/lesões , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Luxações Articulares/diagnóstico , Masculino , Pessoa de Meia-Idade , Radiografia , Resultado do Tratamento , Escala Visual Analógica , Adulto Jovem
10.
Cancers (Basel) ; 11(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330844

RESUMO

Endometrial cancer incidence rates are growing, especially in countries with rapid socioeconomic transitions. Despite recent advances in chemotherapy, hormone therapy, and targeted therapy, advanced/recurrent disease remains a clinical challenge. Palbociclib-a selective inhibitor of cyclin-dependent kinases (CDK) 4/6-has therapeutic potential against estrogen receptor (ER)-positive and HER2-negative breast cancer. However, the question as to whether it can be clinically useful in endometrial cancer remains open. Here, we show that combined treatment with palbociclib and megesterol acetate exerts synergistic antiproliferative effects against endometrial cancer cells. Treatment of cancer cells with palbociclib suppressed NPM/B23 phosphorylation at threonine 199 (Thr199). We further demonstrated that CDK6 acts as a NPM/B23 kinase. Palbociclib-induced NPM/B23 dephosphorylation sensitized endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. Immunohistochemistry revealed an overexpression of phospho-NPM/B23 (Thr199) in human endometrial cancer, and phospho-NPM/B23 (Thr199) expression levels were inversely associated with Erα in clinical specimen. In a xenograft tumor model, the combination of palbociclib and megesterol acetate successfully inhibited tumor growth. Taken together, our data indicate that palbociclib promoted NPM/B23 dephosphorylation at Thr199-an effect mediated by disruption of CDK6 kinase activity. We conclude that palbociclib holds promise for the treatment of endometrial cancer when used in combination with megesterol acetate.

11.
Mol Ther Methods Clin Dev ; 13: 99-111, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-30740472

RESUMO

The delivery of active proteins into cells (protein transfection) for biological purposes offers considerable potential for clinical applications. Herein we demonstrate that, with a readily available, inexpensive organic agent, the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) method can be used for simple and efficient protein transfection. By mixing proteins with a pure HEPES solution before they are applied to live cells, proteins with various molecular weights (including antibodies, recombinant proteins, and peptides) were successfully delivered into the cytoplasm of different cell types. The protein transfection efficiency of the HEPES method was not inferior to that of commercially available systems that are both more expensive and time consuming. Studies using endocytotic inhibitors and endosomal markers have revealed that cells internalize HEPES-protein mixtures through endocytosis. Results that HEPES-protein mixtures exhibited a low diffusion coefficient suggest that HEPES might neutralize the charges of proteins and, thus, facilitate their cellular internalization. Upon internalization, the cytosolic antibodies caused the degradation of targeted proteins in TRIM21-expressing cells. In summary, the HEPES method is efficient for protein transfection and has potential for myriad clinical applications.

12.
Biomed J ; 42(6): 417-421, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948606

RESUMO

BACKGROUND: A proportion of twin-twin transfusion syndrome (TTTS) patients may have elevated liver enzymes (ELEzs) before fetoscopic laser therapy, but the incidence of ELEzs before laser therapy and the association with the perinatal outcomes after laser therapy remain unclear. METHODS: From October 2008 to April 2015, 93 patients with TTTS who received fetoscopic laser therapy at our hospital were included in this study, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured within 24 h before therapy. If ELEzs (AST > 34 U/L or ALT > 36 U/L) were observed before therapy, the AST and ALT levels were evaluated within 24 h after therapy. The pre-operative characteristics and post-therapy outcomes were compared between patients with and without ELEzs. RESULTS: Among 93 TTTS patients before laser operation, 18 patients (were found with ELEzs (19.4%) before laser therapy. In 17 (94.4%) of the 18 cases, their liver enzymes values dropped after laser surgery. Maternal body mass index, age, gestational age of laser therapy, hemoglobin level before laser therapy and survival rates after laser therapy were not significantly different between TTTS with and without ELEzs. The maternal hemoglobin dropped significantly from 10.8 [1.6] g/dL before surgery to 9.6 [1.5] g/dL after laser therapy in TTTS with ELEzs (p < 0.001). CONCLUSION: An elevated liver enzyme was not associated with poor perinatal outcomes in patients with TTTS after laser therapy. The authors suspected that the reduced liver enzymes values after laser therapy could partly arise from the hemo-dilution effect.


Assuntos
Transfusão Feto-Fetal/epidemiologia , Transfusão Feto-Fetal/terapia , Terapia a Laser , Fígado/enzimologia , Feminino , Fetoscopia/métodos , Idade Gestacional , Humanos , Incidência , Fígado/cirurgia , Gravidez , Taxa de Sobrevida
13.
J Mol Med (Berl) ; 96(11): 1251-1266, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30298385

RESUMO

Oncogenic PIK3CA mutations are common in endometrial cancers, and the PI3K/AKT/mTOR pathway is targetable by drugs. We sought to investigate whether the combination of an mTOR inhibitor, everolimus (RAD001), and an AKT inhibitor, terameprocol (M4N), exerts better antiproliferative effects in endometrial cancer. The molecular mechanisms underlying their pharmacological action were also examined. The combination of RAD001 and M4N exerted in vitro synergistic effects on cell viability, apoptosis, and expression of IGFBP2 in endometrial cancer cells. Mechanistically, the Sp1 site on the IGFBP2 promoter was required for RAD001- and M4N-induced downregulation. IGFBP2 protein expression was higher in endometrial cancer than in the normal endometrium (P < 0.001). Furthermore, elevated IGFBP2 histoscores were significantly associated with a lower overall survival (P = 0.021). In conclusion, our in vitro results demonstrate that RAD001 and M4N exert synergistic antiproliferative effects against endometrial cancer cells, which appeared to be mediated by the inhibition of IGFBP2, a key anti-apoptotic regulator. Further clinical studies of this drug combination in patients with endometrial cancer may be warranted, especially in the presence of PIK3CA and IGFBP2 aberrations. KEY MESSAGES: RAD001 and M4N synergistically suppress endometrial cancer growth. IGFBP2 is overexpressed in endometrial cancer. The combination of RAD001 and M4N significantly reduces IGFBP2 overexpression. Sp1 binding site on the IGFBP2 promoter is required for RAD001- and M4N-induced downregulation. High IGFBP2 histoscore in endometrial cancer portends a poor prognosis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Endométrio/metabolismo , Everolimo/farmacologia , Imunossupressores/farmacologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masoprocol/análogos & derivados , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Sinergismo Farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Humanos , Masoprocol/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/genética
15.
BMC Pregnancy Childbirth ; 18(1): 321, 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089456

RESUMO

BACKGROUND: We previously reported that fetal plasma erythropoietin (EPO) concentrations are significantly increased in growth-restricted fetuses with abnormal umbilical artery (UA) Doppler. During hypoxia in an ovine model, the primary site of fetal EPO synthesis was switched from the kidneys to the placenta. Therefore, we designed this study to evaluate human placental EPO gene expression and the correlation to fetal serum EPO concentration in growth-restricted fetuses in a monochorionic (MC) twin model. METHODS: In MC twin pairs, selective intrauterine growth restriction (sIUGR) was defined as the presence of (i) birth weight discordance of > 20% and (ii) a smaller twin with a birth weight less than the 10th percentile. Fetal UA and middle cerebral artery (MCA) Doppler were checked within 1 week before delivery. An abnormal UA Doppler was defined as persistently absent or reverse end-diastolic flow. Cerebroplacental ratio (CPR) was defined as MCA-pulsatility index (PI)/UA-PI. Fetal plasma EPO concentrations were measured in cord blood, and EPO gene expression was assayed in each twin's placental territory. The intertwin plasma EPO ratio was calculated as the cord plasma EPO level of the smaller (or sIUGR) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin, and the intertwin placental EPO gene expression ratio was calculated similarly. RESULTS: Twenty-six MC twins were analyzed, including normal twins (Group 1, n = 9), twins with sIUGR without UA Doppler abnormalities (Group 2, n = 9), and twins with sIUGR and UA Doppler abnormalities (Group 3, n = 8). The CPRs of smaller (sIUGR) fetuses were significantly decreased in Group 3 MC twins (p < 0.001), but not significantly different between Group 1 and Group 2. The highest fetal plasma EPO ratio and placental EPO gene expression ratio were identified in Group 3 MC twins (p < 0.001). The placental EPO gene expression ratios were significantly correlated with the fetal plasma EPO ratios (Pearson's correlation test, p = 0.004). CONCLUSION: This study provides evidence of increased placental EPO expression in MC twin fetuses with sIUGR and abnormal UA Doppler. Future studies are needed to confirm the similar role of placental EPO in severe IUGR singletons.


Assuntos
Eritropoetina/genética , Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/metabolismo , Placenta/metabolismo , Artérias Umbilicais/diagnóstico por imagem , Estudos de Casos e Controles , Córion , Eritropoetina/metabolismo , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Expressão Gênica , Humanos , Recém-Nascido , Masculino , Artéria Cerebral Média/diagnóstico por imagem , Gravidez , Fluxo Pulsátil , Gêmeos , Ultrassonografia Doppler , Ultrassonografia Pré-Natal
16.
J Mol Med (Berl) ; 96(6): 527-536, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29725737

RESUMO

We investigated whether genomic scar signatures associated with homologous recombination deficiency (HRD), which include telomeric allelic imbalance (TAI), large-scale transition (LST), and loss of heterozygosity (LOH), can predict clinical outcomes in patients with ovarian clear cell carcinoma (OCCC). We enrolled patients with OCCC (n = 80) and high-grade serous carcinoma (HGSC; n = 92) subjected to primary cytoreductive surgery, most of whom received platinum-based adjuvant chemotherapy. Genomic scar signatures based on genome-wide copy number data were determined in all participants and investigated in relation to prognosis. OCCC had significantly lower genomic scar signature scores than HGSC (p < 0.001). Near-triploid OCCC specimens showed higher TAI and LST scores compared with diploid tumors (p < 0.001). While high scores of these genomic scar signatures were significantly associated with better clinical outcomes in patients with HGSC, the opposite was evident for OCCC. Multivariate survival analysis in patients with OCCC identified high LOH scores as the main independent adverse predictor for both cancer-specific (hazard ratio [HR] = 3.22, p = 0.005) and progression-free survival (HR = 2.54, p = 0.01). In conclusion, genomic scar signatures associated with HRD predict adverse clinical outcomes in patients with OCCC. The LOH score was identified as the strongest prognostic indicator in this patient group. KEY MESSAGES: Genomic scar signatures associated with HRD are less frequent in OCCC than in HGSC. Genomic scar signatures associated with HRD have an adverse prognostic impact in patients with OCCC. LOH score is the strongest adverse prognostic factor in patients with OCCC.


Assuntos
Adenocarcinoma de Células Claras/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genômica , Recombinação Homóloga , Humanos , Perda de Heterozigosidade , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
17.
Taiwan J Obstet Gynecol ; 57(2): 270-275, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29673672

RESUMO

OBJECTIVE: We have recently reported that stress-induced phosphoprotein 1 (STIP1) is over-expressed in endometriosis/adenomyosis tissues. STIP1 may also be involved in immune regulation, thus we attempted to study the association between STIP1 single nucleotide polymorphisms (SNPs) and endometriosis/adenomyosis. MATERIALS AND METHODS: Five STIP1 SNPs (rs7941773, rs2845597, rs4980524, rs2282490, and rs2236647) were selected for genotyping with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) in 286 patients with endometriosis/adenomyosis and 288 healthy postmenopausal controls. In vitro studies included luciferase promoter reporter assays and western blot analysis for STIP1 and MMP9 proteins. RESULTS: The frequency of the G allele at rs4980524 was significantly higher in patients with endometriosis/adenomyosis than in control women. The promoter reporter with rs4980524 GG genotype significantly increased luciferase activity than that with TT genotype in endometrial cancer RL95-2 cells, and the primary endometrial stromal cells carrying rs4980524 GG genotype expressed higher protein levels of STIP1 and MMP9 than those carrying the TT one. CONCLUSION: The G/G allele of STIP1 SNP rs4980524 is associated with the increased expression of STIP1 and MMP9 in endometriosis. Further validation in independent cohorts of endometriosis patients may prove its usefulness as a genetic risk maker for endometriosis/adenomyosis.


Assuntos
Adenomiose/genética , Endometriose/genética , Proteínas de Choque Térmico/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Metaloproteinase 9 da Matriz/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
BMC Pregnancy Childbirth ; 18(1): 74, 2018 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-29573746

RESUMO

BACKGROUND: Placental mitochondrial DNA (mtDNA) has been proposed to be an indicator for placental hypoxia. This study was designed to evaluate the effect of vascular anastomoses between monochorionic (MC) twins on placental mtDNA. METHODS: In this study, twin-twin transfusion syndrome (TTTS) treated with laser therapy and MC twins without TTTS (without laser therapy) resulting in two live babies were included in this study. The placental mtDNA fold changes (FC) between the small and large twins were analyzed using real-time quantitative PCR. TTTS twins with selective intrauterine growth restriction (sIUGR) are categorized as group 1, TTTS without sIUGR as group 2, MC twins without TTTS but with sIUGR as group 3, and MC twins without both TTTS and sIUGR as group 4. RESULTS: There were seven cases in group 1, eight in group 2, 26 in group 3, and 24 in group 4 cases. The placental mtDNA FC were significantly higher in group 1 (1.57 ± 0.9) compared to that of the group 3 (0.86 ± 0.6). CONCLUSION: In MC twin pregnancies with sIUGR, the placental mtDNA FC between the small and large twins are different between cases with and without inter-twin anastomoses. These findings suggest that the inter-twin anastomoses in the MC twins with sIUGR may provide rescue perfusion from the appropriate-for-gestational-age twin to the sIUGR one.


Assuntos
Anastomose Arteriovenosa/metabolismo , DNA Mitocondrial/sangue , Retardo do Crescimento Fetal/sangue , Placenta/metabolismo , Gravidez de Gêmeos/sangue , Anastomose Arteriovenosa/embriologia , Córion , Feminino , Hipóxia Fetal/sangue , Transfusão Feto-Fetal/terapia , Humanos , Terapia a Laser/métodos , Placenta/irrigação sanguínea , Gravidez
19.
Oncogenesis ; 7(3): 31, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29593255

RESUMO

Stress-induced phosphoprotein 1 (STIP1)-a co-chaperone of heat shock proteins-promotes cell proliferation and may act as an oncogenic factor. Similarly, glycogen synthase kinase-3 beta (GSK3ß)-mediated phosphorylation of lysine-specific demethylase 1 (LSD1)-an epigenetic regulator-can contribute to the development of an aggressive cell phenotype. Owing to their ability to tether different molecules into functional complexes, scaffold proteins have a key role in the regulation of different signaling pathways in tumorigenesis. Here, we show that STIP1 acts as a scaffold promoting the interaction between LSD1 and GSK3ß. Specifically, the TPR1 and TPR2B domains of STIP1 are capable of binding with the AOL domain of LSD1, whereas the TPR2A and TPR2B domains of STIP1 interact with the kinase domain of GSK3ß. We also demonstrate that STIP1 is required for GSK3ß-mediated LSD1 phosphorylation, which promoted LSD1 stability and enhanced cell proliferation. After transfection of cancer cells with double-mutant (S707A/S711A) LSD1, subcellular localization analysis revealed that LSD1 was translocated from the nucleus to the cytoplasm. In vitro experiments also showed that the LSD1 inhibitor SP2509 and the GSK3ß inhibitor LY2090314 acted synergistically to induce cancer cell death. Finally, the immunohistochemical expression of STIP1 and LSD1 showed a positively correlation in human cancer specimens. In summary, our data provide mechanistic insights into the role of STIP1 in human tumorigenesis by showing that it serves as a scaffold for GSK3ß-mediated LSD1 phosphorylation. The combination of LSD1 and GSK3ß inhibitors may exert synergistic antitumor effects and deserves further scrutiny in preclinical studies.

20.
Front Immunol ; 9: 232, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29483918

RESUMO

Background: The immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly understood. Methods: A transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting. Result: The differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (n = 607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes' expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA, p < 2 × 10-16). A 53-gene signature was determined with significant correlation with inhibitory checkpoint PDCD1 (r = 0.59, p = 0.0078) among others, where the nine top genes including IGJ and IGKC were RT-qPCR validated with high diagnostic performance (AUC: 0.920, 95% CI: 0.831-0.985, p = 2.98 × 10-7). Increased staining and expression of IGKC revealed by immunohistochemistry and immunoblotting in tumor adjacent non-neoplastic lung tissues (Wilcoxon signed-rank test, p < 0.001) and in BAL cell lysates (p < 0.01) of NSCLC, respectively, were noted. Conclusion: The BAL cells of tumor-bearing lung segments and tumor adjacent non-neoplastic lung tissues present a unique gene expression characterized by IGKC in relation to inhibitory checkpoints. Further study of humoral immune responses to NSCLC is warranted.


Assuntos
Biomarcadores Tumorais/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Cadeias kappa de Imunoglobulina/imunologia , Neoplasias Pulmonares/imunologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade Humoral , Cadeias kappa de Imunoglobulina/metabolismo , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
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