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1.
Curr Opin Cell Biol ; 67: 1-8, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32763500

RESUMO

Cell competition is a short-range intercellular communication, in which cells compare their fitness with that of their neighbors and eliminate the cells with relatively lower fitness. It is considered important for the formation and maintenance of healthy tissues; however, its exact role during development, especially in mammals, has been obscure. Recent studies in mouse embryonic epiblast and skin tissues revealed that cell differentiation in early embryos and stem cell proliferation tends to produce suboptimal cells, especially during early developmental stages. Cell competition occurs at multiple stages and via multiple mechanisms during development to ensure elimination of such low-quality cells. Thus, quality control via cell competition supports correct development by overcoming the heterogeneity produced during cell differentiation and stem cell proliferation.

2.
Nutrients ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575593

RESUMO

S-allylcysteine (SAC), a major thioallyl compound contained in mature garlic extract (MGE), is known to be a neuroactive compound. This study was designed to investigate the effects of SAC on primary cultured hippocampal neurons and cognitively impaired senescence-accelerated mice prone 10 (SAMP10). Treatment of these neurons with MGE or SAC significantly increased the total neurite length and number of dendrites. SAMP10 mice fed MGE or SAC showed a significant improvement in memory dysfunction in pharmacological behavioral analyses. The decrease of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, N-methyl-d-aspartate (NMDA) receptor, and phosphorylated α-calcium/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal tissue of SAMP10 mice fed MGE or SAC was significantly suppressed, especially in the MGE-fed group. These findings suggest that SAC positively contributes to learning and memory formation, having a beneficial effect on brain function. In addition, multiple components (aside from SAC) contained in MGE could be useful for improving cognitive function by acting as neurotrophic factors.

3.
Dev Biol ; 464(2): 161-175, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32579954

RESUMO

The Dishevelled proteins transduce both canonical Wnt/ß-catenin and non-canonical Wnt/planar cell polarity (PCP) signaling pathways to regulate many key developmental processes during embryogenesis. Here, we disrupt both canonical and non-canonical Wnt pathways by targeting the entire Dishevelled family of genes (Dvl1, Dvl2, and Dvl3) to investigate their functional roles in the early embryo. We identified several defects in anterior-posterior axis specification and mesoderm patterning in Dvl1+/-; Dvl2-/-; Dvl3-/- embryos. Homozygous deletions in all three Dvl genes (Dvl TKO) resulted in defects in distal visceral endoderm migration and a complete failure to induce mesoderm formation. To identify potential mechanisms that lead to the defects in the developmental processes preceding gastrulation, we generated Dvl TKO mouse embryonic stem cells (mESCs) and compared the transcriptional profile of these cells with wild-type (WT) mESCs during germ lineage differentiation into 3D embryoid bodies (EBs). While the Dvl TKO mESCs displayed similar morphology, self-renewal properties, and minor transcriptional variation from WT mESCs, we identified major transcriptional dysregulation in the Dvl TKO EBs during differentiation in a number of genes involved in anterior-posterior pattern specification, gastrulation induction, mesenchyme morphogenesis, and mesoderm-derived tissue development. The absence of the Dvls leads to specific down-regulation of BMP signaling genes. Furthermore, exogenous activation of canonical Wnt, BMP, and Nodal signaling all fail to rescue the mesodermal defects in the Dvl TKO EBs. Moreover, endoderm differentiation was promoted in the absence of mesoderm in the Dvl TKO EBs, while the suppression of ectoderm differentiation was delayed. Overall, we demonstrate that the Dvls are dispensable for maintaining self-renewal in mESCs but are critical during differentiation to regulate key developmental signaling pathways to promote proper axis specification and mesoderm formation.

4.
Cells ; 9(5)2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365498

RESUMO

The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap-a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.

5.
Nat Commun ; 10(1): 5745, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848339

RESUMO

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.


Assuntos
Estrogênios/metabolismo , Neoplasias Hepáticas/secundário , Fígado/patologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral/transplante , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Estradiol/administração & dosagem , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/imunologia , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Ovariectomia , Neoplasias Pancreáticas/patologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fatores Sexuais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
6.
J Alzheimers Dis ; 71(4): 1163-1174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31524172

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-ß peptide (Aß) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aß or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD.


Assuntos
Doença de Alzheimer , Fragmentos de Peptídeos/sangue , Células Piramidais , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Apolipoproteínas E/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cognição/fisiologia , Correlação de Dados , Progressão da Doença , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Fragmentos de Peptídeos/líquido cefalorraquidiano , Prognóstico , Proteômica/métodos , Células Piramidais/metabolismo , Células Piramidais/patologia
7.
Dev Cell ; 50(2): 139-154.e5, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31204175

RESUMO

The epiblast is a pluripotent cell population first formed in preimplantation embryos, and its quality is important for proper development. Here, we examined the mechanisms of epiblast formation and found that the Hippo pathway transcription factor TEAD and its coactivator YAP regulate expression of pluripotency factors. After specification of the inner cell mass, YAP accumulates in the nuclei and activates TEAD. TEAD activity is required for strong expression of pluripotency factors and is variable in the forming epiblast. Cells showing low TEAD activity are eliminated from the epiblast through cell competition. Pluripotency factor expression and MYC control cell competition downstream of TEAD activity. Cell competition eliminates unspecified cells and is required for proper organization of the epiblast. These results suggest that induction of pluripotency factors by TEAD activity and elimination of unspecified cells via cell competition ensure the production of an epiblast with naive pluripotency.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Blastocisto/citologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Proteínas de Ligação a DNA/fisiologia , Camadas Germinativas/citologia , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Pluripotentes/citologia , Fatores de Transcrição/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Blastocisto/metabolismo , Proteínas de Ciclo Celular/genética , Proliferação de Células , Células Cultivadas , Feminino , Camadas Germinativas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Pluripotentes/metabolismo
8.
Ann Gastroenterol Surg ; 2(5): 383-393, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30238080

RESUMO

Aim: We investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells. Methods: We classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences. Results: There were no significant differences in lymphocyte fractions of either PBMC or LMNC between groups, except for the significantly lower percentage of natural killer (NK) cells in LMNC in group B than in group A. Significantly higher percentage of natural-killer group 2, member D (NKG2D)- positive NK cells in PBMC and percentage of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, NKp30-, and signal regulatory protein ß (SIRPß)-positive NK cells in LMNC were found in group B. Furthermore, significantly higher expressions of NKG2D and SIRPß in peripheral blood NK cells and of NKp46 and CD122 in liver NK cells were found in group B. When LMNC were incubated with interleukin (IL)-2 in vitro, no difference was observed in the expression of these molecules in NK cells between groups. Consistently, there was no difference in the cytotoxic activity of those LMNC against a colon adenocarcinoma cell line between groups. Conclusion: Colorectal cancer with liver metastasis patients treated with neoadjuvant chemotherapy showed enhanced expression of activation markers on peripheral blood and liver NK cells in comparison with patients who did not receive therapy; however, the difference in those function remains unclear. These results suggest that neoadjuvant chemotherapy does not have a negative impact on intrahepatic immune cells in resectable CRLM patients.

9.
Int J Surg ; 54(Pt A): 156-162, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29730072

RESUMO

BACKGROUND: The aim of this study is to determine the outcomes and prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative hepatectomy. METHODS: Clinical, histopathological, and treatment data of 53 patients with recurrent cholangiocarcinoma after curative resection from 2005 to 2015 at our institutes were investigated and analyzed by univariate and multivariate analyses (E-788). RESULTS: Recurrent cholangiocarcinoma occurred in 53 of 97 patients who underwent curative resection for intrahepatic cholangiocarcinoma. The median overall survival after recurrence was 13.6 months (range, 1-55 months). Multivariate analysis revealed that recurrent treatment without surgery (p = 0.0007), gross appearance except for mass-forming type (p = 0.0183) and bile duct invasion at the initial surgery (p = 0.0093) were significant poor prognostic factors in recurrent cholangiocarcinoma. Median survival of patients after surgical treatment for recurrent cholangiocarcinoma was 36.7 months versus 13.1 months in patients who did not undergo surgery (p = 0.029). CONCLUSIONS: Surgical treatment, gross appearance in mass-forming type and the absence of bile duct invasion were independent favorable factors for survival among patients with recurrent cholangiocarcinoma. We recommend surgical treatment for localized recurrence, even if it occurs early after the initial hepatectomy.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Hepatectomia/mortalidade , Recidiva Local de Neoplasia/mortalidade , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Feminino , Humanos , Masculino , Análise Multivariada , Invasividade Neoplásica , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/patologia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
10.
Anticancer Res ; 37(5): 2625-2631, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476837

RESUMO

AIM: The aim of this study was to investigate the prognostic factors associated with extrahepatic metastasis of primary hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively analyzed 559 patients with HCC who underwent curative hepatectomy. We divided the patients into no recurrence (NoR), intrahepatic early recurrence (IHER), intrahepatic late recurrence (IHLR), and extrahepatic recurrence (EHR) groups. We compared the non-metastatic group (IHLR and NoR) with the metastatic group (IHER and EHR) and also compared IHER with EHR to determine risk factors for EHR. RESULTS: There were 252, 163, 109, and 35 patients with NoR, IHER, IHLR, and EHR, respectively. For the EHR group, the independent risk factor was vascular invasion. The EHR group had better liver function and worse tumor factors. CONCLUSION: Vascular invasion is predictive of extrahepatic metastasis of HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Idoso , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/cirurgia , Modelos Logísticos , Masculino , Análise Multivariada , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Prognóstico , Fatores de Risco , Albumina Sérica/análise
11.
Asian J Endosc Surg ; 10(2): 209-212, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28547928

RESUMO

INTRODUCTION: This study investigated whether laparoscopic ultrasound-guided segment staining and real-time ultrasound-guided hepatectomy, with endobronchial ultrasonography equipped with a guide sheath, would be useful for laparoscopic liver segmentectomy in a porcine model. MATERIAL AND SURGICAL TECHNIQUE: The abdominal cavity (in two pigs) was reached via a 12-mm umbilical trocar. An artificial tumor was created by radiofrequency ablation within the intended resection area. Portal vein puncture and staining were performed by the endobronchial ultrasonography-guided method. The targeted portal branch was successfully visualized and punctured with a needle through an equipped guide sheath. After targeted segment staining, the liver parenchyma was resected with a bipolar energy device; the regional Glisson's sheath was ligated and cut, and a surgical specimen was extracted. Real-time endobronchial ultrasonography from the cut surface provided information vital for preserving the surgical margin. All procedures were performed laparoscopically. DISCUSSION: This study demonstrated the technical feasibility of laparoscopic ultrasound-guided portal vein staining and safe surgical resection during laparoscopic liver segmentectomy.


Assuntos
Endossonografia/métodos , Hepatectomia/métodos , Laparoscopia/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Cirurgia Assistida por Computador/métodos , Animais , Ablação por Cateter , Modelos Animais de Doenças , Estudos de Viabilidade , Neoplasias Hepáticas/etiologia , Suínos
12.
Langenbecks Arch Surg ; 402(5): 745-755, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28534136

RESUMO

PURPOSE: Although obesity is associated with hepatocellular carcinoma (HCC) development, its impact on the surgical outcomes of patients with hepatitis B virus (HBV)-and hepatitis C virus (HCV)-related HCC remains unclear. METHODS: We retrospectively analyzed 714 patients with HCC who underwent curative hepatectomy. Among them, the HBV-related HCC group (n = 125) and HCV-related HCC group (n = 426) were subdivided according to the presence of body mass index (BMI) ≥ 25 kg/m2. The surgical outcomes were compared. RESULTS: The 5-year overall survival rate after hepatectomy in the HBV-related HCC group was significantly better than that in the HCV-related HCC group. The 5-year overall survival rates of the HBV-related HCC with and without BMI ≥ 25 kg/m2 groups were 65 and 85%, respectively. The 5-year overall survival rates in the HCV-related HCC with and without BMI ≥ 25 kg/m2 groups were 75 and 65%, respectively. The HBV-related HCC with BMI ≥ 25 kg/m2 groups had a significantly worse prognosis than the HBV-related HCC without BMI ≥ 25 kg/m2 groups, while the HCV-related HCC with BMI ≥ 25 kg/m2 groups had a significantly better prognosis than the HCV-related HCC without BMI ≥ 25 kg/m2 groups. Multivariate analysis revealed that BMI ≥ 25 kg/m2 was the positive and negative prognostic factor for the surgical outcomes of patients with HBV- and HCV-related HCC, respectively. CONCLUSIONS: BMI ≥ 25 kg/m2 negatively affected the surgical outcomes of patients with HBV-related HCC and positively affected those of patients with HCV-related HCC.


Assuntos
Índice de Massa Corporal , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Hepatite B/complicações , Hepatite C/complicações , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Adulto , Idoso , Feminino , Hepatectomia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
13.
Surg Res Pract ; 2017: 4907576, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28492061

RESUMO

Background. Laparoscopic surgery has become more widely used, but peritoneal dissemination and port-site metastasis have been reported to occur in these surgeries. One reason for these problems is the ultrasonically activated scalpel (UAS) used for laparoscopic surgery. This study aimed to investigate the viability of airborne cells released during cancer dissection using a UAS. Methods. Flank tumors measuring about 2 cm were induced in male NOD-Cg-Rag1tm1MomIL2rgtm1wjl/SzJ mice by subcutaneous injection of 1 × 106 HepG2 cells. Dissection was performed with UAS (in high or low power modes) and PowerStar bipolar scissors. The mist of released tissue was collected in cell culture medium. The viability of the cellular material was assessed with trypan blue exclusion cell counting, counting after immunofluorescence staining, and flow cytometric analysis. Results. Large quantities of cellular debris were trapped in the tissue dispersed by both devices. In all experiments, there were significantly more viable cells produced by the UAS in high power mode. By using suction at the excision site, the number of viable cancer cells was reduced. Conclusions. This study demonstrates that viable cancer cells can be released into the nearby environment during tumor ablation with a UAS.

14.
Int J Surg ; 42: 209-214, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28483664

RESUMO

BACKGROUND: Systemic inflammation and nutritional status are strongly associated with tumor progression. Inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), reflect these states and are predictive in patients with several types of advanced cancers. The aim of this study was to evaluate the significance of GPS in patients with colorectal liver metastasis (CRLM). PATIENTS AND METHODS: Study subjects were 134 patients with CRLM who underwent initial radical liver resection at Hiroshima University Hospital between January 2000 and December 2013. Univariate and multivariate analyses were performed to identify variables associated with overall and recurrence-free survival following liver resection in two groups based on GPS. RESULTS: There was no significant relationship between overall survival and GPS. Recurrence-free survival was significantly poorer in patients with GPS 1-2 than in those with GPS 0 (p < 0.01). In multivariate analysis for recurrence-free survival, moderate histologic differentiation, carcinoembryonic antigen level ≥10 ng/mL, and GPS 1-2 were identified as independent prognostic factors. CONCLUSION: We suggest that GPS is an important predictor of recurrence following liver resection in patients with CRLM, and it should be considered one of the evaluation criteria for liver resection.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/sangue , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
15.
Dev Cell ; 40(5): 439-452.e4, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28292423

RESUMO

Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. How node cells become polarized has remained unknown, however. Wnt5a and Wnt5b are expressed posteriorly relative to the node, whereas genes for Sfrp inhibitors of Wnt signaling are expressed anteriorly. Here we show that polarization of node cells is impaired in Wnt5a-/-Wnt5b-/- and Sfrp mutant embryos, and also in the presence of a uniform distribution of Wnt5a or Sfrp1, suggesting that Wnt5 and Sfrp proteins act as instructive signals in this process. The absence of planar cell polarity (PCP) core proteins Prickle1 and Prickle2 in individual cells or local forced expression of Wnt5a perturbed polarization of neighboring wild-type cells. Our results suggest that opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry.


Assuntos
Padronização Corporal , Polaridade Celular , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteína Wnt-5a/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Comunicação Celular , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas com Domínio LIM/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Modelos Biológicos , Proteínas/metabolismo
16.
Int J Surg ; 39: 206-213, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28159713

RESUMO

BACKGROUND: The number of patients with hepatocellular carcinoma (HCC) negative for both hepatitis B virus surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) has increased recently. The purpose of the present study was to investigate the clinical characteristics and prognoses of non-B non-C HCC (NBNC-HCC) patients. MATERIALS AND METHODS: From January 2000 to December 2013, 154 patients with NBNC-HCC and 560 patients with HBsAg or HCVAb positive (BC)-HCC who underwent curative resection were analyzed retrospectively. The clinical features of NBNC-HCC and BC-HCC were compared, and the prognoses of NBNC-HCC patients were analyzed. RESULTS: In comparison to patients with BC-HCC, patients with NBNC-HCC had better liver function but higher pathological tumor stages. The disease-free survival (DFS) duration was significantly higher in patients with NBNC-HCC than it was in those with BC-HCC. In patients with NBNC-HCC, aspartate aminotransferase ≥40 IU/L, albumin level <3.5 g/dL, and multiple tumors were independent risk factors of overall survival; and male sex and multiple tumors were independent risk factors of DFS. CONCLUSION: Patients with NBNC-HCC had significantly longer DFS durations than those with BC-HCC. The patient sex had an impact on the postsurgical outcomes of patients with NBNC-HCC in DFS.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Intervalo Livre de Doença , Feminino , Hepatectomia , Hepatite B/complicações , Antígenos de Superfície da Hepatite B/sangue , Hepatite C/complicações , Anticorpos Anti-Hepatite C/sangue , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
17.
Int J Surg ; 36(Pt A): 96-103, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27741421

RESUMO

BACKGROUND: Despite improvements in surgery and chemotherapy, most patients develop recurrence after initial hepatectomy for colorectal liver metastasis (CRLM). Following initial hepatectomy for CRLM, patterns and surgical management of recurrence have not been widely reported. MATERIALS AND METHODS: We identified 128 patients who underwent hepatic resection for CRLM between January 2000 and December 2012. Demographics, operative data, site of recurrence, and long-term survival data were collected and analyzed. Patients were stratified into 3 groups based on their site of recurrence as intrahepatic, intra- and extrahepatic, and extrahepatic. In addition, the influence of potential factors on overall survival (OS) in patients with only liver relapse was analyzed through univariate and multivariate analysis. RESULTS: After curative initial hepatectomy, 87 (68.0%) patients had a recurrence: 33 in the intrahepatic group, 11 in the intra- and extrahepatic group, and 43 in the extrahepatic group. The OS for the intra- and extrahepatic group was significantly lower than that for the intrahepatic group. In the intrahepatic group, disease-free interval (DFI) < 12 months and non-repeat hepatectomy were independent poor prognostic factors. Carcinoembryonic antigen (CEA) at the time of hepatectomy was significantly higher in DFI < 12 group than in the DFI ≥ 12 group. CONCLUSION: Patterns of recurrence following initial hepatectomy for CRLM have important implications for OS. In the intrahepatic recurrence group, short DFI was correlated with high CEA at hepatectomy, and was a poor prognostic factor.


Assuntos
Neoplasias Colorretais/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/secundário , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Prognóstico , Reoperação , Estudos Retrospectivos
18.
Surg Case Rep ; 2(1): 111, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27730536

RESUMO

BACKGROUND: Acute acalculous cholecystitis (AAC) is a relatively rare disorder of the gallbladder. Breast cancer recurrence more than 10 years after curative surgery is also infrequent. CASE PRESENTATION: Here, we report a case of a 59-year-old woman who presented with right flank pain. Her medical history included a lumpectomy for cancer of the left breast 12 years prior. Laboratory tests showed a severe inflammatory reaction and mild liver function abnormalities. Ultrasonography and computed tomography revealed an enlarged gallbladder and inflammation of the surrounding tissues; however, no gallstone was present. She was diagnosed with AAC. We performed an emergency laparoscopic cholecystectomy, and histopathological examination revealed a poorly differentiated adenocarcinoma in the cystic duct. Both metastatic and primary tumor cells were positive for estrogen and progesterone receptors on immunohistochemistry. The final pathological diagnosis was acute cholecystitis due to breast cancer metastasis to the cystic duct. CONCLUSION: Although AAC secondary to metastatic breast cancer is rare, it should be included in the differential diagnosis for abdominal pain in patients with a previous history of breast cancer.

19.
Surg Case Rep ; 2(1): 89, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27589984

RESUMO

BACKGROUND: Indocyanine green (ICG) excretory defect is a dye excretory disorder, and it is characterized by the selective impairment of plasma ICG clearance with normal liver histology. The pathophysiology involves selective loss of active transporters for ICG in the hepatic cell membrane. Several cases of hepatectomy in patients with ICG excretory defect have been reported, but the expression of hepatic transporters involved in ICG excretory defect has not been examined in these cases. CASE PRESENTATION: An 81-year-old man who was hepatitis B and C virus negative was admitted to our hospital with a diagnosis of HCC. Abdominal computed tomography revealed an 8-cm-diameter tumor in hepatic segments 4 and 8. The retention rate of ICG at 15 min (ICGR15), which has been used to evaluate hepatic functional reserve, was markedly elevated (79.1 %), whereas other liver function test results, were normal. Therefore, we diagnosed the patient with HCC with an ICG excretory defect, and considered major hepatectomy. Central bisectionectomy was performed, and the postoperative course was uneventful. Microscopic examination of the resected specimen showed moderately differentiated HCC. Immunohistochemical staining and polymerase chain reaction analysis of a non-neoplastic site of the resected specimen showed very few expression of the organic anion-transporting polypeptide 1B3 (OATP1B3), which is usually expressed on the basolateral membrane of human hepatocytes and mediates the uptake of ICG. CONCLUSIONS: In this case, we present a case of hepatectomy for HCC in a patient with ICG excretory defect, which may be attributable to a congenital disorder of OATP1B3 expression; however, an ICG excretory defect did not seem to have any effect on the short-term prognosis after hepatectomy.

20.
Sci Adv ; 2(9): e1600803, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27652340

RESUMO

Genetically modified pigs for biomedical applications have been mainly generated using the somatic cell nuclear transfer technique; however, this approach requires complex micromanipulation techniques and sometimes increases the risks of both prenatal and postnatal death by faulty epigenetic reprogramming of a donor somatic cell nucleus. As a result, the production of genetically modified pigs has not been widely applied. We provide a simple method for CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing in pigs that involves the introduction of Cas9 protein and single-guide RNA into in vitro fertilized zygotes by electroporation. The use of gene editing by electroporation of Cas9 protein (GEEP) resulted in highly efficient targeted gene disruption and was validated by the efficient production of Myostatin mutant pigs. Because GEEP does not require the complex methods associated with micromanipulation for somatic reprogramming, it has the potential for facilitating the genetic modification of pigs.


Assuntos
Animais Geneticamente Modificados/genética , Reprogramação Celular/genética , Miostatina/genética , Técnicas de Transferência Nuclear , Animais , Animais Geneticamente Modificados/crescimento & desenvolvimento , Sistemas CRISPR-Cas , Fertilização In Vitro , Mutação , Edição de RNA/genética , Suínos/genética , Zigoto/crescimento & desenvolvimento
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