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1.
Front Cell Dev Biol ; 9: 779373, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869383

RESUMO

The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6-8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.

2.
Cancer Manag Res ; 13: 4567-4578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135633

RESUMO

Background: Circulating tumor cells (CTCs) are cells that have been shed into the vasculature from a primary tumor and circulate in the bloodstream. It has been suggested that detecting CTCs could help the clinician to detect early metastasis or recurrence more effectively. This trial sets out to assess the detection and clinical value of CTCs as an assisted prognostic marker in patients with colon cancer and rectal cancer. Methods: A prospective cohort of patients with colorectal cancer (CRC) was enrolled from July 2015 to February 2018 in Shanghai Minimally Invasive Surgery Center, Shanghai, China. In this study, 149 patients with CRC were enrolled and underwent surgical treatment. There were 79 cases of colon cancer and 70 cases of rectal cancer, including 93 males and 56 females. To investigate the correlativity and clinical value of CTCs, the patients were statistically analyzed in different subgroups: colon cancer group vs rectal cancer group, and left hemicolon cancer group vs right hemicolon cancer group. Results: The results of analysis comparing CTC counts and clinical pathological features in colon and rectal cancer indicated that with increased tumor stage, the number of CTCs also increased, with significant statistical differences. CTC counts in patients with colon and rectal cancer showed positive correlations with TNM staging (P=0.001, 0.013, respectively), T staging (P=0.021, 0.001), N staging (P=0.014, 0.035) and M staging (P=0.018, 0.203). Detection of serum biomarkers in CTC-positive and CTC-negative groups indicated a significantly increasing expression in the CTC-positive group. To confirm the correlations between CTCs and histoembryological differences, analysis was conducted with the patients in two subgroups: left hemicolon cancer group and right hemicolon cancer group. The results showed that the positive rate of CTCs increased in both groups with the increase in tumor stage. The survival analysis indicated that there was a steep gradient in survival in the follow-up period, particularly in the CTC-positive group (P=0.000). Risk assessment curves showed that the change escalated more rapidly in the CTC-positive group. Furthermore, with the increase in T stage, changes in the survival curve and risk curve escalated more rapidly in the CTC-positive group. Conclusion: It was confirmed that in the left hemicolon cancer group, a much higher coincidence rate could be found on CTC-positive rate and clinicopathological features, than in the right hemicolon cancer group. The sensitivity of CTCs may be related to the histoembryological location of the tumor, lymphatic metastasis and the depth of infiltration. Monitoring CTCs may have value in evaluating clinical staging and estimating clinical prognosis.

3.
World J Gastrointest Surg ; 13(3): 267-278, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33796215

RESUMO

BACKGROUND: Neoadjuvant therapy (NAT) is becoming increasingly important in locally advanced rectal cancer. Hence, such research has become a problem. AIM: To evaluate the downstaging effect of NAT, its impact on postoperative complications and its prognosis with different medical regimens. METHODS: Seventy-seven cases from Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine were retrospectively collected and divided into the neoadjuvant radiochemotherapy (NRCT) group and the neoadjuvant chemotherapy (NCT) group. The differences between the two groups in tumor regression, postoperative complications, rectal function, disease-free survival, and overall survival were compared using the χ 2 test and Kaplan-Meier analysis. RESULTS: Baseline data showed no statistical differences between the two groups, whereas the NRCT group had a higher rate of T4 (30/55 vs 5/22, P < 0.05) than the NCT groups. Twelve cases were evaluated as complete responders, and 15 cases were evaluated as tumor regression grade 0. Except for the reduction rate of T stage (NRCT 37/55 vs NCT 9/22, P < 0.05), there was no difference in effectiveness between the two groups. Preoperative radiation was not a risk factor for poor reaction or anastomotic leakage. No significant difference in postoperative complications and disease-free survival between the two groups was observed, although the NRCT group might have better long-term overall survival. CONCLUSION: NAT can cause tumor downstaging preoperatively or even complete remission of the primary tumor. Radiochemotherapy could lead to better T downstaging and promising overall survival without more complications.

4.
J Surg Oncol ; 123 Suppl 1: S8-S14, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33818776

RESUMO

BACKGROUND: The prognosis of patients with locally advanced gastric cancer with outlet obstruction is poor. Gastrectomy with curative intent is often initially impossible or difficult. OBJECTIVE: We report our experience of curative distal gastrectomy after laparoscopic gastrojejunostomy and fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy to examine the feasibility and safety of this modified strategy for locally advanced gastric cancer with outlet obstruction, initially deemed unresectable. METHODS: Between October 2017 and June 2019, 15 patients diagnosed with locally advanced gastric cancer with outlet obstruction sequentially underwent gastrojejunostomy, received four cycles of FLOT chemotherapy, and underwent laparoscopic distal gastrectomy with curative intent (R0 resection + D2 lymphadenectomy). Clinical data were retrospectively collected and analyzed. RESULTS: R0 resection was possible in 12/15 patients, laparoscopically in 11, and one conversion to laparotomy was necessary. There was no perioperative mortality in the 12 patients. Pathologic evaluation of the resected specimens revealed that complete tumor grade regression 1a (TRG1a), TRG1b, TRG2, and TRG3 occurred in 3, 2, 4, and 3 patients, respectively. CONCLUSION: This case series showed that curative surgical resection was feasible as a staged approach for patients with locally advanced gastric cancer with outlet obstruction, after initial staged gastrojejunostomy and chemotherapy.


Assuntos
Obstrução da Saída Gástrica/cirurgia , Neoplasias Gástricas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Gastrectomia/métodos , Derivação Gástrica/métodos , Obstrução da Saída Gástrica/etiologia , Obstrução da Saída Gástrica/patologia , Humanos , Infusões Intravenosas , Laparoscopia/métodos , Leucovorina/administração & dosagem , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Omento/cirurgia , Oxaliplatina/administração & dosagem , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia
5.
J Surg Oncol ; 123 Suppl 1: S65-S75, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33646594

RESUMO

BACKGROUND AND OBJECTIVES: We compared the 3-year overall survival between cephalomedial-to-lateral approach proctectomy (CEMP) and medial-to-lateral approach proctectomy (MAP) in patients undergoing laparoscopic total mesorectal excision for rectal cancer. The advantages of CEMP and the clinical value of No. 253 lymph nodes resection have not been objectively analyzed in literature. METHODS: This was a prospective, two-arm, multicenter, single-blinded, randomized trial. The primary endpoint was 3-year overall survival, and secondary endpoints included safety, feasibility, oncological radicality (including number of No. 253 lymph nodes harvested), short-term outcome, 3-year disease-free survival, rate of postoperative complications, mortality, and rate of recurrence. RESULTS: From May 2016 to July 2020, 506 patients were enrolled-256 in the CEMP group and 250 in the MAP group. Comparison of overall survival and disease-free survival showed that there was treatment benefit in the CEMP group (28.22 ± 12.12 vs. 27.44 ± 13.06, p = 0.485; 27.24 ± 12.01 vs. 26.42 ± 12.81; p = 0.457). More No. 253 lymph nodes were harvested in the CEMP group, and cases with positive No. 253 lymph nodes had worse prognosis in stage III. Surgical safety was equal for both approaches. CONCLUSIONS: Dissection of No. 253 lymph nodes may be important to improve clinical prognosis, but further studies with larger samples are needed to confirm this finding.


Assuntos
Neoplasias Retais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pós-Operatório , Protectomia/métodos , Estudos Prospectivos , Neoplasias Retais/patologia , Resultado do Tratamento , Adulto Jovem
6.
J Surg Oncol ; 123 Suppl 1: S59-S64, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33650698

RESUMO

Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer. taTME is associated with the benefits of a higher rate of free distal resection margins (DRM) under direct visualization, better visualization of the mesorectal plane, and the feasibility of overcoming the restriction of the distal pelvis. Thus, it is increasingly used globally. In this review, we investigated whether taTME yields better short- and long-term outcomes than laparoscopic TME.


Assuntos
Neoplasias Retais/cirurgia , Consenso , Estudos de Viabilidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Cirurgia Endoscópica Transanal/métodos , Cirurgia Endoscópica Transanal/normas
8.
J Surg Oncol ; 123 Suppl 1: S81-S87, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33740257

RESUMO

BACKGROUND AND OBJECTIVES: To investigate the effects of different suture reinforcement methods for anastomotic leakage and other postoperative complications after the use of a laparoscopic double stapling technique (DST). METHODS: We collected the data of 124 patients who underwent laparoscopic radical resection of colorectal cancer from July 2017 to September 2018 at our institution. Patients were divided into three groups according to the suture reinforcement methods: intermittent, continuous suture reinforcement, and non-reinforcement (n = 41, 41, and 42, respectively). One-way analysis of variance, χ2 , Fisher's exact, and nonparametric tests were used for statistical analysis. RESULTS: Among the 124 patients, there were no statistically significant differences in operation times, intraoperative blood loss, postoperative hospital stays and recovery of bowel movement. Nine patients were diagnosed with anastomotic leakage (AL). The incidences of serious AL in the intermittent and continuous suture reinforcement groups were lower than that in the control group, with lower reoperation rate, shorter average lengths of stay and lower treatment costs of two experimental groups. CONCLUSION: Intermittent and continuous sutures after laparoscopic DST is effective, safe, and feasible on anastomotic leakage prevention. These procedures could be popularized in rectal surgery on patients with high risk of AL.


Assuntos
Anastomose Cirúrgica/métodos , Fístula Anastomótica/prevenção & controle , Neoplasias Colorretais/cirurgia , Anastomose Cirúrgica/efeitos adversos , Perda Sanguínea Cirúrgica , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Front Cell Dev Biol ; 9: 620883, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33614649

RESUMO

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/ß-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/ß-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.

10.
Neurosci Bull ; 37(4): 478-496, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33355899

RESUMO

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.


Assuntos
Nociceptores , Transmissão Sináptica , Animais , Proteínas de Membrana/metabolismo , Camundongos , Neurônios/metabolismo , Dor , Substância Cinzenta Periaquedutal
11.
Yi Chuan ; 42(8): 810-816, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952116

RESUMO

Medical Genetics is an important research content of basic medicine and closely related to clinical medicine. Medical Genetics can not only lay a solid theoretical foundation for understanding medical problems for medical students, but also provide them an indispensable technical means for clinical medical practice. In order to improve students' understanding and mastery of the core content of Medical Genetics and cultivate senior medical talents with innovative spirit and independent thinking abilities, the PBL (problem-based learning) teaching method was introduced in the teaching of medical genetics for students enrolled in the eight-year medical education program. By integrating formative evaluation and teaching feedback mechanism into PBL teaching, we have achieved good teaching effects. In this paper, we will discuss the importance and necessity of formative evaluation and teaching feedback in PBL teaching, introduce the PBL teaching plan, teaching process and teaching effect of Medical Genetics in our school, share our thoughts on PBL teaching mode, and provide new ideas for the teaching reform of Medical Genetics.


Assuntos
Educação Médica , Genética Médica , Ensino , Educação Médica/normas , Genética Médica/educação , Humanos , Aprendizagem Baseada em Problemas , Estudantes de Medicina , Ensino/normas
12.
Cell Commun Signal ; 18(1): 135, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32843056

RESUMO

BACKGROUND: Glioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated. METHODS: Human samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies. RESULTS: Infection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells. CONCLUSION: ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling. Video abstract.


Assuntos
Infecções por Adenoviridae/complicações , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 88 de Diferenciação Mieloide/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
13.
Gastroenterol Rep (Oxf) ; 8(3): 167-174, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32661490

RESUMO

Novel coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing public-health pandemic worldwide. Although SARS-CoV-2 has been known to spread primarily through respiratory droplets, recent evidence also supports fecal/oral as an additional route of transmission, raising concerns over gastrointestinal (GI) transmission of the infection. Herein, we, as the front-line Chinese GI surgeons, would like to share our experience and lessons in the combat against COVID-19. It is essential to create science-based, rational, and practical strategies during the outbreak of COVID-19. Here, we provide multi-institutional consensus on minimizing disease transmission while continuing to provide care from all aspects for patients in GI surgery, including outpatient clinics, inpatient units, gastrointestinal endoscopy centers, and adjustments in perioperative care. Our experiences and recommendations are worth sharing and may help to establish specific infection-control and outcome measures.

14.
Nat Commun ; 11(1): 1720, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249768

RESUMO

Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.


Assuntos
Carcinogênese/genética , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/metabolismo , Proteínas F-Box/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linhagem Celular Tumoral , Cromatografia Líquida , Neoplasias Colorretais/genética , Citoplasma/metabolismo , Proteínas F-Box/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/genética , RNA Interferente Pequeno , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/genética , Espectrometria de Massas em Tandem , Análise Serial de Tecidos , Transplante Heterólogo , Ubiquitinação
16.
Int J Oncol ; 56(2): 606-617, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894296

RESUMO

Abnormal metabolism serves a critical role in the development and progression of different types of malignancies including glioblastoma (GBM), and may therefore serve as a promising target for treatment of cancer. Preclinical studies have indicated that a ketogenic diet (KD) may exhibit beneficial effects in patients with GBM; however, the underlying mechanisms remain incompletely understood. The aim of the present study was to evaluate the effects of a KD on glioma stem­like cells (GSCs), by culturing patient­derived primary GSCs as well as a GSC cell line in glucose­restricted, ß­hydroxybutyrate­containing medium (BHB­Glow) which was used to mimic clinical KD treatment. GSCs cultured in BHB­Glow medium exhibited reduced proliferation and increased apoptosis compared with cells grown in the control medium. Furthermore, decreased expression of stem cell markers, diminished self­renewal in vitro, and reduced tumorigenic capacity in vivo, providing evidence that the stemness of GSCs was compromised. Mechanistically, culturing in BHB­Glow medium reduced glucose uptake and inhibited glycolysis in GSCs. Furthermore, culturing in the BHB­Glow medium resulted in morphological and functional disturbances to the mitochondria of GSCs. These metabolic changes may have reduced ATP production, promoted lactic acid accumulation, and thus, increased the production of reactive oxygen species (ROS) in GSCs. The expression levels and activation of mammalian target of rapamycin, hypoxia­inducible factor 1 and B­cell lymphoma 2 were decreased, consistent with the reduced proliferation of GSCs in BHB­Glow medium. ROS scavenging reversed the inhibitory effects of a KD on GSCs. Taken together, the results demonstrate that treatment with KD inhibited proliferation of GSCs, increased apoptosis and attenuated the stemness in GSCs by increasing ROS production.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Neoplasias Encefálicas/dietoterapia , Dieta Cetogênica , Glioblastoma/dietoterapia , Células-Tronco Neoplásicas/patologia , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Proliferação de Células/efeitos dos fármacos , Meios de Cultura/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Glioblastoma/cirurgia , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas , Adulto Jovem
17.
Cell Death Dis ; 10(12): 869, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740664

RESUMO

Extracellular vesicles (EVs) including exosomes can serve as mediators of cell-cell communication under physiological and pathological conditions. However, cargo molecules carried by EVs to exert their functions, as well as mechanisms for their regulated release and intake, have been poorly understood. In this study, we examined the effects of endothelial cells-derived EVs on neurons suffering from oxygen-glucose deprivation (OGD), which mimics neuronal ischemia-reperfusion injury in human diseases. In a human umbilical endothelial cell (HUVEC)-neuron coculture assay, we found that HUVECs reduced apoptosis of neurons under OGD, and this effect was compromised by GW4869, a blocker of exosome release. Purified EVs could be internalized by neurons and alleviate neuronal apoptosis under OGD. A miRNA, miR-1290, was highly enriched in HUVECs-derived EVs and was responsible for EV-mediated neuronal protection under OGD. Interestingly, we found that OGD enhanced intake of EVs by neurons cultured in vitro. We examined the expression of several potential receptors for EV intake and found that caveolin-1 (Cav-1) was upregulated in OGD-treated neurons and mice suffering from middle cerebral artery occlusion (MCAO). Knock-down of Cav-1 in neurons reduced EV intake, and canceled EV-mediated neuronal protection under OGD. HUVEC-derived EVs alleviated MCAO-induced neuronal apoptosis in vivo. These findings suggested that ischemia likely upregulates Cav-1 expression in neurons to increase EV intake, which protects neurons by attenuating apoptosis via miR-1290.


Assuntos
Caveolina 1/metabolismo , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Animais , Apoptose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
18.
Surg Laparosc Endosc Percutan Tech ; 29(6): 476-482, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31259865

RESUMO

BACKGROUND: Laparoscopy-assisted gastrectomy (LAG) has been proven to be feasible and oncologically safe for early gastric cancer. Despite the rapid increase in the number of LAG cases, there are few reports on the long-term outcomes of T4a (serosalinvasion) gastric cancer after LAG. The aim of the present study was to evaluate the long-term clinical outcomes in patients with stage T4a gastric cancer after laparoscopic gastrectomy. MATERIALS AND METHODS: A total of 578 patients with gastric cancer were treated with LAG between February 2004 and December 2014. Among these patients, 224 patients were pathologically confirmed with T4a advanced gastric cancer. The clinical and follow-up data were retrospectively analyzed, the survival rates were estimated using the Kaplan-Meier method, and the risk factors for overall and disease-free survival (DFS) were evaluated by Cox regression. RESULTS: Among these 224 patients, 129 patients were above 60 years old, and the male-to-female ratio was 157:67. Furthermore, among these patients, 125 patients received laparoscopy-assisted distal gastrectomy, whereas 99 patients received laparoscopy-assisted total gastrectomy. Forty (17.90%) patients experienced postoperative complications according to the Clavien-Dindo classification. Median follow-up time was 32 months. Recurrence was observed in 99 (44.20%) patients. The cumulative 5-year overall survival (OS) and DFS rates were 47.20% and 43.60%, respectively. The 5-year OS and DFS rates were 72.50% and 70.00% for stage N0, 57.00% and 53.90% for stage N1, 41.60% and 37.00% for stage N2, and 23.30% and 21.30% for stage N3, respectively. In the univariate analysis, tumor size, tumor location, N stage and metastatic lymph node ratio (MLR) were correlated with OS and DFS. The MLR was identified as an independent predictor for OS (P<0.05; hazard ratio=1.828; 95% confidence interval, 1.353-2.469) and DFS (P<0.05; hazard ratio=1.197; 95% confidence interval, 0.945-1.516). CONCLUSIONS: The long-term outcomes of LAG for T4a (M0) gastric cancer were acceptable, compared with previous reports. Therefore, this treatment could be considered as an alternative operative approach for T4a gastric cancer. The MLR was an independent predictor for OS and DFS.


Assuntos
Adenocarcinoma/cirurgia , Gastrectomia/métodos , Laparoscopia/métodos , Estadiamento de Neoplasias , Neoplasias Gástricas/cirurgia , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundário , China/epidemiologia , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento
19.
Biochem Biophys Res Commun ; 514(3): 842-847, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-31079925

RESUMO

Mammalian neural stem cells (NSCs) are not only responsible for normal development of the central nervous system (CNS), but also participate in brain homeostasis and repair, thus hold promising clinical potentials in the treatment of neurodegenerative diseases and trauma. However the molecular networks regulating the stemness and differentiation of NSCs have not been fully understood. In this study, we show that Tweety-homolog 1 (Ttyh1), a five-pass transmembrane protein specifically expressed in mouse brain, is involved in maintaining stemness of murine NSCs. Blocking or activating Notch signal led to downregulation and upregulation of Ttyh1 in cultured NSCs, respectively, suggesting that Ttyh1 is under the control of Notch signaling. Knockdown of Ttyh1 in cultured NSCs resulted in a transient increase in the number and size of neurospheres, followed by a decrease of stemness as manifested by compromised neurosphere formation, downregulated stem cell markers, and increased neuronal differentiation. We generated Ttyh1 knockout mice by deleting its exon 4 using the CRISPR-Cas9 technology. Surprisingly, in contrast to a previous report, Ttyh1 knockout did not result in embryonic lethality. NSCs derived from Ttyh1 knockout mice phenocopied NSCs transfected with Ttyh1 siRNA. Immunofluorescence showed that loss of Ttyh1 leads to the increase of neurogenesis in adult mice. Taken together, these findings indicate that Ttyh1, which is likely downstream to Notch signaling, plays an important role in regulating NSCs.


Assuntos
Diferenciação Celular , Proteínas de Membrana/deficiência , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Perda do Embrião/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neurogênese
20.
Cell Death Dis ; 10(3): 178, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30792394

RESUMO

The mechanisms underlying the role of CXCL5 in tumor angiogenesis have not been fully defined. Here, we examined the effect of CXCL5 on tumor angiogenesis in colorectal cancer (CRC). Immunohistochemistry was used to monitor the expression of CXCL5 and CD31 in CRC patients' tissues. HUVEC cell lines stably transfected with shCXCR2 and shFOXD1 lentivirus plasmids were used in an in vitro study. Based on some molecular biological experiments in vitro and in vivo, we found that CXCL5 was upregulated in tumor tissues and that its level positively correlated with the expression of CD31. Next, we used recombinant human CXCL5 (rhCXCL5) to stimulate HUVECs and found that their tube formation ability, proliferation, and migration were enhanced by the activation of the AKT/NF-κB/FOXD1/VEGF-A pathway in a CXCR2-dependent manner. However, silencing of CXCR2 and FOXD1 or inhibition of the AKT and NF-κB pathways could attenuate the tube formation ability, proliferation, and migration of rhCXCL5-stimulated HUVECs in vitro. rhCXCL5 can promote angiogenesis in vivo in Matrigel plugs, and the overexpression of CXCL5 can also increase microvessel density in vivo in a subcutaneous xenotransplanted tumor model in nude mice. Taken together, our findings support CXCL5 as an angiogenic factor that can promote cell metastasis through tumor angiogenesis in CRC. Furthermore, we propose that FOXD1 is a novel regulator of VEGF-A. These observations open new avenues for therapeutic application of CXCL5 in tumor anti-angiogenesis.


Assuntos
Quimiocina CXCL5/metabolismo , Neoplasias Colorretais/metabolismo , Fatores de Transcrição Forkhead/metabolismo , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL5/genética , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/genética , Fatores de Transcrição Forkhead/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Análise de Sequência com Séries de Oligonucleotídeos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/metabolismo , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/genética , Transplante Heterólogo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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