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Septic shock treatment remains a major challenge for intensive care units, despite the recent prominent advances in both management and outcomes. Vasopressors serve as a cornerstone of septic shock therapy, but there is still controversy over the timing of administration. Specifically, it remains unclear whether vasopressors should be used early in the course of treatment. Here, we provide a systematic review of the literature on the timing of vasopressor administration. Research was systematically identified through PubMed, Embase and Cochrane searching according to PRISMA guidelines. Fourteen studies met the eligibility criteria and were included in the review. The pathophysiological basis for early vasopressor use was classified, with the exploration on indications for the early administration of mono-vasopressors or their combination with vasopressin or angiotensinII. We found that mortality was 28.1%-47.7% in the early vasopressors group, and 33.6%-54.5% in the control group. We also investigated the issue of vasopressor responsiveness. Furthermore, we acknowledged the subsequent challenge of administration of high-dose norepinephrine via peripheral veins with early vasopressor use. Based on the literature review, we propose a possible protocol for the early initiation of vasopressors in septic shock resuscitation.
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Genetic robustness refers to the fact that an organism has a buffer system that can maintain normal development, even if the existence of genetic mutations during biological development. Previous research on the underlying mechanism of genetic robustness mainly involves in genetic redundancy and distributed robustness, both of which are triggered at the protein level. Recently, a new genetic compensation response (GCR) mechanism has been discovered in zebrafish, which occurs in knockout rather than knockdown individuals and is triggered upstream of protein feedback regulation. Since there are many concepts related to genetic robustness, this review attempts to clarify these concepts from the types of compensation genes and triggering modes. Additionally, we aim to understand the latest discovered GCR mechanism and look forward to studying the function of specific genes based on functional compensation mechanisms.
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The brown planthopper (BPH), Nilaparvata lugens, is an important pest that affects rice (Oryza sativa) production in Asia. The flavone tricin (5,7,4'-trihydroxy-3',5'-dimethoxy flavone) is a valuable secondary metabolite commonly found in rice plants that can defend rice plants against infestation by BPH. BPH damage can reduce the metabolic level of tricin in rice. Our preliminary transcriptome research results showed that BPH salivary protein 7 (NlSP7), is highly responsive to tricin stimuli. However, the function of NlSP7 in mediating the interaction between the rice plant and the BPH is unknown. In this study, we cloned the NlSP7 gene in N. lugens and found that its mRNA level was greater in the presence of high tricin content than low tricin content, regardless of whether the BPHs were fed a rice plant diet or an artificial diet containing 100 mg/L tricin. Knocking down NlSP7 resulted in BPH individuals spending more time in the non-penetration and pathway phase, and less time feeding on the phloem of rice plants. These changes decreased BPH food intake, feeding behavior, and fitness, as well as the tricin content of the rice plants. These findings demonstrate that the salivary protein 7 of BPH functions as an effector for tricin metabolism in rice.
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Flavonoides , Hemípteros , Oryza , Animales , Flavonoides/metabolismo , Hemípteros/genética , Oryza/genética , Oryza/metabolismo , Proteínas y Péptidos Salivales/metabolismoRESUMEN
Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.
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Neoplasias de la Mama , Presentación de Antígeno , Neoplasias de la Mama/tratamiento farmacológico , Endonucleasas/metabolismo , Femenino , Humanos , Proteínas de la Membrana/metabolismo , Nucleasa Microcócica/metabolismo , Proteínas Nucleares/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.
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Endonucleasas/metabolismo , Proteínas de la Membrana/metabolismo , Nucleasa Microcócica , Proteínas de Unión al ARN/metabolismo , Neoplasias de la Mama Triple Negativas , Animales , Moléculas de Adhesión Celular/genética , Humanos , Proteínas de la Membrana/genética , Ratones , Proteínas de Unión al ARN/genética , Factores de TranscripciónRESUMEN
BACKGROUND & AIMS: Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. METHODS: Data from The Cancer Genome Atlas were analyzed for association of XBP1 with colorectal cancer (CRC) survival and molecular interactions between XBP1 and p53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in vitro in mouse models of chronic intestinal epithelial cell (IEC) DNA damage (Xbp1/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. RESULTS: In The Cancer Genome Atlas data set of CRC, low XBP1 expression was significantly associated with poor overall survival and reduced p53 pathway activity. In vivo, H2b/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, and H2b/p53ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA-damage-inducible transcript 4-like (Ddit4l) expression. DDIT4L inhibits mechanistic target of rapamycin-mediated phosphorylation of 4E-binding protein 1. Pharmacologic mechanistic target of rapamycin inhibition suppressed epithelial hyperproliferation via 4E-binding protein 1. CONCLUSIONS: Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L-dependent feedback mechanism.
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Adenocarcinoma/metabolismo , Adenoma/metabolismo , Transformación Celular Neoplásica/metabolismo , Daño del ADN , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Neoplasias Intestinales/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenoma/tratamiento farmacológico , Adenoma/genética , Adenoma/patología , Animales , Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Bases de Datos Genéticas , Estrés del Retículo Endoplásmico , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Inhibidores mTOR/farmacología , Ratones Noqueados , Transducción de Señal , Sirolimus/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. SIGNIFICANCE: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.
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Adenocarcinoma/terapia , Neoplasias Colorrectales/terapia , Neoplasias Pulmonares/terapia , Proteínas de la Membrana/antagonistas & inhibidores , Oligonucleótidos Antisentido/uso terapéutico , Proteínas de Unión al ARN/antagonistas & inhibidores , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Terapia Genética/métodos , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida/métodos , Metástasis de la Neoplasia , Oligonucleótidos/farmacología , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/farmacología , Proteínas de Unión al ARN/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BackgroundSince late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. So far, there is rare data on the prevalence of COVID-19 in patients with chronic myelogenous leukemia (CML). We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. MethodsIn this multicentre, cross-sectional survey, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms(fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19. FindingsOf 392 respondents, 223(56.9%) were males, and 240(61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. InterpretationWhile the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death. FundingThis work was supported by grants from the National Natural Science Foundation of China(NSFC)(81873440&81700142).
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The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.
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Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5ß1, αvß1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.
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Proteínas de la Matriz Extracelular/genética , Integrina alfa5beta1/metabolismo , Lipocalinas/genética , Neoplasias Pulmonares/terapia , Receptores de Vitronectina/metabolismo , Neoplasias de la Mama Triple Negativas/terapia , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Proteínas de la Matriz Extracelular/administración & dosificación , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Lipocalinas/administración & dosificación , Lipocalinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Pronóstico , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Objective: To investigate the efficiency and safety of domestic tyrosine kinase inhibitor (TKI) dasatinib (Yinishu) as second-line treatment for patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods: A retrospective analysis of clinical data of CML-CP patients who received domestic dasatinib as second-line treatment in the CML collaborative group hospitals of Hubei province from March 2016 to July 2018 was performed. The optimal response rate, the cumulative complete cytogenetic response (CCyR), the cumulative major molecular responses (MMR), progression free survival (PFS), event free survival (EFS) and adverse effects (AEs) of the patients were assessed at 3, 6 and 12 months of treatment. Results: A total of 83 CML-CP patients were enrolled in this study. The median follow-up time was 23 months. The optimal response rates at 3, 6 and 12 months in 83 CML-CP patients treated with dasatinib were 77.5% (54/71), 72.6% (61/75) and 60.7% (51/69), respectively. By the end of follow-up, the cumulative CCyR and MMR rates were 65.5% (55/80) and 57.1% (48/73), respectively. The median time to achieving CCyR and MMR was 3 months. During follow-up time, the PFS rate was 94.0% (79/83) and the EFS rate was 77.4% (65/83). The most common non-hematological AEs of dasatinib were edema (32.5%), rash itching (18.1%) and fatigue (13.3%). The common hematological AEs of dasatinib were thrombocytopenia (31.3%), leukopenia (19.3%) and anemia (6.0%). Conclusion: Domestic dasatinib was effective and safe as the second-line treatment of CML-CP patients and it can be used as an option for CML-CP patients.
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Humanos , Antineoplásicos , Dasatinib/uso terapéutico , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Objective@#To investigate the efficiency and safety of domestic tyrosine kinase inhibitor (TKI) dasatinib (Yinishu) as second-line treatment for patients with chronic myeloid leukemia in chronic phase (CML-CP).@*Methods@#A retrospective analysis of clinical data of CML-CP patients who received domestic dasatinib as second-line treatment in the CML collaborative group hospitals of Hubei province from March 2016 to July 2018 was performed. The optimal response rate, the cumulative complete cytogenetic response (CCyR), the cumulative major molecular responses (MMR), progression free survival (PFS), event free survival (EFS) and adverse effects (AEs) of the patients were assessed at 3, 6 and 12 months of treatment.@*Results@#A total of 83 CML-CP patients were enrolled in this study. The median follow-up time was 23 months. The optimal response rates at 3, 6 and 12 months in 83 CML-CP patients treated with dasatinib were 77.5% (54/71), 72.6% (61/75) and 60.7% (51/69), respectively. By the end of follow-up, the cumulative CCyR and MMR rates were 65.5% (55/80) and 57.1% (48/73), respectively. The median time to achieving CCyR and MMR was 3 months. During follow-up time, the PFS rate was 94.0% (79/83) and the EFS rate was 77.4% (65/83). The most common non-hematological AEs of dasatinib were edema (32.5%), rash itching (18.1%) and fatigue (13.3%). The common hematological AEs of dasatinib were thrombocytopenia (31.3%), leukopenia (19.3%) and anemia (6.0%).@*Conclusion@#Domestic dasatinib was effective and safe as the second-line treatment of CML-CP patients and it can be used as an option for CML-CP patients.
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Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.
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Transición Epitelial-Mesenquimal , Metástasis de la Neoplasia/patología , Animales , Cadherinas/metabolismo , Línea Celular Tumoral , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Retroalimentación Fisiológica , Femenino , Ratones Endogámicos BALB C , MicroARNs/genética , MicroARNs/metabolismo , Modelos Biológicos , Metástasis de la Neoplasia/genética , Factor de Crecimiento Transformador beta/farmacología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Macrófagos/fisiología , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/crecimiento & desarrollo , Receptores Notch/metabolismo , Nicho de Células Madre/fisiología , Células Madre/fisiología , Animales , Proteínas de Unión al Calcio , Recuento de Células , Femenino , Técnicas de Inactivación de Genes , Péptidos y Proteínas de Señalización Intercelular/genética , Ligandos , Macrófagos/citología , Glándulas Mamarias Animales/metabolismo , Ratones , Ratones Noqueados , Morfogénesis , Transducción de Señal , Células Madre/citología , Células del Estroma/citología , Células del Estroma/fisiología , Proteínas Wnt/metabolismoRESUMEN
Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.
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Neoplasias de la Mama/metabolismo , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Interferones/metabolismo , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Humanas/metabolismo , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Diferenciación Celular , Movimiento Celular , Autorrenovación de las Células , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Glándulas Mamarias Animales/patología , Glándulas Mamarias Humanas/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Metástasis de la Neoplasia , Células Madre Neoplásicas/patología , Fenotipo , Proteínas Represoras/genética , Transducción de Señal , Factores de Transcripción/genética , Transfección , Microambiente TumoralRESUMEN
Objective:To investigate the expression of insulin-like growth factor binding protein 3 (IGFBP-3) in salivary pleomorphic adenoma(SPA).Methods:The expression of IGFBP-3 protein in 40 cases of SPA(group SPA),40 of normal glandular tissue(group N) and 10 of salivary gland malignant tumor(group CA) was detected by Western blot.The expression of IGFBP-3 mRNA in 50 cases of SPA,50 of salivary gland normal tissue and 10 of CA was detected by qRT-PCR.Results:The expression(A value) of IGFBP-3 protein in group N,SPA and CA was 8.54 ± 3.95,4.78 ± 2.07,3.63 ± 2.27 respectively.The expression ration of IGFBP-3 mRNA of group N vs SPA or CA,P < 0.05;SPA vs CA,P > 0.05 (SPA/N was 0.654 ± 0.387,CA/N:0.452 ± 0.229) respectively,but showed no significance difference between SPA and the CA groups(P > 0.05).Difference of IGFBP-3 mRNA expression was observed with different envelope infiltration of SPA (P < 0.05),no significant difference was observed in different age,gender or relapse groups.Conclusion:IGFBP-3 Low expression of IGFBP-3 in pleomorphic adenomas may reduce the antagonism of IGF-1R,causing the proliferation of tumor cells and promote tumor formation.
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Ybox binding protein1 (YB1) has been identified as an oncoprotein in various malignancies. The aim of this study was to investigate the biological role of YB1 and its association with epithelialtomesenchymal transition (EMT) in colorectal cancer (CRC). The expression of YB1 and three EMTrelated proteins (Ecadherin, Ncadherin and vimentin) was analyzed in 80 CRC and matched normal tissue samples, by immunohistochemistry. The results indicated that the expression of YB1 was higher in CRC tissue samples than that in matched normal controls and was significantly correlated with tumor differentiation, tumor invasion, lymph node metastasis and distant metastases. Furthermore, analysis showed that YB1 expression was negatively correlated with Ecadherin and positively correlated with Ncadherin and vimentin expression. In vitro assays showed that knockdown of YB1 inhibited the proliferation, apoptosis resistance, invasion and migration of the HT29 CRC cell line. Of note, following knockdown of YB1, Ecadherin expression was elevated whereas Ncadherin and vimentin expression was reduced. Taken together, these results suggest that YB1 promotes the malignant progression of CRC in part through the induction of EMT, and YB1 may therefore be a potential novel target for CRC treatment.
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Adenocarcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Adenocarcinoma/secundario , Apoptosis , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Femenino , Técnicas de Silenciamiento del Gen , Células HT29 , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteína 1 de Unión a la Caja Y/biosíntesisRESUMEN
Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores Frizzled/metabolismo , Glándulas Mamarias Humanas/metabolismo , Células Madre/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Vía de Señalización Wnt , Animales , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Epiteliales/metabolismo , Receptores Frizzled/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Humanas/citología , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Microscopía Confocal , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/citología , Factores de Transcripción/genética , Trasplante Heterólogo , Proteínas Supresoras de Tumor/genéticaRESUMEN
OBJECTIVE: To compare laparoscopic Nissen fundoplication (LNF)and Toupet laparoscopic fundoplication (LTF) with respect to treatment outcomes and postoperative complications. METHODS: PubMed, Medline, Embase and the Cochrane Library were searched. Only randomized controlled trials (RCTs) comparing laparoscopic Nissen and Toupet fundoplication were included. Outcomes evaluation included occurrences of heartburn, reflux, difficulty swallowing, chest pain, abdominal distention, failure to hiccup, diarrhea, and early complications and degree of patient satisfaction at early (three to six months) and later (one to three years) post-operative periods. RESULTS: Of 939 patients in seven RCTs, 478 received LNF and 461 received LTF. For both groups, control of reflux was good and occurrence of heartburn was similar (P>0.05). A lower incidence of postoperative dysphagia for both early and later post-operative periods, but a higher overall complication rate in early post-operative period were observed in the LTF group (P<0.05). Patient satisfaction was similar (P>0.05). CONCLUSIONS: LNF and LTF are both safe and effective. The adoption of procedure should be based on the patient status and surgeon experience.
Asunto(s)
Fundoplicación/métodos , Reflujo Gastroesofágico/cirugía , Laparoscopía/métodos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
<p><b>OBJECTIVE</b>To compare laparoscopic Nissen fundoplication (LNF)and Toupet laparoscopic fundoplication (LTF) with respect to treatment outcomes and postoperative complications.</p><p><b>METHODS</b>PubMed, Medline, Embase and the Cochrane Library were searched. Only randomized controlled trials (RCTs) comparing laparoscopic Nissen and Toupet fundoplication were included. Outcomes evaluation included occurrences of heartburn, reflux, difficulty swallowing, chest pain, abdominal distention, failure to hiccup, diarrhea, and early complications and degree of patient satisfaction at early (three to six months) and later (one to three years) post-operative periods.</p><p><b>RESULTS</b>Of 939 patients in seven RCTs, 478 received LNF and 461 received LTF. For both groups, control of reflux was good and occurrence of heartburn was similar (P>0.05). A lower incidence of postoperative dysphagia for both early and later post-operative periods, but a higher overall complication rate in early post-operative period were observed in the LTF group (P<0.05). Patient satisfaction was similar (P>0.05).</p><p><b>CONCLUSIONS</b>LNF and LTF are both safe and effective. The adoption of procedure should be based on the patient status and surgeon experience.</p>