ABSTRACT
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.
Subject(s)
Adenocarcinoma/metabolism , Adenoma/metabolism , Cell Transformation, Neoplastic/metabolism , DNA Damage , Epithelial Cells/metabolism , Intestinal Mucosa/metabolism , Intestinal Neoplasms/metabolism , X-Box Binding Protein 1/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenoma/drug therapy , Adenoma/genetics , Adenoma/pathology , Animals , Cell Cycle Proteins/metabolism , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Databases, Genetic , Endoplasmic Reticulum Stress , Epithelial Cells/drug effects , Epithelial Cells/pathology , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Neoplasms/drug therapy , Intestinal Neoplasms/genetics , Intestinal Neoplasms/pathology , MTOR Inhibitors/pharmacology , Mice, Knockout , Signal Transduction , Sirolimus/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , X-Box Binding Protein 1/geneticsABSTRACT
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.
ABSTRACT
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.
Subject(s)
Breast Neoplasms , Antigen Presentation , Breast Neoplasms/drug therapy , Endonucleases/metabolism , Female , Humans , Membrane Proteins/metabolism , Micrococcal Nuclease/metabolism , Nuclear Proteins/genetics , RNA-Binding Proteins/metabolism , Transcription Factors/metabolismABSTRACT
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.
Subject(s)
Flavonoids , Hemiptera , Oryza , Animals , Flavonoids/metabolism , Hemiptera/genetics , Oryza/genetics , Oryza/metabolism , Salivary Proteins and Peptides/metabolismABSTRACT
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.
Subject(s)
Endonucleases/metabolism , Membrane Proteins/metabolism , Micrococcal Nuclease , RNA-Binding Proteins/metabolism , Triple Negative Breast Neoplasms , Animals , Cell Adhesion Molecules/genetics , Humans , Membrane Proteins/genetics , Mice , RNA-Binding Proteins/genetics , Transcription FactorsABSTRACT
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.
Subject(s)
Adenocarcinoma/therapy , Colorectal Neoplasms/therapy , Lung Neoplasms/therapy , Membrane Proteins/antagonists & inhibitors , Oligonucleotides, Antisense/therapeutic use , RNA-Binding Proteins/antagonists & inhibitors , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cells, Cultured , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Genetic Therapy/methods , HEK293 Cells , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Molecular Targeted Therapy/methods , Neoplasm Metastasis , Oligonucleotides/pharmacology , Oligonucleotides/therapeutic use , Oligonucleotides, Antisense/pharmacology , RNA-Binding Proteins/genetics , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To evaluate the feasibility of multi-slice spiral CT scan to localize upper airway stricture in patients with obstructive sleep apnea syndrome (OSAS) during drug-induced sleeping. METHODS: One hundred and fourteen patients diagnosed as OSAS by polysomnography were included in the study. Multi-slice spiral CT scan covering upper airway was performed at the end of inspiration and clear upper airway images were obtained in waking. After injecting 5 mg of midazolam intravenously slowly in 109 patients, CT scan was performed at apnea and clear upper airway images were obtained in sleeping. Cross-section area and minimal diameter of airway were measured and the parameters were compared under those two states. Upper airway was displayed intuitionisticly by using post-processing techniques. RESULTS: One hundred and nine patients with OSAS finished the examination with a success rate of 100 %. Airway obstruction at retropalatal level was observed in 62 patients, among whom 26 were associated with airway obstruction at retroglossal level, 27 with narrower airway at retroglossal level in sleeping compared with that in waking, and 9 with no significant change of the airway at retroglossal level after sleeping. Narrower airway at retropalatal level in sleeping compared with that in waking was observed in 40 patients, among whom 20 were associated with narrower airway at retroglossal level in sleeping compared with that in waking, 10 with complete airway obstruction at retroglossal level in sleeping, and 7 with no significant change of the airway at both retropalatal and retroglossal levels before and after sleeping. Minimal mean cross-section area of airway at retropalatal level was (72.60 +/-45.15)mm(2) in waking and (8.26 +/-18.16)mm(2) in sleeping; and minimal mean cross-section area of airway at retroglossal level was (133.21 +/-120.36)mm(2)in waking and (16.73 +/-30.21)mm(2) in sleeping (P <0.01). Minimal mean diameter of airway at retropalatal level was (6.91 +/-2.23) mm in waking and (1.18 +/-2.14) mm in sleeping; and minimal mean diameter of airway at retroglossal level was (8.68 +/-4.32) mm in waking and (1.68 +/-2.22) mm in sleeping (P <0.01). CONCLUSION: Multi-slice spiral CT with post-processing techniques can display the shape of the upper airway in patients with OSAS in sleeping, and can localize the upper airway stricture and assess its range accurately.
Subject(s)
Airway Obstruction/diagnostic imaging , Oropharynx/physiopathology , Palate, Soft/physiopathology , Sleep Apnea, Obstructive/diagnostic imaging , Tomography, Spiral Computed , Adult , Aged , Female , Humans , Hypnotics and Sedatives/administration & dosage , Male , Middle Aged , Young AdultABSTRACT
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.
ABSTRACT
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.
Subject(s)
Extracellular Matrix Proteins/genetics , Integrin alpha5beta1/metabolism , Lipocalins/genetics , Lung Neoplasms/therapy , Receptors, Vitronectin/metabolism , Triple Negative Breast Neoplasms/therapy , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , ErbB Receptors/metabolism , Extracellular Matrix Proteins/administration & dosage , Extracellular Matrix Proteins/metabolism , Female , Focal Adhesion Kinase 1/metabolism , Gene Expression Regulation, Neoplastic , Humans , Lipocalins/administration & dosage , Lipocalins/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Mice , Prognosis , Signal Transduction , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolismABSTRACT
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.
ABSTRACT
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.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Macrophages/physiology , Mammary Glands, Animal/cytology , Mammary Glands, Animal/growth & development , Receptors, Notch/metabolism , Stem Cell Niche/physiology , Stem Cells/physiology , Animals , Calcium-Binding Proteins , Cell Count , Female , Gene Knockout Techniques , Intercellular Signaling Peptides and Proteins/genetics , Ligands , Macrophages/cytology , Mammary Glands, Animal/metabolism , Mice , Mice, Knockout , Morphogenesis , Signal Transduction , Stem Cells/cytology , Stromal Cells/cytology , Stromal Cells/physiology , Wnt Proteins/metabolismABSTRACT
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.
Subject(s)
Epithelial-Mesenchymal Transition , Neoplasm Metastasis/pathology , Animals , Cadherins/metabolism , Cell Line, Tumor , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition/drug effects , Feedback, Physiological , Female , Mice, Inbred BALB C , MicroRNAs/genetics , MicroRNAs/metabolism , Models, Biological , Neoplasm Metastasis/genetics , Transforming Growth Factor beta/pharmacology , Zinc Finger E-box-Binding Homeobox 1/metabolismABSTRACT
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.
Subject(s)
Breast Neoplasms/metabolism , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Interferons/metabolism , Mammary Glands, Animal/metabolism , Mammary Glands, Human/metabolism , MicroRNAs/metabolism , Neoplastic Stem Cells/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Differentiation , Cell Movement , Cell Self Renewal , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , HEK293 Cells , HeLa Cells , Humans , MCF-7 Cells , Mammary Glands, Animal/pathology , Mammary Glands, Human/pathology , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/genetics , Neoplasm Metastasis , Neoplastic Stem Cells/pathology , Phenotype , Repressor Proteins/genetics , Signal Transduction , Transcription Factors/genetics , Transfection , Tumor MicroenvironmentABSTRACT
OBJECTIVE: To study the effect of insulin on cardiac functional recovery, coronary blood flow (CBF), coronary arterial function and coronary vascular endothelial cell apoptosis following acute myocardial ischemia/reperfusion (MI/R). METHODS: In adult dogs, the left anterior descending coronary artery (LAD) was partially occluded (80% reduction in its blood flow) for 50 min and reperfused for 4 h. Vehicle (0.9% NaCl), GIK (glucose: 250 gxL(-1), insulin: 60 UxL(-1), potassium: 80 mmolxL(-1)), or GK (glucose: 250 gxL(-1), potassium: 80 mmolxL(-1)) were intravenously infused (2 mlxkg(-1)xh(-1)) 5 min before reperfusion, and CBF and left ventricular pressure were monitored. At the end of 4 h reperfusion period, coronary arteries were isolated, and the coronary vascular dysfunction, nitric oxide (NO) production and endothelial apoptosis were determined. RESULTS: During reperfusion, compared with the vehicle, GIK increased CBFLAD (19.2 ml/min +/- 2.2 ml/min) vs (14.6 ml/min +/- 1.8 ml/min) of vehicle at the end of reperfusion, P < 0.05, improved recovery of LVSP and +/- LVdP/dtmax. In vivo ischemia/reperfusion caused significant coronary vascular endothelial dysfunction as evidenced by reduced endothelium dependent vasorelaxation, decreased total NO production, and endothelial cell apoptosis as determined by TUNEL staining. Reperfusion with GIK, but not GK, markedly improved the endothelium-dependent vasorelaxation (80.3% +/- 3.8%) vs. vehicle (28.1% +/- 2.3%, P < 0.01) of coronary artery in response to ACh. GIK significantly increased total NO production (17.19 micromol/L +/- 2.18 micromol/L) versus vehicle (4.74 micromol/L +/- 2.01 micromol/L, P < 0.01) and inhibited apoptosis in coronary arterial endothelial cell (12% +/- 4%) vs vehicle (45% +/- 7%, P < 0.01). GK failed to show any significant vasculoprotection against MI/R-induced coronary vascular injury. CONCLUSION: These results demonstrate that insulin exerts cardioprotective effect by increasing CBF, reducing coronary artery injury and improving cardiac functional recovery during reperfusion, which may be partly attributable to the coronary vasculoprotective effect of insulin. The insulin-induced, NO-mediated anti-endothelial apoptotic effect may play a critical role in the insulin-induced coronary artery protective effect in MI/R.
Subject(s)
Coronary Circulation/drug effects , Insulin/pharmacology , Myocardial Reperfusion Injury/physiopathology , Acute Disease , Animals , Apoptosis/drug effects , Blood Flow Velocity/drug effects , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Disease Models, Animal , Dogs , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Female , Glucose/pharmacology , Male , Nitric Oxide/metabolism , Potassium/pharmacology , Ventricular Dysfunction, Left/physiopathologyABSTRACT
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.
Subject(s)
Breast Neoplasms/metabolism , Frizzled Receptors/metabolism , Mammary Glands, Human/metabolism , Stem Cells/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Wnt Signaling Pathway , Animals , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Epithelial Cells/metabolism , Frizzled Receptors/genetics , Gene Expression Regulation, Neoplastic , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Mammary Glands, Animal/cytology , Mammary Glands, Animal/metabolism , Mammary Glands, Human/cytology , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Mice, Transgenic , Microscopy, Confocal , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/cytology , Transcription Factors/genetics , Transplantation, Heterologous , Tumor Suppressor Proteins/geneticsABSTRACT
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.
Subject(s)
Adenocarcinoma/metabolism , Colorectal Neoplasms/metabolism , Y-Box-Binding Protein 1/genetics , Adenocarcinoma/secondary , Apoptosis , Cell Movement , Cell Proliferation , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition , Female , Gene Knockdown Techniques , HT29 Cells , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Invasiveness , Y-Box-Binding Protein 1/biosynthesisABSTRACT
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.
ABSTRACT
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.
Subject(s)
Humans , Antineoplastic Agents , Dasatinib/therapeutic use , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors , Retrospective Studies , Treatment OutcomeABSTRACT
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.
ABSTRACT
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.