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Objective: To explore the effect of the bromodomain and WD repeat domain containing 3 (BRWD3) on lymph node metastasis in breast cancer and its mechanism. Methods: In vitro cell invasion experiments were used to explore the effect of BRWD3 on the invasion phenotype of breast cancer cell lines. Mouse lymph node metastasis model and lung metastasis model were used to investigate the role of BRWD3 in regulating breast cancer lymph node metastasis and lung metastasis in BALB/c nude mice. The BRWD3 co-expressed genes were searched through cBioPortal databases to analyze the biological functions and pathways of BRWD3, constructed a BRWD3 molecular regulatory network, which is examined with Western blotting analysis partly. The public breast cancer dataset and the KMPLOT analysis platform was used to analyze the expression of BRWD3 in breast cancer and the relationship between the expression of BRWD3 and breast cancer prognosis. Results: In vitro experiments showed that knockdown of BRWD3 significantly enhanced the invasion and migration of breast cancer cells (P<0.01), but did not promote their proliferation. The lymph node metastasis model demonstrated that knockdown of BRWD3 dramatically enhanced lymph node metastasis of breast cancer. Interestingly, the lung metastasis model showed that BRWD3 did not affect the mouse lung metastasis ability. Further functional clustering GO analysis of the co-expressed genes of BRWD3 suggested that they are mainly involved in gene expression regulation, DNA damage repair, chromosome organization and modification, ubiquitination, etc. Meanwhile, KEGG enrichment analysis showed that they were involved in signaling pathways such as ubiquitination, oxidative phosphorylation, MAPK, etc. Besides, via the Western blotting experiment, it was found that knockdown of BRWD3 increased the phosphorylation of ERK1/2. Moreover, BRWD3 expression in breast cancer with lymph node metastasis is significantly lower than in patients without lymph node metastasis. Further, the survival analysis in KMPLOT found that the prognosis of patients with low expression of BRWD3 was poor, which was significantly lower than that of patients with high expression of BRWD3. Conclusions: BRWD3 can regulate breast cancer invasion in vitro and lymph node metastasis in vivo. Afterward, the prognosis of patients with low expression of BRWD3 is poor. Meanwhile, ubiquination, oxidative phosphorylation, MAPK pathway, etc. were the possible regulation pathways of BRWD3, which provide a new theoretical basis for the research and application of molecular markers related to breast cancer lymph node metastasis.
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OBJECTIVE: To investigate the predictive significance of prognostic nutritional index(PNI)for intraabdominal infections(IAIs)in gerontal liver cancer patients who received hepatectomy.METHODS: The clinical data of270 gerontal(age≥60 y)patients with primary liver cancer(PLC)who received hepatectomy in the First Affiliated Hospital of Xi' an Jiaotong University were retrospectively analyzed.Receiver operating characteristic curve(ROC),multivariate analysis and survival curve were used to conduct the predictive significance of preoperative PNI for IAIs.RESULTS: The incidence of IAIs was 12.59%(34/270)in this cohort.The cut-off value of preoperative PNI for the prediction of postoperative IAIs was 47.58(P0.05).CONCLUSION: Preoperative PNI determination has predictive value for postoperative IAIs in gerontal liver cancer patients who received hepatectomy.
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Intra-abdominal infections(IAIs)is common in the clinic which includes a variety of pathological conditions,ranging from uncomplicated appendicitis to fecal peritonitis.IAIs can be classified as healthcare-associated IAIs and community-acquired IAIs according to the circumstance of origin.IAIs can be also classified as uncomplicated IAIs and complicated IAIs according to the extent of infection.However,the circumstance of origin and extent of infection can't predict the therapy difficulty and clinical outcome.So,the authors first propose the new concept of "pan-complicated IAIs" and elaborate its clinical significance which may evoke the interest of clinicians to pay close attention to the diagnosis and treatment of IAIs.
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The incidence of intra-abdominal infections(IAIs)is increasing theses years which receives more and more attention in the clinic.Especially the complicated IAIs,post-operative IAIs,intra-abdominal candidiasis and abdominal sepsis get an unacceptably high mortality,which is the most difficult and dispirited for the clinicians.How to recognize these IAIs and implement adequate treatment in the early time are the keys to improve the prognosis.Early diagnosis and accurate classification are the keys to assess the severity.Effectiveinfection source control is the core of treatment.For the IAIs accompany with organ dysfunction,surgeon-predominant IAIs multiple disciplinary team(MDT)should be establish to improve the diagnosis and treatment of IAIs.
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Objective To study the effect of mesenteric lymph duct ligation(MLDL)on sepsis-induced lung and intestinal injuries in rats.Methods Sepsis was induced by cecal ligation and puncture(CLP)in male rats.The rats were randomly divided into sham control group in which rats received sham operation,sepsis group(CLP group)in which rats received saline after CLP operation,and CLP+MLDL group in which rats received mesenteric lymph duct ligation(MLDL)after CLP operation.The rats were sacrificed at 24 h after CLP modeling. Bronchoalveolar lavage fluid,arterial blood,and intestine and lung tissues were collected to determine organ injuries.Results The lung tissue histopathology and blood gas analysis revealed that MLDL markedly alleviated the lung injury(ALI score:6.14 ± 0.51 vs.8.12 ± 0.63,P=0.029 9),improved oxygen partial pressure[(78.67 ± 4.51)mmHg vs.(64.83 ± 2.90)mmHg,P=0.0273],decreased lung W/D ratio(6.12 ± 0.25 vs.7.63 ± 0.49,P=0.021 2),decreased BALF cytokines levels[TNF-α:(828.17 ± 81.89)pg/mL vs.(1 118.17 ± 79.22)pg/mL,P=0.029 1;IL-6:(39.33 ± 5.50)ng/mL vs.(68.67 ± 5.24)ng/mL,P=0.003 4],alveolar permeability[protein levels:2.117 ± 0.289 2 vs.3.033 ± 0.164 7,P=0.020 3,and cell levels:(30.00 ± 3.587)×106/L vs.(43.83 ± 2.358)×106/L,P=0.009 1].However,according to the results of HE and biochemical detection,MLDL had no protective effect on sepsis-induced intestinal injury.Moreover,MLDL could significantly reduce the bacterial loads of the blood and lung,but do not change the bacterial level in the intestines.Conclusion MLDL has a significant protective effect on sepsis-induced lung injury mainly by decreasing bacterial translocation,but had no effect on intestinal injury.This difference may be related to that MLDL inhibits the bacteria spreading from abdominal cavity to other organs in sepsis but it causes their accumulation in the intestines.
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Objective To analyze and validate the key molecular targets correlated with the overall survival of patients with HER2-positive breast cancer.Methods First,the survival time and transcriptome data of patients with HER2-positive breast cancer in stage Ⅰ / Ⅱ and Ⅲ/Ⅳ were downloaded from the TCGA database.The significantly differential genes between overall survival ＜2 years and ＞8.5 years in stage Ⅰ / Ⅱ were picked out by edgeR package,and the pathways were enriched by KEGG.Similarly,the differential genes between overall survival ＜2 years and ＞7 years in stage Ⅲ/Ⅳ were analyzed.Furthermore,KEGG pathway analysis was performed using the differential genes overlapped by stage Ⅰ /Ⅱ and Ⅲ/Ⅳ.Second,the relationships between the expression levels of key node genes and other genes in enriched pathway and the overall survival of patients with HER2-positive breast cancer were validated by KMplot database.Last,the correlation between the activity of pathway enriched in KEGG and the resistance to anti-HER2 treatment was validated in HER2-positive breast cancer cell line BT474.Results In patients with stage Ⅰ / Ⅱ HER2-positive breast cancer whose overall survival was ＜2 years,PI3K/AKT was the 9th signaling pathway enriched by up-regulated differential genes.In patients with stage Ⅲ/Ⅳ whose overall survival was ＜2 years,PI3K/AKT was the 2nd signaling pathway enriched by up-regulated differential genes.Furthermore,PI3K/AKT was the first signal pathway enriched by the overlapping upregulated genes of patients in stage Ⅰ / Ⅱ and Ⅲ / Ⅳ whose overall survival was ＜2 years.Patients with high expression of PI3K and AKT (key node genes) or CFAP221 and COL4A6 (other genes) of PI3K/AKT pathway had shorter overall survival than those with low expression.PI3K inhibitors could enhance the growth inhibitory effect of HER2 small molecule inhibitor on HER2-positive breast cancer cell line BT474.Conclusions The overexpression of PI3K/AKT pathway is associated with the shorter overall survival in HER2-positive breast cancer patients,and associated with anti-HER2 resistance in HER2-positive breast cancer cell line.
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This study was aimed to compare the expressions of specific transcription factors of CD4(+) T cell subset ( T-bet, GATA-3, RORγt and FoxP3 mRNA) in peripheral blood of patients with aplastic anemia(AA), myelodysplastic syndrome(MDS), and acute myeloid leukemia(AML), and investigate their immune status and pathogenesis, so as to provide experimental basis for the choice of clinical treatment. The expression of T-box (T-bet), GATA-3, ROR-γt and Foxp3 mRNA in PBMNC were examined by RT-PCR in 42 cases of MDS, including 22 refractory anemia(MDS-RA) and 20 refractory anemia with excess blasts (MDS-RAEB), in 23 cases of AA, 17 cases of AML patients and 16 healthy volunteers respectively. The results indicated that, compared with normal control group, expressions of T-bet and RORγt mRNA in AA patient group were significantly higher (P < 0.01), expression levels of GATA3 Foxp3 mRNA were lower (both P < 0.01). There was no significant difference in expression of T-bet and GATA3 mRNA between MDS group and normal control group, but the expression levels of Foxp3 and RORγt mRNA were higher than those in normal controls (P < 0.05); T-bet and RORγt in MDS-RA group were higher than those in the normal controls(P < 0.01), and GATA3 expression significantly reduced (P < 0.05), however, there was no significant difference in expression of Foxp3 between MDS-RA and the controls. Expression levels of T-bet and RORγt mRNA in patients with MDS-RAEB and AML were lower than those in normal controls (P < 0.05), but the expression levels of GATA3 and Foxp3 mRNA were significantly higher than those in normal controls (P < 0.01). It is concluded that the transcription factor expressions are different in PBMNC of patients among these three diseases. Immune-mediated excessive apoptosis may play an important role in pathogenesis, bone marrow failure in patients with AA and MDS-RA, and abnormal clones of immature cells may be one of main reasons for bone marrow failure in AML and late stage of MDS.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Anemia, Aplastic , Blood , CD4-Positive T-Lymphocytes , Metabolism , Case-Control Studies , Forkhead Transcription Factors , Metabolism , GATA3 Transcription Factor , Metabolism , Leukemia, Myeloid, Acute , Blood , Myelodysplastic Syndromes , Blood , Nuclear Receptor Subfamily 1, Group F, Member 3 , Metabolism , T-Box Domain Proteins , MetabolismABSTRACT
This study was purposed to detect the balance and the activity change of cytotoxic T cell subsets in aplastic anemia (AA) patients, myelodysplastic syndrome (MDS) patients and acute myeloid leukemia (AML) patients, and to explore the cellular immune mechanism for abnormal hematopoiesis of the three diseases, so as to provide experimental basis for the choice of clinical treatment. The proportion of the cytotoxic T cells and part of the T-cells subsets in peripheral blood were detected by flow cytometry in 35 cases of MDS, including 19 refractory anemia (MDS-RA), 16 refractory anemia with excess blasts (MDS-RAEB), 17 AA, 15 AML patients and 10 normal donors respectively. The results showed that compared with the control group, the percentage of Tc1, Tc1/Tc2, CD8(+)HLA-DR(+), CD3(+)CD8(+)CD28(+), CD8(+)CD45RO(+) cells was significantly higher and the percentage of CD8(+)CD45RA(+) was significantly lower in AA and MDS-RA group. There was no difference in the percentage of Tc2 cells between AA/MDS-RA and normal controls; the percentage of CD8(+)CD45RO(+) cells was significantly higher and the percentage of Tc1, CD3(+)CD8(+)CD28(+), CD8(+)HLA-DR(+) was significantly lower in MDS-RAEB group, the percentage of CD8(+)CD45RA(+) was lower but the difference was not significant, and there was no difference in the percentage of Tc, Tc1/Tc2 cells between MDS-RAEB group and the control group. The percentage of Tc2 cells was significantly higher and the percentage of other parameters was significantly lower in AML group than those of normal controls. It is concluded that the cellular immune statuses in AA, the different stages of MDS and AML are different. In AA and the early stage of MDS, the balance of Tc1/Tc2 shifts to Tc1, and the activation of T-cell subsets increases. In the late stage of MDS and AML, the balance of Tc1/Tc2 shifts to Tc2, the activation of T-cell subsets decreases. The former may be closely related to bone marrow failure while the latter may be one of the important mechanisms in which the malignant clones escape from immune effect.