Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors.

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown. Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab. Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model. Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Label-free Raman spectroscopy reveals tumor microenvironmental changes induced by intermittent fasting for the prevention of breast cancer in animal model.

The development of tools that can provide a holistic picture of the evolution of the tumor microenvironment in response to intermittent fasting on the prevention of breast cancer is highly desirable. Here, we show, for the first time, the use of label-free Raman spectroscopy to reveal biomolecular alterations induced by intermittent fasting in the tumor microenvironment of breast cancer using a dimethyl-benzanthracene induced rat model. To quantify biomolecular alterations in the tumor microenvironment, chemometric analysis of Raman spectra obtained from untreated and treated tumors was performed using multivariate curve resolution-alternative least squares and support vector machines. Raman measurements revealed remarkable and robust differences in lipid, protein, and glycogen content prior to morphological manifestations in a dynamically changing tumor microenvironment, consistent with the proteomic changes observed by quantitative mass spectrometry. Taken together with its non-invasive nature, this research provides prospective evidence for the clinical translation of Raman spectroscopy to identify biomolecular variations in the microenvironment induced by intermittent fasting for the prevention of breast cancer, providing new perspectives on the specific molecular effects in the tumorigenesis of breast cancer.

Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity. METHODS: We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments. RESULTS: The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients. CONCLUSIONS: Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Ultrasound-Guided Quadratus Lumborum Block Combined with General Anaesthesia or General Anaesthesia Alone for Laparoscopic Radical Gastrectomy for Gastric Adenocarcinoma: A Monocentric Retrospective Study.

Purpose: To investigate, in patients with gastric carcinoma undergoing laparoscopic radical gastrectomy, the effects of ultrasound-guided quadratus lumborum block (UG-QLB) combined with general anaesthesia (GA) on the postoperative recovery compared with GA alone. Patients and Methods: The retrospective study enrolled 231 patients with gastric carcinoma undergoing laparoscopic radical gastrectomy, including 119 patients who received UG-QLB combined with GA (Group QG), and 112 patients undergoing GA alone (Group GA). The primary endpoint was the postoperative 3-year recurrence-free survival (RFS). The secondary endpoints were the average visual analogue scale (VAS) scores within 48 h after surgery, the first time of postoperative ambulation, the first time of flatus, postoperative hospitalization, perioperative opioid requirement and adverse effects after surgery. Results: UG-QLB combined with GA did not affect the 3-year RFS in patients undergoing laparoscopic radical gastrectomy (HR 0.659, 95% CI 0.342-1.269, P=0.212). However, the VAS ranking analysis implicated that it could significantly alleviate the postoperative pain in laparoscopic radical gastrectomy patients (P<0.01). In addition, it dramatically facilitated the early recovery of postoperative ambulation and flatus, while shortening the duration of postoperative hospitalization (P<0.01). The most important was it could remarkably reduce the opioid consumption (P<0.01), which in the meanwhile, reduced the incidence of postoperative nausea and vomiting (PONV) (P=0.01). Conclusion: Although UG-QLB combined with GA did not improve the 3-year RFS for patients with gastric carcinoma undergoing laparoscopic radical gastrectomy, it could provide satisfactory postoperative pain relief, reduce opioid consumption and adverse effects, which subsequently facilitates postoperative early rehabilitation.

Thoracic Paravertebral Block Combined with General Anaesthesia or General Anaesthesia Alone for Thoracoscopic Lung Adenocarcinoma Surgery: A Retrospective Study.

Purpose: To investigate the effects of ultrasound-guided thoracic paravertebral block combined with general anaesthesia or general anaesthesia alone for thoracoscopic lung adenocarcinoma surgery, and to provide new thoughts for improving the clinical outcomes. Methods: This was a retrospective study. Data were retrieved for 195 patients with lung adenocarcinoma undergoing elective radical lobectomy via video-assisted thoracoscopy between January 2018 and August 2019 in The Second Hospital of Shandong University, including 86 patients who received thoracic paravertebral block (TPVB) combined with general anaesthesia (group TG), and 109 patients who received general anaesthesia alone (group GA). All patients were given self-controlled intravenous analgesia pump for 48 h after surgery. The primary outcome was the recurrence-free survival 2 years postoperatively (the time between surgery and the earliest date of recurrence, metastasis or lung cancer-cause death). The secondary outcomes included the average numeric rating scale (NRS) scores within 48 h postoperatively, the first time of postoperative ambulation, duration of chest tube drainage, length of postoperative hospitalization, perioperative opioid consumption and the postoperative side effects. Results: There were no statistical differences in the recurrence-free survival 2 years postoperatively between groups (Multivariate hazard ratio 0.706, 95% CI 0.126-3.941, P=0.691). The average NRS scores within 48 h postoperatively were significantly lower in group TG (P<0.05). The first time of postoperative ambulation, duration of chest tube drainage, and length of postoperative hospitalization in group TG were significantly reduced (P<0.05). Opioid consumption was significantly decreased in group TG (P<0.01). Finally, the incidence of postoperative nausea and vomiting (PONV) was significantly lower in group TG (P<0.05). Conclusion: TPVB for thoracoscopic lung adenocarcinoma surgery did not improve the recurrence-free survival 2 years postoperatively compared with general anaesthesia alone, but it significantly enhanced the postoperative analgesia effect, reduced opioid consumption as well as side effects, and accelerated postoperative early recovery. Clinical Trial Registration Number: The Chinese Clinical Trial Registry (ChiCTR-2100050454).

RNA-seq analysis of peripheral blood dendritic cells maturated by dezocine in patients with lung cancer.

Surgical resection is the most common and effective option for the clinical treatment of lung cancer. Postoperative pain may activate surgically induced stress response, leading to a decrease in human immune function. However, conventional analgesics such as morphine and its derivatives have been reported to have immunosuppressive side effects. In the critical period after surgery, the immunosuppressive effect of analgesics on patients with lung cancer could promote postoperative cancer recurrence and metastasis. Therefore, it will be an ideal scenario for postoperative pain management to maximize pain relief while minimizing immunosuppression side effects. In this study, we found that a novel mixed agonist-antagonist opioid analgesic, dezocine, significantly promoted the morphological maturation of dendritic cells (DCs), and increase the expression of DCs-related surface markers in postoperative peripheral blood of patients with lung cancer. Furthermore, dezocine-matured DCs increased the general immune response by promoting the secretion of IL-12 and IL-6 cytokines and enhancing the proliferation and cytotoxicity of CD8+ T cells. Then genome-wide transcriptomic profiling analyses were performed to identify the specific gene expression of dezocine-matured DCs. The results of transcriptomic analysis as well as in vitro validation showed that the upregulation of CXCL10, CD3G, and GRB2 were significantly associated with dezocine-induced DCs maturation. Overall, our data showed that dezocine might exhibit unique properties by acting as an immunostimulant, which provides new evidence for its application in postoperative pain management of patients with lung cancer.

Prognostic value of gamma-interferon-inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer.

Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma-interferon-inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099-0.361) and breast cancer-specific survival (BCSS; HR = 0.187, 95% CI: 0.080-0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235-0.873 for DFS, HR = 0.488, 95% CI: 0.245-0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression-mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

Effect of Dezocine on the Ratio of Th1/Th2 Cytokines in Patients Receiving Postoperative Analgesia Following Laparoscopic Radical Gastrectomy: A Prospective Randomised Study.

PURPOSE: To evaluate the effect of dezocine on the postoperative ratio of Th1/Th2 cytokines in patients undergoing laparoscopic radical gastrectomy. PATIENTS AND METHODS: Sixty patients undergoing laparoscopic radical gastrectomy were randomly divided into two groups (n=30): dezocine group (Group D) and sufentanil group (Group S). They received patient-controlled intravenous analgesia (PCIA) after the operation with either dezocine 0.8 mg/kg (Group D) or sufentanil 2 µg/kg (Group S). Both groups also received ondansetron 8 mg diluted to 100 mL with saline. The primary outcome was the Th1/Th2 cytokines ratio at predetermined intervals, 30 min before the induction of general anaesthesia and 0, 12, 24 and 48 h after surgery. The secondary endpoints were patients' pain scores, measured on a visual analogue scale (VAS) at predetermined intervals (0, 12, 24 and 48 h after surgery), and side effects at follow-up 48 h after surgery. RESULTS: The Th1/Th2 cytokines ratio in Group D was significantly higher than Group S (P<0.05) 12, 24 and 48 h after the operation. There were no significant differences in VAS pain scores between groups at 0, 12, 24 and 48 h after surgery (P>0.05). Compared to Group S, the incidence of postoperative nausea, vomiting and lethargy was significantly lower in Group D (P<0.05). CONCLUSION: Dezocine increases the ratio of Th1/Th2 cytokines, relieves postoperative pain and causes fewer side effects in patients undergoing laparoscopic radical gastrectomy.

Changes in Alternative Splicing in Response to Domestication and Polyploidization in Wheat.

Alternative splicing (AS) occurs extensively in eukaryotes as an important mechanism for regulating transcriptome complexity and proteome diversity, but variation in the AS landscape in response to domestication and polyploidization in crops is unclear. Hexaploid wheat (AABBDD, Triticum aestivum) has undergone two separate allopolyploidization events, providing an ideal model for studying AS changes during domestication and polyploidization events. In this study, we performed high-throughput transcriptome sequencing of roots and leaves from wheat species with varied ploidies, including wild diploids (AbAb, Triticum boeoticum) and tetraploids (AABB, Triticum dicoccoides), domesticated diploids (AmAm, Triticum monococcum) and tetraploids (AABB, Triticum dicoccum), hexaploid wheat (AABBDD, T aestivum), as well as newly synthesized hexaploids together with their parents. Approximately 22.1% of genes exhibited AS, with the major AS type being intron retention. The number of AS events decreased after domestication in both diploids and tetraploids. Moreover, the frequency of AS occurrence tended to decrease after polyploidization, consistent with the functional sharing model that proposes AS and duplicated genes are complementary in regulating transcriptome plasticity in polyploid crops. In addition, the subgenomes exhibited biased AS responses to polyploidization, and ∼87.1% of homeologs showed AS partitioning in hexaploid wheat. Interestingly, substitution of the D-subgenome modified 42.8% of AS patterns of the A- and B-subgenomes, indicating subgenome interplay reprograms AS profiles at a genome-wide level, although the causal-consequence relationship requires further study. Conclusively, our study shows that AS variation occurs extensively after polyploidization and domestication in wheat species.

Atranones from Stachybotrys chartarum and their antitumor activities in MG-63 human osteosarcoma cells.

Two new atranones T and U (1 and 2), and three known analogues atranone B (3), atranone Q (4), and stachatranone C (5) were isolated from the toxigenic fungus Stachybotrys chartarum. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all the atranones (1-5) were evaluated against MG-63 human osteosarcoma cell lines. Compound 4 exhibited significant cytotoxic effect against MG-63 with IC50 value of 8.6 µM, being more active than the positive control, 5-FU (IC50 10.4 µM). Morphological features of apoptosis activities were evaluated in 4-treated MG-63 cells. Compound 4 effectively induced apoptosis of MG-63, which was associated with G0/G1-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 4 significantly induced MG-63 cell apoptosis in a dose-dependent manner.

Preparation and Characteristics of Ethylene Bis(Stearamide)-Based Graphene-Modified Asphalt.

In this study, graphene-modified asphalt (GMA) was prepared from SK-70# matrix asphalt and ethylene bis(stearamide) (EBS). Based on the uniform design method, a model was created using Data Processing System (DPS) software and First Optimization (1stOpt) software using the graphene mixing amount, EBS mixing amount, shear rate, shear time, and shear temperature as factors and using the asphalt penetration, softening point, force ductility, SHRP-PG test, and multistress creep recovery data as indices. Calculations and analysis showed that the optimal composition and preparation parameters of GMA are as follows: the graphene proportion is 20‰, the EBS proportion is 1%, the shear rate is 6000 r.p.m., the shear time is 180 min, and the shear temperature is 140 °C. The prepared GMA had a significantly improved softening point, low-temperature fracture energy, antirutting factor, and creep recovery rate, indicating that adding graphene can improve the high- and low-temperature performance of asphalt. The prepared GMA was characterized by X-ray diffraction (XRD). The dispersibility of graphene in asphalt was evaluated by fluorescence microscopy and Image-Pro Plus imaging software. The results show that graphene can exist in asphalt in a stable form, which increases the loose-layered structure of stacked asphalt or gum. The intense adsorption effect of graphene strengthens the ordered structure of asphalt. However, due to its dispersibility characteristics, some graphene exists in asphalt in clustered form. When the graphene-to-dispersant ratio approaches the optimal value, the dispersant changes the form of graphene in asphalt from irregular clusters to regular clusters and from large, distinct clusters to small, indistinct clusters. When dispersant cannot uniformly disperse graphene in asphalt, graphene clusters primarily form medium-sized grains.

Clinicopathologic Significance of Intestinal-type Molecules' Expression and Different EGFR Gene Status in Pulmonary Adenocarcinoma.

Variant pulmonary adenocarcinoma with intestinal-type molecules shares similar molecular expression with colorectal carcinoma. However, expression of such molecules and their association with survival time with clinicopathologic parameters, such as epidermal growth factor receptor (EGFR) gene status in other types of pulmonary adenocarcinoma, has been rarely demonstrated. Sixty patients with resected pulmonary adenocarcinoma were divided into the enteric differentiation group (I group, n=30) and the usual group (U group, n=30). Immunohistochemical staining was used to assess the expression of carcinoembryonic antigen (CEA), Villin, CK20, and caudal-related homeobox 2 (CDX2). EGFR gene status was examined by Fluorescence Quantitative polymerase chain reaction. Kaplan-Meier survival curve was drawn by GraphPad Prism 5.0 software. The results showed that there was a significant difference between the 2 groups (P<0.05) in the expression of Villin, CK20, and CDX2, whereas the expression of CEA showed no significant difference (P>0.05). Compared with the U group, patients in the I group were mainly female individuals and in clinical stages III to IV, prone to lymph node metastasis (P<0.05). The patients in the I group with CDX2CK20 phenotype (tumor size>5 cm) had a shorter survival time (P<0.05), and EGFR gene status was not associated with median survival time and the expression of CEA, Villin, CK20, and CDX2 (P>0.05). Thus, our research indicates that patients with enteric differentiation have unique clinical characteristics and different prognosis, which may play important roles in diagnosis and choosing therapeutic strategies for pulmonary adenocarcinoma patients in clinical practice.

Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapy.

The expression of insulin-like growth factor-1 receptor (IGF-1R), which is involved in the genesis and progression of breast cancer, is thought to be associated with the overall survival (OS) of patients. However, the predictive and prognostic significance of the IGF-1R expression in breast cancer remains controversial. The present study aimed to identify the factors associated with the levels of phosphorylated (p)-IGF-1R in breast cancer, their impact on the outcomes of breast cancer patients, and the prognostic value of alterations of p-IGF-1R during neoadjuvant chemotherapy (NAC). The present study included 348 female breast cancer patients whose paraffin-embedded tumor tissue sections had been collected by biopsy and/or resection, among which the pre-NAC and post-NAC sections were available from 40 patients. Human epidermal growth factor receptor 2 (HER2) positivity and molecular subtype were significantly associated with the presence of p-IGF-1R in the tumor tissue (P<0.05). Patients with p-IGF-1R present in the tumor tissue had a shorter OS (P=0.003). The p-IGF-1R levels in the tumor after NAC differed significantly from those prior to NAC (P=0.005); however, this alteration in p-IGF-1R levels was not associated with a shorter OS. In parallel with HER2, p-IGF-1R appears to be a promising indicator for predicting clinical outcomes and may be an attractive target for improving the efficacy of antitumor therapy, particularly for patients with HER2-negative, estrogen receptor-positive and luminal B tumors.

Genomic Imprinting Was Evolutionarily Conserved during Wheat Polyploidization.

Genomic imprinting is an epigenetic phenomenon that causes genes to be differentially expressed depending on their parent of origin. To evaluate the evolutionary conservation of genomic imprinting and the effects of ploidy on this process, we investigated parent-of-origin-specific gene expression patterns in the endosperm of diploid (Aegilops spp), tetraploid, and hexaploid wheat (Triticum spp) at various stages of development via high-throughput transcriptome sequencing. We identified 91, 135, and 146 maternally or paternally expressed genes (MEGs or PEGs, respectively) in diploid, tetraploid, and hexaploid wheat, respectively, 52.7% of which exhibited dynamic expression patterns at different developmental stages. Gene Ontology enrichment analysis suggested that MEGs and PEGs were involved in metabolic processes and DNA-dependent transcription, respectively. Nearly half of the imprinted genes exhibited conserved expression patterns during wheat hexaploidization. In addition, 40% of the homoeolog pairs originating from whole-genome duplication were consistently maternally or paternally biased in the different subgenomes of hexaploid wheat. Furthermore, imprinted expression was found for 41.2% and 50.0% of homolog pairs that evolved by tandem duplication after genome duplication in tetraploid and hexaploid wheat, respectively. These results suggest that genomic imprinting was evolutionarily conserved between closely related Triticum and Aegilops species and in the face of polyploid hybridization between species in these genera.

The Clinical Implications of Human Telomerase Reverse Transcriptase Expression in Grade and Prognosis of Gliomas: a Systematic Review and Meta-analysis.

Human telomerase reverse transcriptase (hTERT), a ribonucleoprotein, is reported as an important complex, which is required for stability of DNA molecular structure at the rear of the chromosome. Until now, hTERT has been linked to cell immortalization and tumorigenesis. A couple of articles have been published about the telomerase function in the gliomas; however, these results are conflicting in some degree. Thus, it is crucial to perform a meta-analysis to identify their real actions. We included eligible articles, and estimated odds ratios (ORs) with 95 % confidence intervals (95 % CIs). In our meta-analysis, all 15 eligible articles included 932 patients. Results from 10 studies on WHO grade showed that high hTERT gene or protein expression in glioma tissues was obviously related to high WHO grade (III + IV) (OR 2.45, 95 % CI 1.92-3.13; p = 0.000). What is more, hTERT expression was not associated with old age (OR 0.91, 95 % CI 0.72-1.16; p = 0.448) as well as gender (OR 1.06, 95 % CI 0.82-1.37; p = 0.664). Importantly, hTERT expression was significantly associated with 5-year overall survival (OS; n = 3; hazard ratio (HR) 2.25, 95 % CI 1.36-3.70; p = 0.002) of glioma patients. No heterogeneity was found in all studies. In conclusion, this meta-analysis suggests that hTERT is significantly associated with high glioma grade and poor 5-year overall survival, and pathological test of hTERT mRNA and protein in glioma tissues should be suggested as criteria of glioma grade in the clinical practice.

Histopathological alterations during breast carcinogenesis in a rat model induced by 7,12-Dimethylbenz (a) anthracene and estrogen-progestogen combinations.

Studies have shown that the development of breast cancer (BC) is a multi-step process that occurs sequentially from normal to usual hyperplasia, atypical hyperplasia, carcinoma in situ, and finally the invasive stages of carcinoma. Our study investigated the histopathological alterations in breast tissue in a Sprague-Dawley (SD) rat model induced by 7,12-Dimethylbenz (a) anthracene (DMBA) and estrogen-progestogen (E-P). Fifty rats were randomly divided into five groups (n = 10 each) and administered the E-P/DMBA combination. After the induction of BC, breast tissue samples were obtained from the rats and stained with hematoxylin-eosin (HE). Breast tissues from 10 rats and 10 human patients were obtained for comparison. The expression of P63, CK5/6 and CK34ßE12 was observed and analyzed using the SPSS 17.0 software. The HE results showed ductal epithelial hyperplasia with forming a second lumen or papillary structure, atypical hyperplasia with atypical proliferative cells, forming a cross-bridge or cribriform structure in breast tissues from the rats samples. The IHC results showed that the expression of P63 was not significantly different between rat and human breast tissue (P > 0.05), but its expression in rat and human tissue was significantly different between UDH, ADH, DCIS and IDC (P < 0.01). A similar trend was observed for the expression of CK5/6 and CK34ßE12 too. Thus, the findings in this model may reflect the histopathological changes that occur during the progression of human BC. Therefore, this model could be used for the establishment of BC models to investigate the prevention and treatment of BC.

CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma.

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4.

Absence of gamma-interferon-inducible lysosomal thiol reductase (GILT) is associated with poor disease-free survival in breast cancer patients.

Tumor immunosurveillance is known to be of critical importance in controlling tumorigenesis and progression in various cancers. The role of gamma-interferon-inducible lysosomal thiol reductase (GILT) in tumor immunosurveillance has recently been studied in several malignant diseases, but its role in breast cancer remains to be elucidated. In the present study, we found GILT as a significant different expressed gene by cDNA microarray analysis. To further determine the role of GILT in breast cancer, we examined GILT expression in breast cancers as well as noncancerous breast tissues by immunohistochemistry and real-time PCR, and assessed its association with clinicopathologic characteristics and patient outcome. The absence of GILT expression increased significantly from 2.02% (2/99) in noncancerous breast tissues to 15.6% (34/218) in breast cancer tissues (P<0.001). In accordance with its proliferation inhibiting function, GILT expression was inversely correlated with Ki67 index (P<0.05). In addition, absence of GILT was positively correlated with adverse characteristics of breast cancers, such as histological type, tumor size, lymph nodes status, and pTNM stage (P<0.05). Consistently, breast cancers with reduced GILT expression had poorer disease-free survival (P<0.005). Moreover, significantly decreased expression of GILT was found in both primary and metastatic breast cancer cells, in contrast to normal epithelial cells. These findings indicate that GILT may act as a tumor suppressor in breast cancer, in line with its previously suggested role in anti-tumor immunity. Thus, GILT has the potential to be a novel independent prognostic factor in breast cancer and further studies are needed to illustrate the underlying mechanism of this relationship.