Comparison of the prognostic effect of pyrotinib plus trastuzumab and chemotherapy different lines therapy in HER2-positive advanced breast cancer.

This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2- (HER2-) positive advanced breast cancer (ABC) and analyze the factors affecting the prognosis. A total of 84 patients with median age of 49 year-old. The mPFS of patients receiving first-line pyrotinib plus trastuzumab and chemotherapy was the longest (11 months) compared with second- and third line patients (p = 0.106). The objective response rate (ORR) and disease control rate (DCR) of the total population were 33.3% and 82.1% respectively. Subgroup analysis suggested that using pyrotinib plus trastuzumab and Albumin-bound paclitaxel was not inferior to combine with Vinorelbine in regards of PFS. Histological grade (OR: 0.233[0.069 ∼ 0.781], p = 0.018) and tumor location (OR: 0.286[0.087 ∼ 0.942], p = 0.040) were independent factors influencing the ORR. Multivariate cox analysis showed that Ki-67 was independently associated with increased risk of progression (HR: 1.843[1.044-3.254], p = 0.035). The most common adverse events were diarrhea (17.9%) and neutropenia (11.9%). In the first-, second- and third-line treatment, pyrotinib plus trastuzumab and chemotherapy is effective and safe. Pyrotinib and trastuzumab combined with Albumin-bound paclitaxel may be a potential ideal treatment plan for HER2-positive advanced breast cancer.

Real-world data of pyrotinib-based therapy for patients with brain metastases of HER2-positive advanced breast cancer: a single-center retrospective analysis and molecular portraits.

Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined. Methods and materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM. Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038). Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.

Nomogram for predicting preoperative regional lymph nodes metastasis in patients with metaplastic breast cancer: a SEER population-based study.

BACKGROUND: Metaplastic breast cancer (MBC) is a rare subtype of breast cancer, and generally associated with poor outcomes. Lymph nodes metastasis (LNM) is confirmed as a critical independent prognostic factor and determine the optimal treatment strategies in MBC patients. We aimed to develop and validate a nomogram to predict the possibility of preoperative regional LNM in MBC patients. METHODS: MBC patients diagnosed between 1990 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database were included and stochastically divided into a training set and validation set at a ratio of 7:3. The risk variables of regional LNM in the training set were determined by univariate and multivariate logistic regression analyses. And then we integrated those risk factors to construct the nomogram. The prediction nomogram was further verified in the verification set. The discrimination, calibration and clinical utility of the nomogram were evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), calibration plots and decision curve analysis (DCA), respectively. RESULTS: A total of 2205 female MBC patients were included in the study. Among the 2205 patients, 24.8% (546/2205) had positive regional lymph nodes. The nomogram for predicting the risk of regional LNM contained predictors of grade, estrogen receptor (ER) status and tumor size, with AUC of 0.683 (95% confidence interval (CI): 0.653-0.713) and 0.667 (95% CI: 0.621-0.712) in the training and validation sets, respectively. Calibration plots showed perfect agreement between actual and predicted regional LNM risks. At the same time, DCA of the nomogram demonstrated good clinical utilities. CONCLUSIONS: The nomogram established in this study showed excellent prediction ability, and could be used to preoperatively estimate the regional LNM risk in MBC.

A nomogram for predicting survival in patients with de novo metastatic breast cancer: a population-based study.

BACKGROUND: 5-10% of patients are diagnosed with metastatic breast cancer (MBC) at the initial diagnosis. This study aimed to develop a nomogram to predict the overall survival (OS) of these patients. METHODS: de novo MBC patients diagnosed in 2010-2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. They were randomly divided into a training and a validation cohort with a ratio of 2:1. The best subsets of covariates were identified to develop a nomogram predicting OS based on the smallest Akaike Information Criterion (AIC) value in the multivariate Cox models. The discrimination and calibration of the nomogram were evaluated using the Concordance index, the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curves. RESULTS: In this study, we included 7986 patients with de novo MBC. The median follow-up time was 36 months (range: 0-83 months). Five thousand three-hundred twenty four patients were allocated into the training cohort while 2662 were allocated into the validation cohort. In the training cohort, age at diagnosis, race, marital status, differentiation grade, subtype, T stage, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery and chemotherapy were selected to create the nomogram estimating the 1-, 3- and 5- year OS based on the smallest AIC value in the multivariate Cox models. The nomogram achieved a Concordance index of 0.723 (95% CI, 0.713-0.733) in the training cohort and 0.719 (95% CI, 0.705-0.734) in the validation cohort. AUC values of the nomogram indicated good specificity and sensitivity in the training and validation cohort. Calibration curves showed a favorable consistency between the predicted and actual survival probabilities. CONCLUSION: The developed nomogram reliably predicted OS in patients with de novo MBC and presented a favorable discrimination ability. While further validation is needed, this may be a useful tool in clinical practice.

Cell-Type-Specific Metabolic Profiling Achieved by Combining Desorption Electrospray Ionization Mass Spectrometry Imaging and Immunofluorescence Staining.

Cell-type-specific metabolic profiling in tissue with heterogeneous composition has been of great interest across all mass spectrometry imaging (MSI) technologies. We report here a powerful new chemical imaging capability in desorption electrospray ionization (DESI) MSI, which enables cell-type-specific and in situ metabolic profiling in complex tissue samples. We accomplish this by combining DESI-MSI with immunofluorescence staining using specific cell-type markers. We take advantage of the variable frequency of each distinct cell type in the lateral septal nucleus (LSN) region of mouse forebrain. This allows computational deconvolution of the cell-type-specific metabolic profile in neurons and astrocytes by convex optimization-a machine learning method. Based on our approach, we observed 107 metabolites that show different distributions and intensities between astrocytes and neurons. We subsequently identified 23 metabolites using high-resolution mass spectrometry (MS) and tandem MS, which include small metabolites such as adenosine and N-acetylaspartate previously associated with astrocytes and neurons, respectively, as well as accumulation of several phospholipid species in neurons which have not been studied before. Overall, this method overcomes the relatively low spatial resolution of DESI-MSI and provides a new platform for in situ metabolic investigation at the cell-type level in complex tissue samples with heterogeneous cell-type composition.

Clinicopathological features, survival and risk in breast cancer survivors with thyroid cancer: an analysis of the SEER database.

BACKGROUND: The co-occurrence of breast cancer (BC) and thyroid cancer (TC) has been mentioned for several years, researchers observed an increased risk of BC patients to develop TC, but few researches concern about the features, survival of BC patients followed by TC and the influent factors of the incidence risk. The present study aimed to estimate the clinicopathological features, survival of BC survivors who had primary TC and the predictive factors on the risk of BC patients to develop TC. METHODS: Women diagnosed with BC between 1992 and 2011, and then developed TC from the Surveillance, Epidemiology, and End Results Database were included. Standardized incidence ratios (SIRs) was used to perform multiple primary analyses, generated from the multiple primary-SIR program in SEER*Stat. RESULTS: A total of 842 BC then TC patients were included, the median age was 54 years. Additionally, 78.39% were white, 60.45% had T1 cancer, 62.47% had negative lymph nodes, and more than 75% had infiltrating duct carcinoma, 5-year survival rate was 95.4%. Compared with BC only patients, they were younger, had smaller tumor size and a relatively better prognosis. The risk of developing TC was higher in BC patients than in the general population (SIR 1.22, 95% CI [1.14, 1.31]), especially within 3 years. The influent factors of SIR were black race, BC tumor site, grade and ER/PR positive expression. CONCLUSIONS: BC patients followed by TC had its particular clinicopathological features. Compared with the features and survival of BC only patients, they were younger, had a smaller tumor size and a relatively better prognosis. Furthermore, BC patients had a high risk of developing TC, especially within 3 years. Black women, primary tumor located in an upper-outer, central, or overlapping site, high grade tumor and with positive hormone receptor expression were predictive factors to develop TC.

The role of radiotherapy in patients with resected ampullary carcinoma: findings based on the SEER database.

BACKGROUND: The role of adjuvant radiotherapy for resected ampullary carcinoma (AC) remains controversial. The aim of this study was to assess the effect of adjuvant radiotherapy on survival in patients who underwent resection for AC. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients diagnosed with AC from 2004 to 2012. Kaplan-Meier survival curve and multivariable Cox proportional hazards analyses were conducted to determine the effect of adjuvant radiotherapy on overall survival (OS) and disease-specific survival (DSS). Propensity score matching (PSM) method was used to balance the differences of clinicopathological characteristics between groups. RESULTS: A total of 1227 patients were included. Patients who received adjuvant radiotherapy were younger, had more advanced T stage and N stage tumors and were more likely to receive chemotherapy (p < 0.001). Adjuvant radiotherapy failed to improve either OS (p = 0.119) or DSS (p = 0.188) in PSM cohorts. In subgroup analysis, no subgroup benefited from adjuvant radiotherapy and in patients older than 70 years, radiotherapy was associated with a worse OS and DSS. CONCLUSION: Patients with resected AC do not benefit from adjuvant radiotherapy.

SLC1A5 glutamine transporter is a target of MYC and mediates reduced mTORC1 signaling and increased fatty acid oxidation in long-lived Myc hypomorphic mice.

Mice that express reduced levels of the c-Myc gene (Myc+/- heterozygotes) are long-lived. Myc hypomorphic mice display reduced rates of protein translation and decreased activity of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Given the prominent effect of mTOR on aging, lower mTORC1 activity could contribute to the exceptional longevity and enhanced healthspan of Myc+/- animals. However, given the downstream position of MYC in these signaling cascades, the mechanism through which mTORC1 activity is downregulated in Myc+/- mice is not understood. We report that the high-affinity glutamine transporter SLC1A5, which is critical for activation of mTORC1 activity by amino acids, is a transcriptional target of MYC. Myc+/- cells display decreased Slc1a5 gene expression that leads to lower glutamine uptake and consequently reduced mTORC1 activity. Decreased mTORC1 activity in turn mediates an elevation of fatty acid oxidation (FAO) by indirectly upregulating the expression of carnitine palmitoyltransferase 1a (Cpt1a) that mediates the rate-limiting step of ß-oxidation. Increased FAO has been noted in a number of long-lived mouse models. Taken together, our results show that transcriptional feedback loops regulated by MYC modulate upstream signaling pathways such as mTOR and impact FAO on an organismal level.

Clinical use of trastuzumab combined with different chemotherapy regimens in multi-line treatment of advanced human epidermal growth factor receptor 2-positive gastric cancer: A case report.

It is generally acknowledged that gastric cancer requires comprehensive treatment approaches to be adopted. For patients with human epidermal growth factor receptor-2 (HER2)-overexpressing gastric cancer, targeting HER2 with trastuzumab in first-line therapy combined with standard chemotherapy significantly improves the prognosis. However, there is a lack of international guidance for second-line treatment if a patient experiences disease progression. There is also no accepted conclusion regarding the efficiency of cross-line therapy with trastuzumab. The present study reports the case of a 55-year-old male with gastric cancer who underwent radical gastrectomy. Immunohistochemistry indicated that samples were EGFR(+) and HER-2(3+), with Ki-67 (20%). From abdominal computed tomography scanning and contrast-enhanced ultrasound following surgery, hepatic metastasis was identified and the patient was administered microwave thermocoagulation therapy. Since December 2012, the patient received multi-line chemotherapy regimens as follows: i) Oxaliplatin, tegafur/gimeracil/oteracil and trastuzumab; ii) paclitaxel liposome and S-1 plus trastuzumab; iii) apatinib; iv) epirubicin/oxaliplatin/xeloda; and v) irinotecan plus trastuzumab. During the course of therapy, the trastuzumab served an important function in multi-line therapy and the patient benefited from the combined therapy. The application of trastuzumab in the multi-line treatment of a patient with HER2-positive advanced gastric cancer may be worthy of investigation for use in the clinic.

Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging.

In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.

Tumor vasculogenic mimicry formation as an unfavorable prognostic indicator in patients with breast cancer.

Vasculogenic mimicry (VM), a newly defined pattern of tumor blood perfusion, describes the functional plasticity of aggressive tumor cells forming de novo vascular networks and is associated with the cancer progression and metastasis. However, the VM-positive rate and the impact of VM status on breast cancer patients' clinicopathological parameters and prognosis remain unclear. Thus, we performed a meta-analysis by incorporating all available evidence to clarify these issues. Eight studies that involved 1,238 breast cancer patients were eligible for inclusion in our study. We found the VM-positive rate was 24% (pooled proportion was 0.24, 95% CI= 0.13-0.34), and VM was significantly associated with larger tumor size (>2 cm) (OR=0.49, 95% CI=0.26-0.90, P=0.02) and lymph node metastasis (OR=0.27, 95% CI=0.13-0.57, P=0.0005). A boardline correlation was also identified between VM and poorer differentiation (Grade II-III) (OR=0.07, 95% CI=0.00-1.24, P=0.07). Nevertheless, no statistically significant associations were observed between VM and hormone receptor and human epidermal growth factor receptor 2 status. Moreover, the results showed that breast cancer patients with VM-positive have a shorter overall survival than those with VM-negative (HR=0.23, 95% CI=0.08-0.38,P=0.003). In summary, VM was associated with more aggressive tumor phenotype and poor prognosis in patients with breast cancer. Developing strategies against the VM formation would be a promising therapeutic approach to breast cancer.

Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma.

The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease-specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survival[DSS]; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered.

Celecoxib induced apoptosis against different breast cancer cell lines by down-regulated NF-κB pathway.

Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the effect of Celecoxib, a COX-2 inhibitor on two molecular breast cancer subtypes-MDA-MB-231 and SK-BR-3. Firstly, MDA-MB-231 and SK-BR-3 cells were treated with various concentration of Celecoxib for 24 and 48 h. Celecoxib-inhibition of NF-κB (p52 and p65) transcriptional activity and effect of Caspase 3 pathway were examined by western blotting. COX-2 mRNA was assessed by RT-PCR. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT) assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. We found that Celecoxib inhibited the proliferation of the MDA-MB-231 cell line in a dose-time dependent manner versus SK-BR-3 in a dose dependent manner only (p < 0.05). Celecoxib induced apoptosis of the MDA-MB-231 and SK-BR-3 cell lines in a dose-time dependent manner (p < 0.05) with more mean apoptotic cells in MDA-MB-231 than SK-BR-3. Significant cell-cycle arrest at the G1 phase in the MDA-MB-231 versus G2 phase in SK-BR-3 cell lines. NF-κB (p52 and p65) and COX-2 expressions were downregulated in a dose dependent manner, while Caspase 3 expression was upregulated in both cell lines. In this present study, our data indicated Celecoxib might affect each breast cancer subtype independently. Therefore, when using Celecoxib in treatment of breast cancer, it is imperative to consider the subtype of breast cancer on a molecular level.

Label-free pharmacological profiling based on dynamic mass redistribution for characterization and authentication of hazardous natural products.

Natural products are becoming increasingly popular in multiple fields involving medicines, foods and beverages. However, due to the frequent occurrence of poisoning incidents, their toxicity and safety have caused a serious concern. Here we report a method of biosensor-based two-phase pharmacological profiling (BTPP) for discovery, monitor and control of receptor-targeted natural products. BTPP uses a resonant waveguide grating biosensor for label-free and non-invasive detection of intracellular dynamic mass redistribution (DMR), a phenomenon caused by protein relocalization after receptors receiving stimulation from toxicants. The method can not only facilitate the identification of hazardous materials but also quantify their bioactivity by EC50. As a proof of concept, the method was successfully applied to recognize Daturae Flos (DF), an herb that can antagonize muscarinic acetylcholine M2 receptor and further cause poisoning, from other easily confused species. BTPP combined with high performance liquid chromatography revealed that scopolamine and hyoscyamine in DF were the key marker compounds. Moreover, the method accurately picked out 2 M2 receptor antagonists from 25 natural compounds, displaying its potential in high-throughput screening. This study provides a systematic illustration about the establishment, applicability and advantages of BTPP, which contributes to the safety assessment of natural products in related fields.

Combined detection of the expression of Nm23-H1 and p53 is correlated with survival rates of patients with stage II and III colorectal cancer.

Molecular tumor markers hold considerable promise for accurately predicting the recurrence and progression of colorectal cancer (CRC) in patients. However, in the majority of cases, single marker analysis has been found to have low accuracy, and is of little practical use in clinical practice. The present study investigated the prognostic value of the combined detection of the protein expression of metastasis suppressor 23-H1 (Nm23-H1) and p53 using immunohistochemical analysis, and the mRNA expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction in 110 cases of stage II and III CRC. The results revealed that the expression levels of Nm23-H1 in CRC tissues were lower, compared with those in normal tissues (χ2=18.249; P<0.001), and the protein expression levels of p53 were higher in the CRC tissues (χ2=23.940; P<0.001); although the mRNA expression levels of Nm23-H1 and p53 presented with the same trend. The protein expression of Nm23-H1 was correlated with lymph node metastases (χ2=11.847; P=0.001) and pathological patterns (χ2=6.911; P=0.032). However, it did not correlate with patient gender or age, or with tumor World Health Organization classification or invasive depth (P>0.05). No significant correlation was observed between the expression of p53 and clinicopathological features (P>0.05). Patients with CRC with Nm23-H1(+)/p53(-) tumors had increased survival rates, with a five-year overall survival rate of 83.8% and a five-year disease-free survival rate of 70.2%. The five-year overall survival rates in other study cohorts were lower, compared with the Nm23-H1(+)/p53(-) group (P<0.0125), and this was the same for the five-year disease-free survival rate (P<0.0125). In conclusion, the present study demonstrated that the combined detection of the protein expression of Nm23-H1 and p53 was associated with the long term survival rates of patients with stage II and III CRC; and this may offer potential for use as a predictor of survival rates in patients with CRC.

Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner.

BACKGROUND: The epithelial-mesenchymal transition (EMT) is crucial for the invasion and metastasis of breast cancer. However, how Notch signaling regulates the EMT process and invasion in breast cancer remains largely unknown. METHODS: The impact of Notch1 silencing by specific shRNAs on the EMT and invasion of human breast cancer MCF-7 and MDA-MB-231 cells as well as xenografts was tested by western blot, real-time polymerase chain reaction (RT-PCR), immunofluorescence, transwell, and immunohistochemistry assays. The effect of Slug silencing or upregulation on the EMT and invasion of breast cancer cells was analyzed, and the effect of Notch1 signaling on Slug expression was determined by the luciferase reporter assay. RESULTS: The Notch1 intracellular domain (N1ICD) and Jagged1 were expressed in breast cancer cells. Notch1 silencing reversed the spontaneous EMT process and inhibited the migration and invasion of breast cancer cells and the growth of xenograft breast cancers. The expression of N1ICD was upregulated significantly by Jagged1-mediated Notch signaling activation. Moreover, Jagged1-mediated Notch signaling promoted the EMT process, migration, and invasion of breast cancer cells, which were abrogated by Notch silencing. Furthermore, the N1ICD positively regulated the Slug expression by inducing Slug promoter activation. Importantly, the knockdown of Slug weakened the invasion ability of breast cancer cells and reversed the Jagged1-induced EMT process with significantly decreased expression of vimentin and increased expression of E-cadherin. In addition, Slug overexpression restored the Notch1 knockdown-suppressed EMT process. CONCLUSIONS: Our novel data indicate that Notch signaling positively regulates the EMT, invasion, and growth of breast cancer cells by inducing Slug expression. The Notch1-Slug signaling axis may represent a potential therapeutic target for breast cancer therapy.

Reduced expression of MYC increases longevity and enhances healthspan.

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role.

Breast cancer is the most common malignancy in women. The Notch signaling pathway has been shown to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism remains unknown. Here, the influence of Notch1 signaling in mammary epithelial cells was studied. We showed that Notch1 promotes proliferation in MCF7 and MCF10A cells. Transwell assay indicated that Notch1 overexpression promotes cell migration and the invasion of breast cancer cells. We showed that MCF7 and MCF10A cells overexpressing Notch1 acquired features of epithelial-mesenchymal transition (EMT) and displayed a cancer stem cell (CSC) phenotype. The expression levels of the epithelial markers E-cadherin and occludin were decreased, while the expression levels of the mesenchymal markers N-cadherin, vimentin and fibronectin were increased in cells overexpressing Notch1. We demonstrated that Notch1 induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) in breast cancer cells and increased the expression of p65 and interleukin (IL)-1ß. Inhibition of STAT3 activity by JSI124 reduced the expression of p65 and IL-1. Treatment of MCF7-notch1 and MCF10A-notch1 cells with JSI124 also reduced the expression of N-cadherin, markers of epithelial mesenchymal transition and increased the expression of E-cadherin. Our results suggest that Notch1 promotes EMT and the CSC phenotype through induction of STAT3.

Clinical characteristics and prognostic analysis of Krukenberg tumor.

Krukenberg tumor is a rare metastastic tumor of the ovary, characterized by poor prognosis. In order to analyze the clinical characteristics and prognostic factors, we retrospectively investigated 128 patients who were diagnosed with Krukenberg tumor between January, 1990 and December, 2010. The median patient age was 48 years. The median overall survival (OS) of Krukenberg tumor for all patients was 16 months (95% CI: 15-19 months). The median OS among patients with Krukenberg tumors of gastric, colorectal, breast and other origins (including appendix, gallbladder, small intestine and unknown primary) was 11, 21.5, 31 and 19.5 months, respectively (P<0.0001). In the univariate analysis, synchronous metastasis, no chemotherapy, ovarian metastasis beyond the pelvis, ascites and no metastasectomy were identified as significant poor prognostic factors. The multivariate analysis suggested that synchronous metastasis (P=0.0080), pelvic invasion (P=0.0138), ascites (P<0.0001) and no metastasectomy (P=0.0060) were independent factors for predicting unfavorable OS. It was suggested that the prognosis of Krukenberg tumor is dismal and ovarian metastasectomy may prove beneficial. Adequate treatment planning is required for this group of patients.

Death by transposition - the enemy within?

Here we present and develop the hypothesis that the derepression of endogenous retrotransposable elements (RTEs) - "genomic parasites" - is an important and hitherto under-unexplored molecular aging process that can potentially occur in most tissues. We further envision that the activation and continued presence of retrotransposition contribute to age-associated tissue degeneration and pathology. Chromatin is a complex and dynamic structure that needs to be maintained in a functional state throughout our lifetime. Studies of diverse species have revealed that chromatin undergoes extensive rearrangements during aging. Cellular senescence, an important component of mammalian aging, has recently been associated with decreased heterochromatinization of normally silenced regions of the genome. These changes lead to the expression of RTEs, culminating in their transposition. RTEs are common in all kingdoms of life, and comprise close to 50% of mammalian genomes. They are tightly controlled, as their activity is highly destabilizing and mutagenic to their resident genomes.