Prognostic impact of PTK6 expression in triple negative breast cancer.

BACKGROUND: The aim of this study was to investigate the expression of PTK6 in different groups of triple negative breast cancer and its impact on prognosis. METHODS: Retrospective study of a total of 209 surgical specimens of breast cancer were identified by IHC or FISH methods as triple negative,and divided into a lymph node metastasis positive (LNM +)group (n = 102) and a lymph node metastasis negative(LNM-) group (n = 107) according to the lymph node status of the surgical specimen. PTK6 expression was detected by IHC technique in all surgical specimens. PTK6 expression and clinicopathological features was explored by Chi-square test. The prognosis of different groups of patients was analyzed by Kaplan-Meier survival analysis and COX analysis. RESULTS: The incidence of PTK6 expression in the LNM + group (78.4%) was significantly higher than in the LNM- group (28%). Clinicopathological analysis showed that PTK6 expression in the LNM + group was negatively correlated with the 5-year survival of patients. Kaplan-Meier analysis showed that only PTK6 expression in the LNM + group was negatively correlated with OS and DFS. COX analysis also showed that PTK6 expression and N stage were independent prognostic factors for DFS in the LNM + group. No correlation was observed between HER2 and PTK6 expression in any of the groups. CONCLUSIONS: This study suggests that PTK6 promotes tumor development and was associated with poor prognosis in the LNM + group of triple negative breast cancer. Inhibition of PTK6 may be a new approach for the treatment of triple negative breast cancer patients, especially those with metastasis.

Implications of Advances in Studies of O6-Methylguanine-DNA- Methyltransferase for Tumor Prognosis and Treatment.

O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair enzyme, which reverses the alkylation of guanine O6 through directtransfer of the methyl group, maintains the gene stability and avoids tumor occurrence. Studies have shown that MGMT gene methylation, polymorphism and protein expression are involved in the process of various tumor development, such as colon cancer, gastric carcinoma, etc. MGMT gene promotes methylation, protein expression and enzyme activity from various tissues, which resultsin different effects on the prognosis of patients. MGMT promoter methylation is a positive factor for the prognosis of Glioblastoma (GBM), which can prolong overall survival and progression-free survival, reduce the resistance of tumor cells to temozolomide treatment, and improve the prognosis. The treatment of tumors based on MGMT focuses on three aspects: targeting MGMT to increase the sensitivity of alkylated drug therapy in tumors, immunotherapy combined with alkylated agents on tumor treatment, and treatment for patients with MGMT promoter non-methylation. Similarly, a number of studies have targeted MGMT to reduce alkylated agent resistance in other systems. Although numerous studies on MGMT in tumors have been reported, there are problems that need to be solved, such as selection and consensus of MGMT promoter methylation detection methods (CpG detection sites, cut-off value) and the treatment of MGMT non-methylated GBM patients, especially elderly patients. In this review, we describe the regulation of MGMT expression and its role inchemotherapy, especially in gliomas. Further studies exploring new methods targeting MGMT with better curative effect and less toxicity are advocated. We anticipate that these developments will be progressive and sufficiently used for clinical application.

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.

The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network's nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal's genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.

A study on the accuracy of a new fluorescent detection method for vaginal fungi.

BACKGROUND: To investigate the positive rate and clinical applicability of liquid-based fungal method for detecting of vaginal fungi. We collect the secretions from the posterior vaginal fornix and the vaginal wall of 198 patients with clinically suspected fungi vaginitis patients for study. METHODS: The vaginal fungi of vaginal discharge were detected by fluorescence method, i.e., by liquid-based thin-layer fungi fluorescence morphology staining detection kit (liquid-based fungal method), saline smear method and fungal culture method. RESULTS: The positive rate of liquid-based fungal method, saline smear method was 50%, 25.75% respectively. The positive rate of liquid-based fungal method were 50%. The true positive rate of liquid-based fungal method (87.85%) was higher than that of saline smear method (45.79%, P < 0.001), which was easy to miss diagnosis. Moreover, the Kappa (K) of liquid-based fungal method was 0.81, and P < 0.01, which was statistically significant, indicating that the consistency of the two detection methods is good. Of the eight common symptoms of fungal vaginitis, the positive symptom coincidence rate of liquid-based fungal method was consistent with that of fungal culture method. It was also easier to see fungi under a microscope than with saline smear method. CONCLUSION: The liquid-based fungal method has a high positive coincidence rate and accuracy in the detection of vaginal fungi, and it is convenient to operate and implement steps. Therefore, it may be applied in clinical practice. Or a combination of several detection methods can be used.

Non-islet cell tumor hypoglycemia caused by breast tumor: A case report.

INTRODUCTION: Non-islet cell tumor hypoglycemia (NICTH) generally refers to hypoglycemia caused by tumors other than islet cell tumors. Although hypoglycemia is a common clinical emergency, NICTH rarely occurs in patients with breast cancer. PATIENT CONCERNS: A 47-year-old woman presented with repeated hypoglycemia hypoglycemia caused by a lobulated breast tumor. DIAGNOSES: Hypoglycemic symptoms occurred many times during fasting and in the early morning. Insulin and C-peptide levels were decreased; insulin-like growth factor (IGF)-II: IGF-I was greater than 10. Postoperative pathology revealed a lobulated tumor in the breast. After excluding other causes of hypoglycemia, the patient was diagnosed with NICTH due to breast cancer. INTERVENTIONS: Total mastectomy of right breast was performed. OUTCOMES: After 3 years of follow-up, hypoglycemia did not recur. CONCLUSION: Patients with breast cancer may experience recurrent hypoglycemia. After exclusion of insulinomatous and pancreatic origin of hypoglycemia, the possibility of NICTH should be considered, and surgical resection of the primary tumor should be performed as soon as possible.

LncRNA MALAT1 promotes relapse of breast cancer patients with postoperative fever.

Postoperative fever is prevalent in many breast cancer patients. Some retrospective studies proposed that postoperative fever might also be considered as a rapid rough indicator for the poor prognosis of breast cancer patients. This study aims to explore the possible molecular mechanisms underlying the relapse of breast cancer patients with early postoperative fever. Our results indicated plasma levels of lncRNA MALAT1 were elevated in breast cancer patients with early postoperative fever and were associated with RFS. Lipopolysaccharide (LPS) was able to induce fever and systemic inflammatory responses in 4T1 xenograft mice, and promote lung metastasis. But after knocking down lncRNA MALAT1, the inflammatory responses and metastasis of lung were significantly reduced. Moreover, after knocking down lncRNA MALAT1 in the 4T1 cells, TNF-α level in the supernatants was sharply decreased, and the invasion and migration induced by LPS was also weakened. Cumulatively, our data indicates that MALAT1 is closely related to recurrence and metastasis of breast cancer patients with early postoperative fever.

Analysis of 246 sentinel lymph node biopsies of patients with clinical primary breast cancer by application of carbon nanoparticle suspension.

AIM: This study aims to explore the accuracy, specificity and laws of axillary lymph node metastasis predicted by sentinel lymph node biopsy (SLNB) by comparing axillary lymph node status via SLNB and axillary lymph node dissection (ALND) with nanocarbon as the tracer. METHODS: Forty six patients were retrospectively analyzed. These patients underwent SLNB with nanocarbon as the tracer from March 2013 to April 2014. RESULTS: Two hundred and forty six patients of sentinel lymph node (SLN) were successfully detected. Among these patients, 8 patients had 1 SLN (3.25%), 33 patients had 2 SLN (13.41%), 46 patients had 3 SLN (18.70%), 51 patients had 4 SLN (20.73%), 40 patients had 5 SLN (16.26%), 24 patients had 6 SLN (9.76%) and 24 patients had 7 or more SLN (9.76%). The SLNB success rate of nanocarbon staining in the 246 cases was 99.59%, accuracy rate was 97.06% and sensitivity was 93.22%. Furthermore, false negatives were found in four patients, and the false-negative rate was 6.78%. The number of lymph node metastasis in the SLNB and ALND of early-stage breast cancer was analyzed. When the number of SLN dissection was 1, 2, 3, 4, 5, 6 or 7, the coincidence rate of lymph node metastasis for SLNB and ALND was 80.00, 84.36, 78.57, 88.89, 90.48, 80.00, 73.68 and 78.36, respectively. CONCLUSION: Sentinel lymph node biopsy performed using the nanocarbon staining method is simple, easy and reliable, and it can be used to predict the axillary status of breast cancer in the early stage.

Panduratin A Inhibits Cell Proliferation by Inducing G0/G1 Phase Cell Cycle Arrest and Induces Apoptosis in Breast Cancer Cells.

Because of the unsatisfactory treatment options for breast cancer (BC), there is a need to develop novel therapeutic approaches for this malignancy. One such strategy is chemotherapy using non-toxic dietary substances and botanical products. Studies have shown that Panduratin A (PA) possesses many health benefits, including anti-inflammatory, anti-bacterial, anti-oxidant and anti-cancer activities. In the present study, we provide evidence that PA treatment of MCF-7 BC cells resulted in a time- and dose-dependent inhibition of cell growth with an IC50 of 15 µM and no to little effect on normal human MCF-10A breast cells. To define the mechanism of these anti-proliferative effects of PA, we determined its effect critical molecular events known to regulate the cell cycle and apoptotic machinery. Immunofluorescence and flow cytometric analysis of Annexin V-FITC staining provided evidence for the induction of apoptosis. PA treatment of BC cells resulted in increased activity/expression of mitochondrial cytochrome C, caspases 7, 8 and 9 with a significant increase in the Bax:Bcl-2 ratio, suggesting the involvement of a mitochondrial-dependent apoptotic pathway. Furthermore, cell cycle analysis using flow cytometry showed that PA treatment of cells resulted in G0/G1 arrest in a dose-dependent manner. Immunoblot analysis data revealed that, in MCF-7 cell lines, PA treatment resulted in the dose-dependent (i) induction of p21WAF1/Cip1 and p27Kip1, (ii) downregulation of Cyclin dependent kinase (CDK) 4 and (iii) decrease in cyclin D1. These findings suggest that PA may be an effective therapeutic agent against BC.

miR-29a regulated ER-positive breast cancer cell growth and invasion and is involved in the insulin signaling pathway.

Increasing amounts of evidence show that insulin can activate different insulin signaling pathways to promote breast cancer growth and invasion. miR-29a plays crucial roles in decreasing glucose-stimulated insulin secretion, as well as in regulating breast cancer cell proliferation and EMT. However, the mechanism responsible for the regulatory effects of miR-29a on breast cancer growth and invasion and the relationship between these effects and insulin signaling remains unclear. Herein, we showed that human insulin increased miR-29a expression in ER-positive breast cancer cells and that miR-29a facilitated the ability of insulin to promote breast cancer cell proliferation and migration. We found that miR-29a-induced cell proliferation and metastasis acceleration occurred primarily through ERK phosphorylation. The IGF-1R is the upstream target gene of miR-29a, while CDC42 and p85α are the downstream target genes of miR-29a. These results have provided us with information regarding the molecular mechanisms by which hyperinsulinemia promotes breast cancer occurrence and development and thus leads to a poor prognosis in breast cancer patients and indicate that miR-29a plays an important role in breast cancer development and invasion.

miR-34a expression in human breast cancer is associated with drug resistance.

miR-34a is significantly down-regulated in breast cancer tissues and cell lines, which may be correlated with breast cancer multi-drug resistance (MDR). Here, we conducted cell-based experiments and clinical studies in a cohort of 113 breast cancer samples to analyze miR-34a expression and breast cancer MDR. Expression of miR-34a is down-regulated in the multi-drug resistant MDR-MCF-7 cells compared with its parental cells. Patients with miR-34a low expression had poorer overall survival (OS) and disease free survival (DFS) in comparison with those with high expression. Transfecting miR-34a mimics into MDR-MCF-7 breast cancer cells led to partial MDR reversal. Compared with the control group, miR-34a significantly reduced both the mRNA and protein expressions of BCL-2, CCND1 and NOTCH1, but no obvious changes were found in P53 or TOP-2a expression. In breast cancer tissue samples, the expression of miR-34a was related to BCL-2, CCND1 and NOTCH1, but not to HER-2, P53 and TOP-2a. Altogether, our findings suggest that miR-34a is an MDR and prognosis indicator of breast cancer, which may participate in the regulation of drug-resistant breast cancer by targeting BCL-2, CCND1, and NOTCH1.

Interleukin-12 activated CD8+ T cells induces apoptosis in breast cancer cells and reduces tumor growth.

During the past two decades, cytokines have emerged as key molecules to modulate innate and adaptive immunity and mediate anti-tumor activity. Although multiple cytokine types are implicated for such anti-tumor activity in several cancer types, it remains largely unknown in breast cancer. In this study, cytokines that are prior known for antitumor activity in different cancer types were examined against breast cancer using a 4T1 cells based xenograft-model. Our results showed Interleukin-12 (IL-12) (500ng/mouse) significantly suppressed the growth of tumors, while other cytokines showed minimal suppression. Subsequent molecular analysis by flow cytometry and immunohistochemistry confirmed the CD8+ cells infiltration and Interferon-γ (IFN-γ) production by them in tumor environment. In addition, we observed that IFN-γ production by activated CD8+ cells directly induced apoptosis in tumor cells, which together indicate that IL-12 causes CD8+ cells to infiltrate and secrete IFN-γ in tumor environment, which induce apoptosis in them and causes tumor growth suppression. Furthermore, we showed that lower dosage of IL-12 and chemotherapy drug tamoxifen combinations enhanced the tumor suppression as opposed to single treatments, and thereby propose an alternate option for high dosage associated effects for both drug and cytokine treatments.

Luminal B breast cancer: patterns of recurrence and clinical outcome.

In recent years, most studies on breast cancer relapse and metastasis have focused on non-luminal breast cancers (including the basal-like and HER-2 subtypes) because of their poor prognosis. However, the luminal B subtype is more common, but this type has not been investigated as thoroughly. In the current study, we collected data on 258 patients with luminal-B breast cancer patients with recurrence and metastasis served as the observation group, and 189 patients with non-luminal breast cancer during the same period served as the control group. This study aimed to investigate the pattern of recurrence and clinical outcome after follow-up treatment for luminal B breast cancer. We found a higher proportion of local recurrence and single bone metastasis in patients with luminal B breast cancer than in patients in the non-luminal groups. The risk of recurrence and metastasis in patients with luminal B breast cancer during a 2- to 5-year period and after 5 years was still present, but the risk in patients with non-luminal breast cancers had obviously decreased during the same period. Patients with luminal B breast cancer with recurrence or/and metastasis had a better prognosis after reasonable treatment. The recurrence patterns and clinical outcomes of patients with luminal B breast cancer according to HER2 status were also different, to some degree. These results are of potential clinical relevance especially for the monitoring of clinical prognosis and targeted therapy intervention for luminal B breast cancer.

[Correlation between Tau expression and clinicopathological characteristics of breast invasive ductal carcinomas].

OBJECTIVE: To explore the expression of Tau protein in breast invasive ductal carcinomas and examine the correlation between its expression and clinicopathological characteristics of breast cancer. METHODS: The clinicopathological data of 150 breast cancer patients at Third Municipal Hospital from October 2007 to June 2011 were collected and analyzed. Immunohistochemical method was used to detect the expressions of estrogen receptor (ER), progesterone receptor (PR), HER-2 and Tau protein. RESULTS: No correlations existed between the expression of Tau protein and age, tumor size or node metastasis of breast cancer patients (χ(2) = 0.02, P = 0.88; χ(2) = 0.55, P = 0.46; χ(2) = 1.02, P = 0.31). The expressions of Tau in ER positive patients were significantly higher than ER negative patients. And this trend extended to PR positive and HER-2 negative patients (χ(2) = 15.77, P = 0.00; χ(2) = 5.03, P = 0.03; χ(2) = 8.00, P = 0.01). The expression of Tau protein in Luminal A subtype was significantly higher than in Luminal B subtype, HER-2 over-expression subtype and basal like subtype (χ(2) = 7.26, P = 0.01). CONCLUSIONS: Over-expressed in breast cancer, Tau protein is associated with ER, PR and HER-2. However, the relation between Tau protein and prognosis of breast cancer requires further researches.

Tau proteins expressions in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy.

Tau is a microtubule-associated protein and expressed in normal breast epithelial cells and breast cancer. Tau expression in breast cancer may be important for chemotherapy optimization. This study is to investigate the expression of Tau in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy. Levels of Tau protein in advanced breast cancer were detected immunohistochemically. The chemotherapeutic efficacy indexes in Tau(-) group, which includes the remission rate, Miller-Payne pathological reactive grade, and pathologic complete response rate, were improved compared with that in Tau(+) group. There was difference in the efficacy indexes among ER+ subgroups but not among ER- patients. In addition, Tau expression was positively correlated (r = 0.32, P < 0.00). In multivariate analysis, when age, clinical stage, postoperative lymph node metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status were included, postoperative lymph node metastasis and Tau-negative status were identified as independent predictors of pathologic complete response. In conclusion, negative Tau protein expression may be an effective predictor for taxane-containing neoadjuvant chemotherapy, especially in ER+ subgroups. Further study on the molecular mechanism and utility of Tau for individualizing adjuvant chemotherapy is warranted.

Clinical features and molecular phenotypes of breast cancer in patients with type-2 diabetes mellitus.

OBJECTIVE: To investigate the clinical features, molecular phenotypes and clinical prognosis of breast cancer patients with type-2 diabetes mellitus, thereby providing a basis for individualized therapy of breast cancer. METHODS: 105 breast cancer patients with type-2 diabetes mellitus (DM) presenting from January 2005 to December 2010 were enrolled in this study. 200 breast cancer non-diabetic patients in the same period were randomly selected as the control group. The clinical data of DM group and control group were retrospectively analyzed. The SPSS12.0 software was used for statistics and survival analysis. RESULTS: The mean age of the patients in DM group were of 57.2∓11.8 years, which was older compared with the control group. The percentage of postmenopausal patients was 71.4% and the ratio of grade II+III was 98.8%, which was higher than the control group. The neoadjuvant chemotherapy response rate of DM group was 67.5%, which was lower than control group. The patients in DM group had later clinical stage and more lymph metastasis. The proportion of advanced breast cancer was 68.57% and the ratio of lymph node metastasis was 66.01%. All the difference was significant (P<0.05). But there was no significant difference in tumor size and molecular phenotype between the diabetic group with breast cancer and the control group. Disease-free survival and overall survival rates of DM group were 80.2% and 84.2%, which were worse than those in the control group. All the differences were significant (P<0.05). After excluding the patients with other causes of death, results of overall survival still showed worse in DM group, but the difference was not statistically significant (P>0.05). Serum insulin at fasting and two hours postprandial were higher than normal value in DM group, but serum insulin levels in the control group changed in the normal range. CONCLUSION: There were older patients, higher proportion of high pathological grade, more lymph node metastasis, later clinical stages in the diabetic group with breast cancer. Breast cancer patients with type-2 diabetes mellitus were at risk of a poor prognosis. Hyperinsulinemia may be the real cause of poor prognosis in breast cancer patients with type-2 diabetes.