Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines

Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer

Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited

Effect of Uterine Massage to Women during Third Stage of Labor on Preventing Postpartum Hemorrhage

Background: Postpartum hemorrhage is still the leading cause of death of birthing mothers in the world today. The aim of this study is to assess the effect of uterine massage to women during the third stage of labor on preventing postpartum hemorrhage. Method: The Design of this study was quasi-experimental. The study sample consisted of 400 women divided into 4 groups. The study was conducted at Menoufia University Hospital. The tool of this study was a structured interview questionnaire. The validity of the tool was ascertained by a group of experts who reviewed the tool for content validity. The reliability of the tool was assessed through testing their internal consistency. Results: there was statistically significant difference between the studied groups as regards the amount of blood loss, time of placental delivery, the use of uterotonics and the occurrence of postpartum hemorrhage. Conclusion, uterine massage during and after placental delivery is effective in reducing blood loss. uterine massage during and after placental delivery must be applied. It is also recommended to teach nurses how to apply uterine massage.

Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib

The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer

Computing stress intensity factors for curvilinear cracks

The use of the interaction integral to compute stress intensity factors around a crack tip requires selecting an auxiliary field and a material variation field. We formulate a family of these fields accounting for the curvilinear nature of cracks that, in conjunction with a discrete formulation of the interaction integral, yield optimally convergent stress intensity factors. We formulate three pairs of auxiliary and material variation fields chosen to yield a simple expression of the interaction integral for different classes of problems. The formulation accounts for crack face tractions and body forces. Distinct features of the fields are their ease of construction and implementation. The resulting stress intensity factors are observed converging at a rate that doubles the one of the stress field. We provide a sketch of the theoretical justification for the observed convergence rates, and discuss issues such as quadratures and domain approximations needed to attain such convergent behavior. Through two representative examples, a circular arc crack and a loaded power function crack, we illustrate the convergence rates of the computed stress intensity factors. The numerical results also show the independence of the method on the size of the domain of integration

CD40 signaling predicts response to preoperative trastuzumab and concomitant paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide in HER-2-overexpressing breast cancer

Introduction We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (T/FEC). Methods Pretreatment fine-needle aspiration specimens from 45 patients with HER-2-overexpressing stage II to IIIA breast cancer were subjected to transcriptional profiling and examined for differential expression of various genes and gene sets. The primary endpoint for tumor response was pathologic complete response (pCR). Correlations between pCR and gene expression were sought. Results The overall pCR rate was 64%. Age, nuclear grade, tumor size, nodal status, quantitative expression of estrogen and HER-2 receptor mRNA, and HER-2 gene copy number showed no correlation with pCR. Results of gene set enrichment analysis suggested that the lower expression of genes involved with CD40 signaling is associated with a greater risk of residual cancer after the preoperative chemotherapy that includes trastuzumab. Conclusion CD40 signaling may play a role in determining response to trastuzumab-plus-T/FEC therapy in patients with HER-2-overexpressing breast cancer.PubMedWoSScopu

HER2 therapy: Molecular mechanisms of trastuzumab resistance

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. The majority of patients with metastatic breast cancer who initially respond to trastuzumab develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse despite trastuzumab-based therapy. In this review, we discuss potential mechanisms of antitumor activity by trastuzumab, and how these mechanisms become altered to promote therapeutic resistance. We also discuss novel therapies that may improve the efficacy of trastuzumab, and that offer hope that the survival of breast cancer patients with HER2-overexpressing tumors can be vastly improved

What's in a name? developing definitions for common health technology assessment product types of the international network of agencies for health technology assessment (Inahta)

Objectives: A mapping exercise was undertaken to determine how HTA is being described and conducted across the International Network of Agencies for Health Technology Assessment (INAHTA), with the aim of harmonizing terminologies and approaches. Methods: Three progressive surveys were undertaken. In 2010, INAHTA agencies were asked to provide details on all of their HTA products. In 2013, additional information was sought on key methodological characteristics of five of the most common HTA product types. Subsequently, final agreement was sought on three proposed product types. Results: Forty-five HTA agencies responded to at least one of the surveys. In 2010, twenty-one agencies reported publishing over seventy named HTA products. Core domains associated with full HTA reports were reported by a third of agencies but were labeled differently, so products were classified according to product type (n =17). Agencies producing short, tailored products increased between 2010 and 2013, with the publication of rapid reviews doubling from 33 percent to 66 percent. In 2013, half of the agencies adapted their common HTA products from documents produced by other agencies. A consensus (>70 percent) was achieved on definitions for HTA reports, mini-HTAs, and rapid reviews. Conclusions: The product label for an HTA is not always indicative of its content. Terminology has, therefore, been agreed to make explicit the trade-off between rigor and timeliness in three common HTA product types. An INAHTA Product Type (IPT) Mark has been created to identify each of these. It is hoped this will further facilitate HTA adaptation between agencies and reduce duplication of effort.Tracy Merlin, David Tamblyn, Benjamin Ellery and the INAHTA Quality Assurance Grou