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In a pooled analysis of nine clinical trials involving almost 5000 women with breast cancer who underwent examination of the bone marrow for metastatic cancer cells, the presence of metastases in the bone marrow at the time of diagnosis of breast cancer was associated with a poor prognosis. In trials involving almost 5000 women with breast cancer, the presence of micrometastases in the bone marrow at the time of diagnosis of breast cancer was associated with a poor prognosis. Data from experiments in animals 1 performed in the 1960s and from more recent immunocytochemical 2 , 3 and molecular 4 , 5 studies suggest that lymph-node involvement does not accurately predict hematogenous dissemination of cancer cells, nor is hematogenous dissemination necessarily associated with lymph-node involvement. 6 , 7 During the past two decades, several studies have assessed the prevalence and prognostic value of hematogenous dissemination of tumor cells in patients with node-positive and node-negative breast cancer. 3 , 8 – 15 The influence of the presence of micrometastasis in the bone marrow on prognosis has been shown in patients with identical stages of breast cancer, as defined by tumor . . .

Triple negative breast cancer (TNBC) is characterized by the absence of hormones and growth factor receptors. It is typically responsive to anthracycline/taxol-based conventional chemotherapy. However, major therapeutic limitations include systemic toxicity and acquired resistance to chemotherapeutics. To combat this, nutritional herbs from traditional Chinese medicine (TCM) with limited reported toxicity may represent treatment alternatives for TNBC. Such herbs can effectively target multiple signaling pathways in numerous breast cancer models. The efficacy of various nutritional herbs in a cellular model of TNBC is associated with the downregulation of retinoblastoma (RB) signaling through the cyclin D-CDK4/6-RB axis. Therefore, the present study was designed to examine the effects of Drynaria fortunei (DF) in the same cellular model of TNBC to identify potential mechanistic leads for its efficacy. DF is a nutritional herb that represents a common component of herbal formulations used in TCM. The estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative MDA-MB-231 human breast carcinoma-derived cell line was used as the cellular model for TNBC in the present study. Non-fractionated aqueous extract from the bark of DF represented the test agent. Quantitative end-point biomarkers for the efficacy of DF assessed in the present study included cell cycle progression, RB signaling and caspase 3/7 activity. Treatment with DF at cytostatic concentration induced S phase cell cycle arrest and inhibited RB signaling as evidenced by the downregulated expression of cyclin E, CDK2, E2F1 and RB phosphorylation. DF treatment increased pro-apoptotic caspase 3/7 activity which was inhibited by the pan-caspase inhibitor Z-VAD-FMK. DF treatment also exhibited increased expression of cleaved ADP-ribose) polymerase-1. These data identify potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present TNBC model. The present experiments validated a mechanism-driven experimental approach to identify efficacious nutritional herbs and/or their bioactive constituents as treatment alternatives for TNBC.

Triple-negative breast cancer (TNBC) lacks the expressions of estrogen receptor-α, progesterone receptor and human epidermal growth factor receptor-2. The treatment options for TNBC include anthracyclin/taxol based conventional chemotherapy and small molecular inhibitor based targeted therapy. However, the therapeutic efficacy is limited by systemic toxicity and acquired tumor resistance; identification of less toxic testable alternatives is urgently required. Non-toxic nutritional herbs are commonly used in traditional Chinese herbal medicine for general health management and may additionally represent a testable therapeutic alternative for TNBC. The present study examined the growth inhibitory efficacy of the nutritional herb Cornus officinalis (CO) in MDA-MB-231 cells, which represent a cell culture model for TNBC, and identified potential mechanistic leads. In MDA-MB-231 cells, CO induced dose-dependent cytostatic growth arrest [inhibitory concentration (IC)50, 0.1% and IC90, 0.5%], and inhibited anchorage independent colony formation. Mechanistically, CO inhibited G1 to S phase transition leading to G1 arrest and decreased the expression of cyclin D1 and phosphorylated-retinoblastoma proteins. CO additionally altered apoptosis specific BCL-2 associated X protein/B-cell lymphoma-2 expression and upregulated pro-apoptotic caspase-3/7 activity. Collectively, these data provided mechanistic evidence for the efficacy of CO, and validated a mechanism-based approach to prioritize efficacious nutritional herbs as testable alternatives for secondary prevention/treatment of TNBC.

Aromatase inhibitors (AIs) represent a treatment option for post-menopausal estrogen receptor-positive (ER+) breast cancer as monotherapy, or in combination with cyclin-dependent kinase 4/6 or mTOR inhibitors. Long-term treatment with these agents leads to dose-limiting toxicity and drug resistance. Natural substances provide testable alternatives to current therapy. Tabebuia avellanedae (TA) tree is indigenous to the Amazon rainforest. The inner bark of TA represents a medicinal dietary supplement known as Taheebo. Non-fractionated aqueous extract from TA is an effective growth inhibitor in the Luminal A and triple negative breast cancer models. The quinone derivative naphthofurandione (NFD) is a major bioactive agent in TA. The present study examined the efficacy of finely ground powder from the inner bark of TA, available under the name of Taheebo-NFD-Marugoto (TNM). The ER+ MCF-7 cells stably transfected with the aromatase gene MCF-7AROM represented a model for aromatase-expressing post-menopausal breast cancer. Anchorage-independent colony formation, cell cycle progression, pro-apoptotic caspase 3/7 activity, apoptosis-specific gene expression, aromatase activity and select estradiol (E2) target gene expression represented the mechanistic end points. Treatment of MCF-7AROM cells with TNM induced a dose-dependent reduction in E2-promoted anchorage-independent colony number. Mechanistic assays on TNM-treated MCF-7AROM cells demonstrated that TNM at a concentration of 10 µg (NFD content: 2 ng), induced S-phase arrest, increased pro-apoptotic caspase 3/7 activity, increased pro-apoptotic BAX and decreased anti-apoptotic BCL-2 gene expression, and inhibited aromatase activity. Additionally, TNM treatment downregulated ESR-1 (gene for ER-α), aromatase and progesterone gene expression and reduced mRNA levels of E2 target genes pS2, GRB2 and cyclin D1. Inhibition of aromatase activity, based on the NFD content of TNM was superior to the clinical AIs Letrozole and Exemestane. These data demonstrated the potential efficacy of TNM as a nutritional alternative for current therapy of aromatase positive, post-menopausal breast cancer.

The Luminal A subtype of breast cancer expresses the estrogen receptor (ER)-α and progesterone receptor (PR), but not the human epidermal growth factor receptor (HER)-2 oncogene. This subtype of breast cancer responds to endocrine therapy involving the use of selective estrogen receptor modulators and/or inhibitors of estrogen biosynthesis. However, these therapeutic agents are frequently associated with long-term systemic toxicity and acquired tumor resistance, emphasizing the need to identify non-toxic alternative treatments for chemo-endocrine therapy responsive breast cancer. The present study utilized the human mammary carcinoma-derived, ER+/PR+/HER-2− MCF-7 cell line as a model of the Luminal A subtype of breast cancer to examine the growth inhibitory effect of the Chinese nutritional herb Epimedium grandiflorum (EG) and determine the mechanisms underlying this effect. MCF-7 cells maintained in a serum-depleted culture medium retained their ability to grow in response to 17β-estradiol (E2). Treatment of the MCF-7 cells with EG resulted in dose-dependent inhibition of E2-promoted growth. Mechanistically, EG inhibited E2-promoted cell cycle progression through G1 stage arrest and modulated the cellular metabolism of E2, increasing the formation of the anti-proliferative metabolites 2-hydroxyestrone and estriol. Long-term treatment of MCF-7 cells with EG inhibited E2-promoted anchorage independent growth, a surrogate in vitro biomarker of tumorigenesis. In conclusion, the results of the present study demonstrate the growth inhibitory effects of EG on MCF-7 cells and identified clinically relevant mechanistic leads for its anti-tumorigenic efficacy.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC.

Consider a linear regression model where the response variable may be right-censored. The standard maximum likelihood estimator (MLE)-based parametric approach to estimation of regression coefficients requires that the parametric form of the error distribution be known. Given a dataset, we may not be able to find a valid parametric form for the error distribution. In such a case the error distribution is unknown and arbitrary, and a semiparametric approach is plausible. A special modified semiparametric MLE (MSMLE) of the regression coefficients is proposed. Simulation suggests that the MSMLE is consistent is asymptotically normally distributed and may be efficient. The new procedure is applied to engineering data.

<正> Consider a linear regression model Y=β’X+e.where Y may be right censored and thecdf F+o of e is unknown.We show that a modified semi-parametric MLE.denoted by .is stronglyconsistent under certain regularity conditions.Moreover.if F_o is discontinuous,then P(≠βi.o.)=0,which means that P(=βif the sample size is large)=1.The latter property has not been reportedfor the existing estimators.By contrast,most estimators,such as the Buckley-James estimator andM-estimators .satisfy that P(≠βi.o.)=1.

Consider the model $Y=\\beta ^{\\prime}\\text{X}+\\epsilon $. Let F0 be the unknown cumulative distribution function of the random variable ε. Consistency of the semi-parametric Maximum likelihood estimator of (β, F0), denoted by $(\\hat{\\beta},\\hat{F})$, has not been established under any interval censorship (IC) model. We prove in this paper that β̂ is consistent under the mixed case IC model and some mild assumptions.