An affinity tool for the isolation of endogenous active mTORC1 from various cellular sources.

The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of mammalian cell growth that is dysregulated in a number of human diseases, including metabolic syndromes, aging, and cancer. Structural, biochemical, and pharmacological studies that have increased our understanding of how mTORC1 executes growth control often relied upon purified mTORC1 protein. However, current immunoaffinity-based purification methods are expensive, inefficient, and do not necessarily isolate endogenous mTORC1, hampering their overall utility in research.

PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.

Background: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance.

Pharmacists' warfarin therapy knowledge and counseling practices in the Eastern Province, Saudi Arabia: A cross-sectional study.

Context: For several decades, warfarin has been considered the mainstay anticoagulant for patients who require long-term prevention or treatment of thromboembolic disorders in outpatient settings. Hospital and community pharmacists--with adequate knowledge level and counseling skills--can play a significant role in improving warfarin therapy.

Aims: The aim of this study was to assess the hospital and community pharmacists' warfarin therapy knowledge and counseling practices in the eastern province of Saudi Arabia.

Awareness of Physicians and Clinical Pharmacists About ACC/AHA Guidelines for Dyslipidemia Management: A Cross-Sectional Study.

Introduction: Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality worldwide. Although genetics could contribute to the incidence of CVD, they are mostly acquired conditions. Management of precipitating factors such as hyperlipidemia can prevent CVD.

Patterns and sociodemographic characteristics of substance abuse in Al Qassim, Saudi Arabia: a retrospective study at a psychiatric rehabilitation center.

Background: The problem of substance abuse is one of the top 20 risk factors for poor health worldwide. Though widely prevalent in the Middle East, there are few studies in Saudi Arabia.

Objective: Record the pattern of substances abuse and the sociodemographic characteristics of abusers attending the local rehabilitation center.

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored.

Stratification and therapeutic potential of PML in metastatic breast cancer.

Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer.

Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer.

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins.

MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.

Purpose: PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors.

Experimental Design: In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways.

PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes.

Targeting a cell state common to triple-negative breast cancers.

Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their 'basal-like' transcriptional profiles.

mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.

Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited.

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer.

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds.

PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.

Unlabelled: PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors.

Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.

Unlabelled: There is a need to improve treatments for metastatic breast cancer. Here, we show the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in a MMTV-CreBrca1(f/f)Trp53(+/-) mouse model of breast cancer. When treated with the pan-class IA PI3K inhibitor NVP-BKM120, tumor doubling was delayed from 5 to 26 days.

Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy.

Purpose: The PI3K/Akt/mTOR pathway is an attractive target in HER2-positive breast cancer that is refractory to anti-HER2 therapy. The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance.

Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients.

Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene.

The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells.

The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a critical component of IGF and estrogen receptor (ER)α cross talk. The insulin receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor and dictate a specific biological response, in which IRS-1 drives proliferation and IRS-2 is linked to motility.

Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2.

Progesterone action contributes to the signaling of many growth factor pathways relevant to breast cancer tumor biology, including the insulin-like growth factor (IGF) system. Previous work has shown that insulin receptor substrate-2 (IRS-2) but not IRS-1 levels were regulated by progestin in progesterone receptor-B (PR-B) isoform expressing MCF-7 cells (C4-12 PR-B). Furthermore, type 1 IGF receptor (IGF1R) signaling via IRS-2 correlated with the increased cell migration observed in a number of breast cancer cell lines.

Session 1.2: national health perspectives of the Tsunami crisis.

This is a summary of the presentations and discussion of Session 1.2 of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related national health perspectives as pertaining to the responses to the damage created by the Tsunami.

Insulin-like growth factor-I and breast cancer therapy.

Targeting hormonal and growth factor signaling pathways has proven to be useful in the treatment of breast cancer. In vitro, animal, and epidemiologic evidence provide a rationale for the relevance of the insulin-like growth factor (IGF) system to breast cancer biology. The IGF system has been implicated in promoting mitogenic, metastatic, and antiapoptotic phenotypes in breast cancer.

Insulin-like growth factor-I and cancer risk.

Growth factor pathways are fundamental in normal tissue regulation and development. In many tissues, factors that function in normal growth and development also have important regulatory roles in transformed malignant cells. The insulin-like growth factor (IGF) system is implicated in the regulation of the malignant phenotype by its effects on proliferation, differentiation, and apoptosis.