LDL-mimetic lipid nanoparticles prepared by surface KAT ligation for MRI of atherosclerosis.

Low-density lipoprotein (LDL)-mimetic lipid nanoparticles (LNPs), decorated with MRI contrast agents and fluorescent dyes, were prepared by the covalent attachment of apolipoprotein-mimetic peptide (), Gd(iii)-chelate (), and sulforhodamine B () moieties on the LNP surface. The functionalized LNPs were prepared using the amide-forming potassium acyltrifluoroborate (KAT) ligation reaction. The KAT groups on the surface of LNPs were allowed to react with the corresponding hydroxylamine (HA) derivatives of and to provide bi-functionalized LNPs ().

Impact of sex hormones dysregulation and adiposity on the outcome of postmenopausal breast cancer patients.

Epidemiological studies demonstrated that, in postmenopausal women, high circulating levels of testosterone, especially when associated with weight gain, positively correlated with an increased risk of breast cancer because of the augmented production of oestrogen via testosterone aromatization in the adipose tissue. Besides, growing evidence suggests that sulfatase can increase the tissue concentration of bioactive estradiol through the reconversion of estrone sulfate, thus providing a favourable milieu for epithelial cells expressing the oestrogen receptor. In this review, we will discuss how the "obesity-insulin-testosterone" connection and the abnormal production of bioactive oestrogen - as a result of the conversion of the androgens by aromatase and the estrone reconversion by sulfatase-, may affect the response to hormone therapy and the outcome of postmenopausal breast cancer patients, and how a combined therapy including metformin, anti-inflammatory drugs, and aromatase/sulfatase inhibitors could successfully improve patient's outcome.

Adipokines expression and epithelial cell polarity in normal and cancerous breast tissue.

Cell polarity is crucial for the correct structural and functional organization of epithelial tissue. Its disruption can lead to loss of the apicobasal polarity, alteration in the intracellular components, misregulation of the pathways involved in cell proliferation and cancer promotion. Very recent in vitro/in vivo findings demonstrated that obesity-associated alterations in tissue adipokines protein level negatively affect epithelial polarity.

Body mass index and γ-glutamyl transferase expression in normal and cancerous breast tissue.

Background: Localized to cell membrane, γ-glutamyl transferase (GGT) is a reliable marker for the evaluation of cell distress occurring in several pathological conditions including obesity, metabolic syndrome, and cancer. In particular, high GGT serum levels are associated with breast cancer incidence and progression.

Methods: The tissue expression of GGT1, the gene coding for GGT, was investigated in silico in a large case series of paired samples of breast cancer and adjacent histologically normal (HN) tissue, and in a collection of healthy breast tissues from reduction mammoplasty.

Covalent Surface Modification of Lipid Nanoparticles by Rapid Potassium Acyltrifluoroborate Amide Ligation.

Because of the recent increasing demand for the synthetic biomimetic nanoparticles as in vivo carriers of drugs and imaging probes, it is very important to develop reliable, stable, and orthogonal methods for surface functionalization of the particles. To address these issues, in this study, a recently reported chemoselective amide-forming ligation reaction [potassium acyltrifluoroborate (KAT) ligation] was employed for the first time, as a mean to provide the surface functionalization of particles for creating covalent attachments of bioactive molecules. A KAT derivative of oleic acid (OA-KAT, 1) was added to a mixture of three lipid components (triolein, phosphatidyl choline, and cholesteryl oleate), which have been commonly used as substrates for lipid nanoparticles.

Serum levels of testosterone and SHBG in association with body mass index improve the predictive capability of consolidate tumor biomarkers in pre- and postmenopausal breast cancer patients.

Objective: To investigate the contribution of serum levels of testosterone (TS) and sex hormone binding globulin (SHBG) in association with body mass index (BMI) as a surrogate marker of obesity, to the predictive capability of tumor size (T), lymph node (N) and estrogen receptor (ER) status and proliferative activity (TLI).

Methods: We investigated 120 women with primary breast cancer and median follow-up of 138 months. Serum levels of TS and SHBG and patient's BMI were evaluated before surgery.

Synthesis of tri-functionalized MMP2 FRET probes using a chemo-selective and late-stage modification of unprotected peptides.

A polymeric FRET probe for the detection of MMP2 was prepared using a new N-hydroxylamine derivative of lysine (1), which was successfully incorporated into the natural peptide sequence by solid phase peptide synthesis (SPPS). Following the attachment of a PEG group to the N-terminus, a peptide was cleaved from the resin. The fully-deprotected peptide-PEG conjugate was subsequently subjected to the α-ketoacid-hydroxylamine (KAHA) ligation and Michael addition of FRET donor (MCA) and acceptor (DNP) moieties, respectively.

Epithelial cell identity in hyperplastic precursors of breast cancer.

Introduction: In the adult human breast, hyperplastic enlarged lobular unit (HELU) and atypical ductal hyperplasia (ADH) are two common abnormalities that frequently coexist with ductal carcinoma in situ (DCIS). For this reason, they have been proposed as the early steps in a biological continuum toward breast cancer.

Methods: We investigated in silico the expression of 369 genes experimentally recognized as involved in establishing and maintaining epithelial cell identity and mammary gland remodeling, in HELUs or ADHs with respect to the corresponding patient-matched normal tissue.

Differential expression of genes involved in the epigenetic regulation of cell identity in normal human mammary cell commitment and differentiation.

The establishment and maintenance of mammary epithelial cell identity depends on the activity of a group of proteins, collectively called maintenance proteins, that act as epigenetic regulators of gene transcription through DNA methylation, histone modification, and chromatin remodeling. Increasing evidence indicates that dysregulation of these crucial proteins may disrupt epithelial cell integrity and trigger breast tumor initiation. Therefore, we explored in silico the expression pattern of a panel of 369 genes known to be involved in the establishment and maintenance of epithelial cell identity and mammary gland remodeling in cell subpopulations isolated from normal human mammary tissue and selectively enriched in their content of bipotent progenitors, committed luminal progenitors, and differentiated myoepithelial or differentiated luminal cells.

Cell identity disruption in breast cancer precursors.

Background: Mammary epithelial cell identity depends on a set of genes epigenetically-regulated by maintenance proteins, the best-characterized of which belong to the Trithorax and Polycomb groups. Perturbations in expression of these proteins may disrupt cell identity and trigger tumor initiation.

Materials And Methods: The pattern of expression of a panel of genes involved in control of cell identity and mammary gland remodeling was investigated in two precancerous lesions, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) and compared to the corresponding histologically normal tissue.

Water-soluble C60- and C70-PVP polymers for biomaterials with efficient (1)O2 generation.

Highly water-soluble fullerene polymers were successfully prepared by a simple direct free-radical copolymerization of N-vinylpyrrolidone and intact C60 or C70 as a radical-capping agent. Using AIBN as a radical initiator, the polymers (C60- or C70-PVP) with significantly high molecular weight (~30 kDa) and with efficient (1)O2 generation were obtained.

The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation.

During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals.

Functionalized low-density lipoprotein nanoparticles for in vivo enhancement of atherosclerosis on magnetic resonance images.

To allow visualization of macrophage-rich and miniature-sized atheromas by magnetic resonance (MR) imaging, we have converted low-density lipoprotein (LDL) into MR-active nanoparticles via the intercalation of a 1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid (DO3A) derivative and the subsequent coordination reaction with Gd(3+). After careful removal of nonchelated Gd(3+), an MR-active LDL (Gd(3+)-LDL) with a remarkably high payload of Gd(3+) (in excess of 200 Gd(3+) atoms per particle) and a high relaxivity (r(1) = 20.1 s(-1) mM(-1) per Gd(3+) or 4040 s(-1) mM(-1) per LDL) was obtained.

Cell polarity, epithelial-mesenchymal transition, and cell-fate decision gene expression in ductal carcinoma in situ.

Loss of epithelial cell identity and acquisition of mesenchymal features are early events in the neoplastic transformation of mammary cells. We investigated the pattern of expression of a selected panel of genes associated with cell polarity and apical junction complex or involved in TGF-β-mediated epithelial-mesenchymal transition and cell-fate decision in a series of DCIS and corresponding patient-matched normal tissue. Additionally, we compared DCIS gene profile with that of atypical ductal hyperplasia (ADH) from the same patient.

Epithelial cell polarity and tumorigenesis: new perspectives for cancer detection and treatment.

Loss of cell-cell adhesion and cell polarity is commonly observed in tumors of epithelial origin and correlates with their invasion into adjacent tissues and formation of metastases. Growing evidence indicates that loss of cell polarity and cell-cell adhesion may also be important in early stage of cancer. In first part of this review, we delineate the current understanding of the mechanisms that establish and maintain the polarity of epithelial tissues and discuss the involvement of cell polarity and apical junctional complex components in tumor pathogenesis.

Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties.

Membrane receptors for steroid hormones are currently a subject of considerable debate. One approach to selectively target these putative receptors has been to couple ligands to substances that restrict cell permeability. Using this approach, an analogue of the estrogen receptor ligand 4-hydroxytamoxifen was attached to fluorescent dyes with differing degrees of predicted cell permeability.

A prediction model for breast cancer recurrence after adjuvant hormone therapy.

Hormone therapy with tamoxifen has long been the established adjuvant treatment for node-positive, estrogen-receptor-positive breast cancer in postmenopausal women. Since 30-40% of these patients fail to respond, reliableoutcome prediction is necessary for successful treatment allocation. Using pathobiological variables (available in mostclinical records: tumor size, nodal involvement, estrogen and progesterone receptor content) from 596 patients recruitedat a comprehensive cancer center, we developed a prediction model which we validated in an independent cohort of 175patients recruited at a general hospital.

The controversial clinicobiological role of breast cancer stem cells.

Breast cancer remains a leading cause of morbidity and mortality in women mainly because of the propensity of primary breast tumors to metastasize. Growing experimental evidence suggests that cancer stem cells (CSCs) may contribute to tumor progression and metastasis spread. However, despite the tremendous clinical potential of such cells and their possible therapeutic management, the real nature of CSCs remains to be elucidated.

A randomized trial comparing axillary dissection to no axillary dissection in older patients with T1N0 breast cancer: results after 5 years of follow-up.

Summary Background Data: Axillary dissection, an invasive procedure that may adversely affect quality of life, used to obtain prognostic information in breast cancer, is being supplanted by sentinel node biopsy. In older women with early breast cancer and no palpable axillary nodes, it may be safe to give no axillary treatment. We addressed this issue in a randomized trial comparing axillary dissection with no axillary dissection in older patients with T1N0 breast cancer.

Vascular endothelial growth factor in node-positive breast cancer patients treated with adjuvant tamoxifen.

In 212 postmenopausal women with node-positive oestrogen receptor-positive (ER(LBA)) breast cancer subjected to radical surgery and adjuvant tamoxifen, the risk of 6-year relapse increased with increasing values of intratumoral vascular endothelial growth factor (VEGF) in patients whose tumours had a low/intermediate ER(LBA) content compared to patients with high-ER(LBA) tumours. These findings indicate that tumour progression, activated or sustained by high VEGF levels, may be counteracted in high-ER(LBA) cancers by tamoxifen, which in contrast fails to contrast the metastatic potential in low-ER(LBA) tumours.

Time-dependent relevance of steroid receptors in breast cancer.

Purpose: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation.

Patients And Methods: We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered.

Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma.

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days.