Nanoliposome targeting in breast cancer is influenced by the tumor microenvironment.

MM-302 is an anti-HER2 antibody-targeted pegylated liposomal doxorubicin designed to deliver doxorubicin specifically to HER2-expressing solid tumors. The delivery and activity of MM-302 were evaluated in orthotopic, transgenic, and intravenous breast cancer models expressing varying levels of HER2 that metastasize to some of the most common sites of dissemination for breast cancer, namely, lung, liver, and brain. Metastatic burden was quantified by gross evaluation, immunohistochemistry (IHC), and bioluminescent imaging.

Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer.

Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart.

Cyclophosphamide-Mediated Tumor Priming for Enhanced Delivery and Antitumor Activity of HER2-Targeted Liposomal Doxorubicin (MM-302).

Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody-liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin.

Impact of tumor HER2/ERBB2 expression level on HER2-targeted liposomal doxorubicin-mediated drug delivery: multiple low-affinity interactions lead to a threshold effect.

Numerous targeted nanotherapeutics have been described for potential treatment of solid tumors. Although attention has focused on antigen selection and molecular design of these systems, there has been comparatively little study of how cellular heterogeneity influences interaction of targeted nanoparticles with tumor cells. Antigens, such as HER2/ERBB2, are heterogeneously expressed across different indications, across patients, and within individual tumors.

Elevated GM-CSF and IL-1beta levels compromise the ability of p38 MAPK inhibitors to modulate TNFalpha levels in the human monocytic/macrophage U937 cell line.

Rheumatoid arthritis (RA) is a complex, multicellular disease involving a delicate balance between both pro- and anti-inflammatory cytokines which ultimately determines the disease phenotype. The simultaneous presence of multiple signaling molecules, and more specifically their relative levels, potentially influences the efficacy of directed therapies. Using the human U937 monocytic cell line, we generated a self-consistent dataset measuring 50 cytokines and 23 phosphoproteins in the presence of 6 small molecule inhibitors under 15 stimulatory conditions throughout a 24 hour time course.

DataPflex: a MATLAB-based tool for the manipulation and visualization of multidimensional datasets.

Motivation: DataPflex is a MATLAB-based application that facilitates the manipulation and visualization of multidimensional datasets. The strength of DataPflex lies in the intuitive graphical user interface for the efficient incorporation, manipulation and visualization of high-dimensional data that can be generated by multiplexed protein measurement platforms including, but not limited to Luminex or Meso-Scale Discovery. Such data can generally be represented in the form of multidimensional datasets [for example (time x stimulation x inhibitor x inhibitor concentration x cell type x measurement)].

Spindle checkpoint proteins and chromosome-microtubule attachment in budding yeast.

Accurate chromosome segregation depends on precise regulation of mitosis by the spindle checkpoint. This checkpoint monitors the status of kinetochore-microtubule attachment and delays the metaphase to anaphase transition until all kinetochores have formed stable bipolar connections to the mitotic spindle. Components of the spindle checkpoint include the mitotic arrest defective (MAD) genes MAD1-3, and the budding uninhibited by benzimidazole (BUB) genes BUB1 and BUB3.

Binding of the essential Saccharomyces cerevisiae kinetochore protein Ndc10p to CDEII.

Chromosome segregation at mitosis depends critically on the accurate assembly of kinetochores and their stable attachment to microtubules. Analysis of Saccharomyces cerevisiae kinetochores has shown that they are complex structures containing >/=50 protein components. Many of these yeast proteins have orthologs in animal cells, suggesting that key aspects of kinetochore structure have been conserved through evolution, despite the remarkable differences between the 125-base pair centromeres of budding yeast and the Mb centromeres of animal cells.