Review of the patient-centered communication landscape in multiple myeloma and other hematologic malignancies.

OBJECTIVES: To identify factors limiting and facilitating patient-centered communication (PCC) in the United States hematology-oncology setting, with a focus on multiple myeloma (MM), given the limited attention to PCC and rapid pace of change that has taken place in this setting. METHODS: A literature search was performed from 2007 to 2017 to identify published articles and congress abstracts related to clinician-patient communication and treatment decision-making in oncology. Search results were evaluated by year of publication and disease area. A thematic assessment was performed to identify factors limiting and promoting PCC for patients with MM and other hematologic malignancies. RESULTS: Of the 6673 publications initially retrieved, 18 exclusively reported findings in patients with hematologic malignancies and were included in this review. We identified three critical, but modifiable, barriers to PCC in the hematologic malignancy setting, including insufficient information exchange, treatment goal misalignment, and discordant role preferences in treatment decision-making. Factors that enhanced interaction quality included educational programs for clinicians and patients. CONCLUSIONS: Patients with MM and other hematologic malignancies experience a distinct set of challenges that may affect PCC. PRACTICE IMPLICATIONS: Clinicians have the opportunity to improve patient care by proactively addressing the identified barriers and implementing strategies demonstrated to improve PCC.

A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities.

Wnt ligands are secreted morphogens that control multiple developmental processes during embryogenesis and adult homeostasis. A diverse set of receptors and signals have been linked to individual Wnts, but the lack of tools for comparative analysis has limited the ability to determine which of these signals are general for the entire Wnt family, and which define subsets of differently acting ligands. We have created a versatile Gateway library of clones for all 19 human Wnts. An analysis comparing epitope-tagged and untagged versions of each ligand shows that despite their similar expression at the mRNA level, Wnts exhibit considerable variation in stability, processing and secretion. At least 14 out of the 19 Wnts activate ß-catenin-dependent signaling, an activity that is cell type-dependent and tracks with the stabilization of ß-catenin and LRP6 phosphorylation. We find that the core Wnt modification and secretion proteins Porcupine (PORCN) and Wntless (WLS) are essential for all Wnts to signal through ß-catenin-dependent and independent pathways. This comprehensive toolkit provides critical tools and new insights into human Wnt gene expression and function.

Wnt signaling and colon carcinogenesis: beyond APC.

Activation of the Wnt signaling pathway via mutation of the adenomatous polyposis coli gene (APC) is a critical event in the development of colon cancer. For colon carcinogenesis, however, constitutive signaling through the canonical Wnt pathway is not a singular event. Here we review how canonical Wnt signaling is modulated by intracellular LEF/TCF composition and location, the action of different Wnt ligands, and the secretion of Wnt inhibitory molecules. We also review the contributions of non-canonical Wnt signaling and other distinct pathways in the tumor micro environment that cross-talk to the canonical Wnt pathway and thereby influence colon cancer progression. These 'non-APC' aspects of Wnt signaling are considered in relation to the development of potential agents for the treatment of patients with colon cancer. Regulatory pathways that influence Wnt signaling highlight how it might be possible to design therapies that target a network of signals beyond that of APC and ß-catenin.

Microdevice to capture colon crypts for in vitro studies.

There is a need in biological research for tools designed to manipulate the environment surrounding microscopic regions of tissue. In the current work, a device for the oriented capture of an important and under-studied tissue, the colon crypt, has been designed and tested. The objective of this work is to create a BioMEMs device for biological assays of living colonic crypts. The end goal will be to subject the polarized tissue to user-controlled fluidic microenvironments in a manner that recapitulates the in vivo state. Crypt surrogates, polymeric structures of similar dimensions and shape to isolated colon crypts, were used in the initial design and testing of the device. Successful capture of crypt surrogates was accomplished on a simple device composed of an array of micron-scale capture sites that enabled individual structures to be captured with high efficiency (92+/-3%) in an ordered and properly oriented fashion. The device was then evaluated using colon crypts isolated from a murine animal model. The capture efficiency attained using the fixed biologic sample was 37+/-5% due to the increased variability of the colon crypts compared with the surrogate structures, yet 94+/-3% of the captured crypts were properly oriented. A simple approach to plug the remaining capture sites in the array was performed using inert glass beads. Blockage of unfilled capture sites is an important feature to establish a chemical gradient across the arrayed crypts. A chemical concentration gradient (Cluminal/Cbasal>10) was demonstrated across the arrayed crypts for over 8 h. Finally unfixed colon crypts were demonstrated to be effectively captured by the micromesh array and to remain viable on the capture sites at 5 h after mouse sacrifice. The present study demonstrates the feasibility and potential for rationally microengineered technologies to address the specific needs of the biologic researcher.

Ty3 capsid mutations reveal early and late functions of the amino-terminal domain.

The Ty3 retrotransposon assembles into 50-nm virus-like particles that occur in large intracellular clusters in the case of wild-type (wt) Ty3. Within these particles, maturation of the Gag3 and Gag3-Pol3 polyproteins by Ty3 protease produces the structural proteins capsid (CA), spacer, and nucleocapsid. Secondary and tertiary structure predictions showed that, like retroviral CA, Ty3 CA contains a large amount of helical structure arranged in amino-terminal and carboxyl-terminal bundles. Twenty-six mutants in which alanines were substituted for native residues were used to study CA subdomain functions. Transposition was measured, and particle morphogenesis and localization were characterized by analysis of protein processing, cDNA production, genomic RNA protection, and sedimentation and by fluorescence and electron microscopy. These measures defined five groups of mutants. Proteins from each group could be sedimented in a large complex. Mutations in the amino-terminal domain reduced the formation of fluorescent Ty3 protein foci. In at least one major homology region mutant, Ty3 protein concentrated in foci but no wt clusters of particles were observed. One mutation in the carboxyl-terminal domain shifted assembly from spherical particles to long filaments. Two mutants formed foci separate from P bodies, the proposed sites of assembly, and formed defective particles. P-body association was therefore found to be not necessary for assembly but correlated with the production of functional particles. One mutation in the amino terminus blocked transposition after cDNA synthesis. Our data suggest that Ty3 proteins are concentrated first, assembly associated with P bodies occurs, and particle morphogenesis concludes with a post-reverse transcription, CA-dependent step. Particle formation was generally resistant to localized substitutions, possibly indicating that multiple domains are involved.