Structural Limits of Orbital Compliance and Treatment Options for Pathologic Orbital Pressure.

PURPOSE: The integrity of the orbit has a finite structural limit due to the compliance of its tissue. The authors investigate these limits to quantify them and inform the treatment of heightened ocular and orbital pressure. METHODS: Cadaveric study with 12 orbits being volumized before randomization of treatment for pathologic levels of ocular and orbital pressure. First-line and second-line treatment was chosen randomly (lateral cantholysis, superior septolysis, inferior septolysis). Prior to treatment, IOP, orbital compartment pressure, and axial globe projection was measured after delivery of each 1cc aliquot and surgical treatment. RESULTS: Orbital compartment pressure and IOP were well correlated (r = 0.99). The average reduction in IOP after treatment averaged a 56.2 mm Hg reduction in IOP. All treatments were statistically equivalent ( p < 0.01). Loss of compliance (P LOC ) was determined when the mean plus 1 standard deviation of change in IOP/ml volume was achieved with simultaneous change in exophthalmometry of <0.5 mm change/ml added volume, indicating an acceleration in pressure in the face of a steady volume. This criteria was met for 11 of 12 orbits. The 12th orbit missed this threshold by 1 mm Hg in IOP. P LOC occurred at an average IOP of 43.0 mm Hg (±5.8 mm Hg, 90% CI) and after an average injection of 13 ml (±1.4 mm, 90% CI). Additionally, lateral cantholysis, superior septolysis, and inferior septolysis were statistically equivalent in reducing IOP after P LOC . CONCLUSIONS: IOP and orbital compartment pressure are excellent proxies for each other in the authors' model. Orbital compliance is a mathematic phenomenon that can be quantified, as evident in this investigation. P LOC can inform timing for orbital decompressions in the presence of heightened IOP. Multiple procedures can be used to extinguish dangerously high orbital compartment pressure.

Rapid and robust directed differentiation of mouse epiblast stem cells into definitive endoderm and forebrain organoids.

Directed differentiation of pluripotent stem cells (PSCs) is a powerful model system for deconstructing embryonic development. Although mice are the most advanced mammalian model system for genetic studies of embryonic development, state-of-the-art protocols for directed differentiation of mouse PSCs into defined lineages require additional steps and generates target cell types with lower purity than analogous protocols for human PSCs, limiting their application as models for mechanistic studies of development. Here, we examine the potential of mouse epiblast stem cells cultured in media containing Wnt pathway inhibitors as a starting point for directed differentiation. As a proof of concept, we focused our efforts on two specific cell/tissue types that have proven difficult to generate efficiently and reproducibly from mouse embryonic stem cells: definitive endoderm and neural organoids. We present new protocols for rapid generation of nearly pure definitive endoderm and forebrain-patterned neural organoids that model the development of prethalamic and hippocampal neurons. These differentiation models present new possibilities for combining mouse genetic tools with in vitro differentiation to characterize molecular and cellular mechanisms of embryonic development.

Consideration for eliminating conjunctival closure in the enucleation procedure.

To compare post-operative results and complications in patients who undergo enucleation with or without suture closure of the conjunctiva. This was a retrospective chart review study. Review of 50 cases of enucleation surgery at the University of Arkansas for Medical Sciences and Arkansas Children's Hospital between July 2011 and December 2014. Criteria for inclusion in the study were all cases of enucleation that had extraocular muscles attached to a spherical orbital implant with or without conjunctival closure, and at least 2 months of postoperative follow up. Post-operative complications were evaluated. A total of 36 cases fulfilled the criteria for inclusion in the study; 12 cases with direct sutured layered direct closure of Tenon's and then conjunctiva and 24 cases with Tenon's capsule sutured closure but without direct conjunctival sutured closure. No implant complications were identified in either group (p = 1.0). Mean follow-up for all groups was 16.71 months (range 2 to 43 mo., SD 11.94). Mean follow up for the non-closure group was 14.42 months (range 2.25 to 36 mo., SD 10.35). Two cases in the conjunctival closure group developed a conjunctival cyst, affecting prosthesis fit, approximately 3 months postoperatively: no such cysts were identified in the non-conjunctival closure group. Fisher exact test for cyst formation between the two groups was not statistically significant (p = 0.1048). Direct conjunctival closure following enucleation surgery does not appear to increase the risk of extrusion, exposure, or infection. Foregoing direct closure decreases surgical time and reduces cost. It is unclear if this decreases conjunctival cyst formation.

A CXCL1 paracrine network links cancer chemoresistance and metastasis.

Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.

WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.

Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.

Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.