Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis.

Insulin growth factor 1 (IGF1) is a major anabolic signal that is essential during skeletal development, cellular adhesion and migration. Recent transcriptomic studies have shown that there is an upregulation in IGF1 expression in calvarial osteoblasts derived from patients with single-suture craniosynostosis (SSC). Upregulation of the IGF1 signaling pathway is known to induce increased expression of a set of osteogenic markers that previously have been shown to be correlated with contractility and migration. Although the IGF1 signaling pathway has been implicated in SSC, a correlation between IGF1, contractility and migration has not yet been investigated. Here, we examined the effect of IGF1 activation in inducing cellular contractility and migration in SSC osteoblasts using micropost arrays and time-lapse microscopy. We observed that the contractile forces and migration speeds of SSC osteoblasts correlated with IGF1 expression. Moreover, both contractility and migration of SSC osteoblasts were directly affected by the interaction of IGF1 with IGF1 receptor (IGF1R). Our results suggest that IGF1 activity can provide valuable insight for phenotype-genotype correlation in SSC osteoblasts and might provide a target for therapeutic intervention.

Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance.

Approximately one-third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing-risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non-regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I-III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin-only distant metastasis was associated with lower MCC-specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1-pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis.

Hyaluronan-CD44 interactions mediate contractility and migration in periodontal ligament cells.

The role of hyaluronan (HA) in periodontal healing has been speculated via its interaction with the CD44 receptor. While HA-CD44 interactions have previously been implicated in numerous cell types; effect and mechanism of exogenous HA on periodontal ligament (PDL) cells is less clear. Herein, we examine the effect of exogenous HA on contractility and migration in human and murine PDL cells using arrays of microposts and time-lapse microscopy. Our findings observed HA-treated human PDL cells as more contractile and less migratory than untreated cells. Moreover, the effect of HA on contractility and focal adhesion area was abrogated when PDL cells were treated with Y27632, an inhibitor of rho-dependent kinase, but not when these cells were treated with ML-7, an inhibitor of myosin light chain kinase. Our results provide insight into the mechanobiology of PDL cells, which may contribute towards the development of therapeutic strategies for periodontal healing and tissue regeneration.

Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck.

PURPOSE: Merkel cell carcinoma (MCC) is a rare and often aggressive skin cancer. Typically, surgery is the primary treatment. Postoperative radiation therapy (PORT) is often recommended to improve local control. It is unclear whether PORT is indicated in patients with favorable Stage IA head and neck (HN) MCC. METHODS AND MATERIALS: We conducted a retrospective analysis of 46 low-risk HN MCC cases treated between 2006 and 2015. Inclusion criteria were defined as a primary tumor size of ≤ 2 cm, negative pathological margins, negative sentinel lymph node biopsy, and no immunosuppression. Local recurrence (LR) was defined as tumor recurrence within 2 cm of the primary surgical bed and estimated with the Kaplan-Meier method. RESULTS: Omission of PORT was offered to all 46 patients, of which 23 patients received PORT and 23 did not. No patient received adjuvant chemotherapy. There were no significant differences in surgical margins, tumor size, depth, lympho-vascular invasion status, or demographics between the two patient groups. Median follow-up for all patients was 3.7 years. Six of the 23 patients who did not receive PORT developed an LR. Compared to the group that received PORT, there was a significantly higher risk of LR in the group treated without PORT (26% vs. 0%, P = .02). Median time to LR was 11 months. All local failures were effectively salvaged. There was no difference in MCC-specific and overall survival between the 2 groups. CONCLUSIONS: For patients with HN MCC, omission of PORT was associated with a significantly higher risk of local recurrence even among those patients with the lowest-risk tumors (i.e., Stage IA without immune suppression). Thus, it is important to weigh the benefits of PORT against the side effect profile on a case-specific basis for each patient.