Non-stabilized and stabilized fracturesMmp9 -/-mice [3-to 5-month old; 30-35 grams (g)] and their wildtype littermates were anesthetized with an intraperitoneal injection of 2% Avertin (0.015 ml/g body weight). Closed, standardized non- The regeneration of adult skeletal tissues requires the timely recruitment of skeletal progenitor cells to an injury site, the differentiation of these cells into bone or cartilage, and the re-establishment of a vascular network to maintain cell viability. Disturbances in any of these cellular events can have a detrimental effect on the process of skeletal repair. Although fracture repair has been compared with fetal skeletal development, the extent to which the reparative process actually recapitulates the fetal program remains uncertain. Here, we provide the first genetic evidence that matrix metalloproteinase 9 (MMP9) regulates crucial events during adult fracture repair. We demonstrate that MMP9 mediates vascular invasion of the hypertrophic cartilage callus, and that Mmp9 -/-mice have non-unions and delayed unions of their fractures caused by persistent cartilage at the injury site. This MMP9-dependent delay in skeletal healing is not due to a lack of vascular endothelial growth factor (VEGF) or VEGF receptor expression, but may instead be due to the lack of VEGF bioavailability in the mutant because recombinant VEGF can rescue Mmp9 -/-non-unions. We also found that Mmp9 -/-mice generate a large cartilage callus even when fractured bones are stabilized, which implicates MMP9 in the regulation of chondrogenic and osteogenic cell differentiation during early stages of repair. In conclusion, the resemblance between Mmp9 -/-fetal skeletal defects and those that emerge during Mmp9 -/-adult repair offer the strongest evidence to date that similar mechanisms are employed to achieve bone formation, regardless of age.

We have developed a method to study the molecular basis of intramembranous fracture healing. Unlike intramedullary rods that permit rotation of the fractured bone segments, our murine model relies on an external fixation device to provide stabilization. In this study we compare stabilized fracture callus tissues with callus tissues from non-stabilized fractures during the inflammatory, soft callus, hard callus, and remodeling stages of healing. Histological analyses indicate that stabilized fractures heal with virtually no evidence of cartilage whereas non-stabilized fractures produce abundant cartilage at the fracture site. Expression patterns of collrigen type Ira (colIIa) and osteocrrlciiz (oc) reveal that mesenchymal cells at the fracture site commit to either a chondrogenic or an osteogenic lineage during the earliest stages of healing. The mechanical environment influences this cell fate decision, since mesenchymal cells in a stabilized fracture express ac and fail to express colIIu. Future studies will use this murine model of intramembranous fracture healing to explore, at a molecular level, how the mechanical environment exerts its influence on healing of a fracture.

No abstract

An amphiphilic block copolymer toughener was incorporated into a liquid epoxy resin formulation and self-assembled into well-dispersed nanometer scale spherical micelles with a size of about 15 nm. The nanosized block copolymer at 5 wt % loading can significantly improve the fracture toughness of cured epoxy thermosets without reduction in modulus at room temperature and with only a slight drop in glass transition temperature. The toughening mechanisms were investigated, and it was found that the 15 nm size block copolymer micelles could cavitate to induce matrix shear banding, which mainly accounted for the observed remarkable toughening effect. Other mechanisms, such as crack tip blunting, may also play a role in the toughening. A discussion of the possible reasons responsible for the observed attractive mechanical property improvements due to the block copolymer modification is given. Implications of the present finding for designing toughened polymers are also discussed.

An amphiphilic poly(ethylene-alt-propylene)-b-poly(ethylene oxide) (PEP-PEO) block copolymer (BCP) was blended with a bisphenol A-based epoxy resin formulation and self-assembled into a wormlike micelle structure. With an incorporation of 5 wt % of the BCP material, the fracture toughness was improved by >100% over the neat epoxy. The morphology and mechanical properties of this BCP-modified epoxy were investigated using transmission electron microscopy, dynamic mechanical analysis, tensile tests, and fracture toughness measurements. Toughening mechanisms from the wormlike micelle-modified material were investigated using the double-notch four-point-bending technique, and the results are compared with data obtained from the same epoxy thermoset formulation containing a BCP that selfassembled into spherical micelles. Elongated cylindrical micelles produce improved toughness, which is interpreted on the basis of a combination of mechanisms including crack tip blunting, cavitation, particle debonding, limited shear yielding, and crack bridging. The implications of the present study for polymer toughening in general are also discussed.

No abstract

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% (45) of the nodules. Mutations in were the most prevalent (21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III.

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.