Role of Matrix Metalloproteinase 13 in Both Endochondral and Intramembranous Ossification during Skeletal Regeneration

Extracellular matrix (ECM) remodeling is important during bone development and repair. Because matrix metalloproteinase 13 (MMP13, collagenase-3) plays a role in long bone development, we have examined its role during adult skeletal repair. In this study we find that MMP13 is expressed by hypertrophic chondrocytes and osteoblasts in the fracture callus. We demonstrate that MMP13 is required for proper resorption of hypertrophic cartilage and for normal bone remodeling during non-stabilized fracture healing, which occurs via endochondral ossification. However, no difference in callus strength was detected in the absence of MMP13. Transplant of wild-type bone marrow, which reconstitutes cells only of the hematopoietic lineage, did not rescue the endochondral repair defect, indicating that impaired healing in Mmp13−/− mice is intrinsic to cartilage and bone. Mmp13−/− mice also exhibited altered bone remodeling during healing of stabilized fractures and cortical defects via intramembranous ossification. This indicates that the bone phenotype occurs independently from the cartilage phenotype. Taken together, our findings demonstrate that MMP13 is involved in normal remodeling of bone and cartilage during adult skeletal repair, and that MMP13 may act directly in the initial stages of ECM degradation in these tissues prior to invasion of blood vessels and osteoclasts

Somatic mutations of KIT in familial testicular germ cell tumours

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino acid substitutions in exon 17 and one was a 12bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with 3 out 116 unilateral cases (p = 0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes

Quark-Hadron Duality in the 't Hooft Model for Meson Weak Decays: Different Quark Diagram Topologies

We compare the effects of different quark diagram topologies on the weak hadronic width of heavy-light mesons in the large N_c limit. We enumerate the various topologies and show that the only one dominant (or even comparable) in powers of N_c to the noninteracting spectator "tree" diagram is the "annihilation" diagram, in which the valence quark-antiquark pair annihilate weakly. We compute the amplitude for this diagram in the 't Hooft model (QCD in 1+1 spacetime dimensions with a large number of colors N_c) at the hadronic level and compare to the Born term partonic level. We find that quark-hadron duality is not well satisfied, even after the application of a smearing procedure to the hadronic result. A number of interesting subtleties absent from the tree diagram case arise in the annihilation diagram case, and are described in detail.Comment: 29 pages, 13 figs (of 18 eps files

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Engrailed-2 (EN2) - a novel biomarker in epithelial ovarian cancer

YesBackground: Epithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker. Methods: We evaluated 8 Epithelial ovarian cancer cell lines, along with > 100 surgical specimens from the Royal Surrey County Hospital (2009–2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/−resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in > 150 tumours (immunohistochemistry). Results: En2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p < 0.001), particularly in high-grade serous ovarian cancer (p < 0.0001) and in platinum-resistant tumours (p = 0.0232). Median Overall Survival and Progression-free Survival were reduced with high En2 expression (OS = 28 vs 42 months, p = 0.0329; PFS = 8 vs 27 months; p = 0.0004). Positive cytoplasmic EN2 staining was demonstrated in 78% of Epithelial ovarian cancers, with absence in normal ovary. EN2 positive high-grade serous ovarian cancer patients had a shorter PFS (10 vs 17.5 months; p = 0.0103). Conclusion: The EN2 transcription factor is a novel ovarian cancer biomarker. It demonstrates prognostic value, correlating with worse Overall Survival and Progression-free Survival. It is hoped that further work will validate its use as a biomarker, and provide insight into the role of EN2 in the development, progression and spread of ovarian cancer.Oncology Research and Development Departments at the Royal Surrey County Hospital and the University of Surre

Testicular cancer: The usage of central review for pathology diagnosis of orchiectomy specimens

Radical orchiectomy specimens present a unique set of challenges for pathology assessment owing to their rarity and complexity. This study compares second opinion pathology reports generated at a single, large academic institution to primary reports from outside hospitals

BLOOD PRESSURE CONTROL BY DRUG GROUP IN THE ANTIHYPERTENSIVE AND LIPID-LOWERING TREATMENT TO PREVENT HEART ATTACK TRIAL (ALLHAT)

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d ( n =15,255), amlodipine 2.5-10 mg/d ( n =9,048), or lisinopril 10-40 mg/d ( n =9,054) in a randomized double-blind hypertension trial. Participants were hypertensives age t55 with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mmHg (27% control) to 134/76 mmHg (chlorthalidone, 68% control), 135/75 mmHg (amlodipine, 66% control), and 136/76 mmHg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. A majority achieved BP control in each randomized group--a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP<140/90 mmHg in a majority of patients