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Aims The diagnosis of undifferentiated pleomorphic sarcoma ( UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (Mi TF) stains naevi and epithelioid melanomas, as well as some mesenchymal neoplasms. The aim of this study was to evaluate the prevalence of Mi TF and melanocytic markers in UPS and a subset of atypical fibroxanthoma ( AFX). Methods and results Mi TF, SOX10, Melan-A, HMB45 and S100 immunostaining was performed on resection specimens from 19 UPSs and five AFXs. Next-generation sequencing of 50 genes was performed in UPSs to exclude dedifferentiated melanoma. In 17 of 19 UPSs (89%), tumour cells showed nuclear positivity for Mi TF that was not eliminated by casein block. Three showed focal nuclear staining for HMB45, which was eliminated by casein block. One showed focal nuclear vacuole staining for S100 with red but not brown chromogen. None expressed SOX10 or Melan-A. Mutational analysis of 15 UPSs with adequate DNA showed no mutations within hotspot regions of BRAF, KIT, or NRAS. Four of five AFXs (80%) stained with Mi TF; other markers were negative. Conclusion There is a high prevalence of nuclear Mi TF expression in UPSs (89%) and AFXs (80%). Rare UPSs showed non-specific nuclear HMB45 or S100 staining. These findings argue against using Mi TF in isolation to differentiate between UPS or AFX and melanoma, and caution in interpreting focal staining for a single additional melanocytic marker. Casein block may eliminate non-specific staining. Mi TF should be used to support a diagnosis of melanoma only if multiple melanocytic markers are positive. [ABSTRACT FROM AUTHOR]

A number of transcription factors have been identified as important in guiding normal Schwann cell development. This study used immunohistochemistry on tissue arrays to assess the expression of some of these transcription factors (Sox5, Sox9, Sox10, AP-2α, Pax7, and FoxD3) on 76 schwannomas, 105 neurofibromas, and 34 malignant peripheral nerve sheath tumors (MPNSTs). Sox9 and Sox10 were found to be widely expressed in all tumor types. FoxD3 reactivity was stronger and more frequently found in schwannomas and MPNSTs than neurofibromas. AP-2α was positive in 31% to 49% of all tumors, but strong reactivity was limited to MPNSTs and schwannomas. Pax7 and Sox5 expression was restricted to subsets of MPNSTs. Statistical analysis showed significant differences between the 3 tumor types in the expression of these markers. No differences were found in the analyzed tumor subgroups, including schwannomas of different sites, schwannomas with or without NF2 association, neurofibromas of different types, or sporadic versus NF1-associated MPNSTs. These results suggest that the transcription factors that guide normal Schwann cell development also play a role in the biology of neoplastic cells with Schwannian differentiation. FoxD3, AP-2α, Pax7, and Sox5 are upregulated in MPNSTs compared with neurofibromas and may be markers of malignant transformation. Screening the expression of FoxD3, Sox9, and Sox10 on 23 cases of other spindle-cell proliferations that may be considered in the differential diagnosis of MPNST, including synovial sarcoma and spindle cell melanoma, suggests that these 3 are helpful markers of Schwannian differentiation in the context of diagnosing MPNSTs. [ABSTRACT FROM PUBLISHER]

Background: Molecular and cellular-based enhancements of healing combined with conventional methods may yield better outcomes after the surgical management of tendon injury. We examined the histological and biomechanical effects of adenovirus-mediated transgene expression of bone morphogenetic protein-14 (BMP-14) on healing in a rat Achilles tendon laceration model. Specifically, we hypothesized that this delivery system for gene therapy would hasten the restoration of the normal histological appearance and tensile strength of a surgically repaired tendon. Methods: The right Achilles tendon of ninety male Sprague-Dawley rats was transected, repaired, and immediately infected with adenovirus expressing either the gene for green fluorescent protein (AdGFP) or the gene for human BMP-14 and green fluorescent protein (AdBMP-14). A sham control group received no viral-mediated infection after repair. Animals from each of the three groups were killed at one, two, and three weeks after surgery. The retrieved tendons were inspected, examined under light and fluorescent microscopy, and tested to determine their tensile strength. Results: Tendons transduced with BMP-14 exhibited less visible gapping, a greater number of neotenocytes at the site of healing, and 70% greater tensile strength than did either those transduced with GFP or the sham controls at two weeks after repair. Histological examination revealed no inflammatory response to the adenovirus in tendons transduced with BMP-14 or GFP No ectopic bone or cartilage formed in the tendons transduced with BMP-14. Conclusions: Adenovirus-mediated gene therapy with BMP-14 expedites tendon-healing in this animal model. No adverse immunological response to the adenoviral vector was detected in the host tissue, and the local production of BMP-14 did not induce unwelcome bone or cartilage formation within the healing tendon. Clinical Relevance: The results of this animal study suggest that gene therapy with BMPs may improve the capacity of injured musculoskeletal tissue to heal. [ABSTRACT FROM AUTHOR]

Efficacious bone regeneration could revolutionize the clinical management of many bone and musculoskeletal disorders. Bone morphogenetic proteins (BMPs) can regulate the differentiation of mesenchymal stem cells into cartilage, bone, tendon/ligament, and fat lineages. Early data documented the osteogenic potential of rhBMP2 and rhBMP7/OP-1. However, prior to this work that summarized several of our recent studies, no comprehensive analysis had been undertaken to characterize relative osteogenic activity of all BMPs. Using recombinant adenoviruses expressing 14 BMPs, we have demonstrated that, besides BMP2 and BMP7, BMP6 and BMP9 exhibit the highest osteogenic activity both in vitro and in vivo. We further demonstrated that several BMPs may exert synergistic effect on osteogenic differentiation, and that osteogenic BMPs produce a distinct set of molecular fingerprints during osteogenic differentiation. The reported work should expand our current understanding of BMP functions during osteogenic differentiation. It is conceivable that osteogenic BMPs (i.e., BMP2, 4, 6, 7, and 9) may be used to formulate synergistic pairs among themselves and/or with other less osteogenic BMPs for efficacious bone regeneration in clinical settings. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:665-677, 2007 [ABSTRACT FROM AUTHOR]

Objective: To confirm previous known relationships between Fetal Inflammatory Response Syndrome (FIRS) and neonatal bronchopulmonary dysplasia (BPD) and to present information on previously unknown special relationships between inflammatory variables and BPD. Study design: At delivery, we obtained biological specimens including umbilical cord venous blood for plasma interleukin-6 levels, as well as placental histology and bacteriology. Among other neonatal outcomes, we collected prospective information on BPD. Results: Of 141 newborns in the study, 16 had BPD; 79% of these had antecedent FIRS, 27% of those without FIRS had BPD. By multivariable regression, only very low birth weight (adjusted [adj] odds ratio [OR] 32.0, 95% Confidence Interval [CI] 5.0 to positive infinity) and FIRS (adj OR 5.7, 95% CI 1.1 to 42.3) remained significant risk factors. Escherichia coli, perhaps due to its pyogenic nature (strongly elicits inflammatory responses), may have had a special relationship with BPD. Conclusions: In our data, FIRS and neonatal BPD are highly associated. It is possible that certain pyogenic bacteria in the chorioamnion space may be implicated more often than others. Condensation: Neonates having Fetal Inflammatory Response Syndrome at delivery may later develop BPD. Pyogenic bacteria, such as Escherichia coli, may be implicated more frequently. [ABSTRACT FROM AUTHOR]

Purpose. We examined the interaction between cyclophosphamide (CPA) and angiostatin (AS) on the growth of primary Lewis lung carcinoma (LLC) tumors and on the development of LLC pulmonary metastases. We studied the effects of AS and CPA on the stages of angiogenesis employing in vitro assays. Methods. Primary tumor growth and pulmonary metastases were measured to evaluate the effects of treatment with AS alone, CPA alone or the combination of CPA and AS. We examined the effects of CPA plus AS on endothelial cell (HUVEC) survival, migration and tube formation. Results. Combined treatment with CPA and AS did not significantly affect primary tumor growth when compared with CPA treatment alone. However, a significant decrease in the number of pulmonary metastases was observed following CPA plus AS treatment when compared with CPA treatment alone (P<0.001). AS did not enhance CPA-mediated HUVEC cytotoxicity, and CPA failed to enhance AS-mediated inhibition of migration. However, tube formation was inhibited following combined treatment with CPA and AS when compared with either treatment alone. Conclusions. AS enhanced the antimetastatic effects of CPA without significantly influencing the effects of CPA on primary tumor growth. CPA plus AS inhibited tube formation, suggesting that interrupting specific steps in the angiogenesis process might be an effective approach to the treatment of subclinical distant metastases. [ABSTRACT FROM AUTHOR]

Three adenosquamous carcinomas and 2813 adenocarcinomas of the colon proximal to a line 7 cm craniad to the dentate line were treated between 1946 and 1986. Of these, one adenosquamous carcinoma and 42 adenocarcinomas were associated with ulcerative colitis. Therefore it was calculated that adenosquamous carcinoma occurs 0.07 percent as frequently as adenocarcinoma of the colon in the general hospital population and 2.4 percent as frequently in patients with ulcerative colitis, a 33-fold increase. It is concluded that, although adenosquamous-cell carcinoma of the colon is a rare tumor, its frequency in relation to adenocarcinoma increases in the presence of ulcerative colitis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "BMP-14 Gene Therapy Increases Tendon Tensile Strength in a Rat Model of Achilles Tendon Injury" by Bolt and other in the 2007;89:1315-20 issue.

Marrow mesenchymal stem cells are pluripotent progenitors that can differentiate into bone, cartilage, muscle, and fat cells. Wnt signaling has been implicated in regulating osteogenic differentiation of mesenchymal stem cells. Here, we analyzed the gene expression profile of mesenchymal stem cells that were stimulated with Wnt3A. Among the 220 genes whose expression was significantly changed by 2.5-fold, we found that three members of the CCN family, CCN1/Cyr61, CCN2/connective tissue growth factor (CTGF), and CCN5/WISP2, were among the most significantly up-regulated genes. We further investigated the role of CCN1/Cyr61 in Wnt3A-regulated osteogenic differentiation. We confirmed that CCN1/Cyr61 was up-regulated at the early stage of Wnt3A stimulation. Chromatin immunoprecipitation analysis indicates that CCN1/Cyr61 is a direct target of canonical Wnt/beta;-catenin signaling. RNA interference-mediated knockdown of CCN1/Cyr61 expression diminished Wnt3A-induced osteogenic differentiation. Furthermore, exogenously expressed CCN1/Cyr61 was shown to effectively promote mesenchymal stem cell migration. These findings suggest that tightly regulated CCN1/Cyr61 expression may play an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. [ABSTRACT FROM AUTHOR]