Achondroplasia is the most common of the heritable skeletal dysplasias. Compression at the cervicomedullary junction can result in myelopathy, hypotonia, sleep apnea, and even sudden death. However, ...most children with achondroplasia do not suffer from severe neurological symptoms and achieve normal motor and intellectual development without surgical intervention. At the authors' institution, magnetic resonance (MR) imaging and cerebrospinal fluid (CSF) flow studies have been incorporated in the assessment of children with achondroplasia for cervicomedullary junction compression. The authors recently identified four children with achondroplasia who had normal findings on MR imaging and flow studies obtained in the neutral position. On flexion studies, however, three had complete blockage of CSF flow, and more dramatic posterior cervicomedullary compression was demonstrated on extension studies. Some of these patients had severe neurological abnormalities and sleep apnea, while others just developed headaches and/or had apnea episodes when sleeping or in a car seat. Three children underwent decompressive surgery with dramatic improvement or resolution of signs and symptoms. The fourth patient had increased CSF pressure on MR images obtained in the flexed position, possibly due to venous outflow obstruction. Her condition improved dramatically after placement of a ventriculoperitoneal shunt. The increased risk of dynamic cord compression and alterations in CSF dynamics in patients with achondroplasia constitute indications for surgical intervention.
The E3 ubiquitin ligase human murine double minute (HDM2) is overexpressed in 40%-80% of late-stage metastatic cancers in the absence of gene amplification. Hdm2 regulates p53 stability via ...ubiquitination and has also been implicated in altering the sensitivity of cells to TGF-beta1. Whether TGF-beta1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-beta1-activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-beta1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-beta1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-beta1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.
Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel ...therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.
HYPOTHESIS Experimental work raises the possibility that in utero repair of myelomeningocele (mmc) may improve lower extremity, bladder, and bowel function, ameliorate the arnold-chiari malformation, ...and decrease the need for postnatal shunting. DESIGN We previously developed fetal lamb models to create and reverse lower extremity damage and the arnold-chiari malformation in utero. we then applied our extensive experience with fetal surgery, including fetal endoscopic (fetoscopic) surgical manipulation, to develop techniques for mmc repair. SETTING A tertiary referral center. PATIENTS All patients treated between 1998 and 2002 for a prenatally diagnosed mmc. INTERVENTIONS Either fetoscopic mmc repair, fetoscopic patch repair, or limited maternal hysterotomy and microsurgical 3-layered fetal mmc repair was performed. MAIN OUTCOME MEASURES Gestational age at delivery, survival, neurologic outcome, and need for ventricular shunting at 1 year. RESULTS Complete fetoscopic repair was accomplished in 1 fetus. two other fetuses underwent partial fetoscopic procedures. the remaining 10 patients underwent limited maternal hysterotomy and microsurgical 3-layered fetal mmc repair. four of 13 patients died, and the mean gestational age at delivery of 11 fetuses born alive was 31 weeks. five of 9 required ventricular shunting by age 1 year. in 2 patients, lower extremity function improved by more than 2 vertebral levels compared with prenatal ultrasonography. five of 10 patients who lived longer than 3 weeks required postnatal wound revision within 7 days after birth. CONCLUSIONS Fetoscopic repair, although feasible, does not yet yield optimal surgical results. open surgical repair before 22 weeks' gestation is physiologically sound and technically feasible. one third of patients appear to be spared the need for a shunt at age 1 year, but improvement in distal neurologic function is less clear. additionally, fetal mortality is associated with this procedure. our results complement the data published by groups at children's hospital of philadelphia, in pennsylvania, and vanderbilt university, nashville, tenn. a national institutes of health–sponsored prospective randomized trial is now underway at these 3 centers to compare fetal repair with postnatal repair.Arch Surg. 2003;138:872-878-->
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