The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
The homeobox gene Pdx1 is a key regulator of pancreas and foregut development. Loss of Pdx1 expression results in pancreas agenesis and impaired development of the gastro-duodenal domain including Brunners glands. We previously demonstrated a key role for Pdx1 in maintaining the integrity and function of insulin-secreting beta cells in the adult pancreas. In the present study, we aimed to determine if expression of Pdx1 is required to maintain the cellular identity of the gastro-duodenal domain in adult mice. Immunohistological studies were performed in a mouse model in which expression of Pdx1 was conditionally repressed with the doxycycline-responsive tetracycline transactivator system. Mice in which Pdx1 was chronically repressed developed hamartomas in the gastro-duodenal domain. These lesions appeared to arise from ectopic foci of anteriorized cells, consistent with a localised anterior homeotic shift. They emerge with the intercalation of tissue between the anteriorized and normal domains and appear strikingly similar to lesions in the colon of mice heterozygous for another Parahox gene, Cdx2. Continuing expression of Pdx1 into adult life is required to maintain regional cellular identity in the adult foregut, specifically at the gastro-duodenal boundary. Loss of Pdx1 expression leads to anterior transformation and intercalary regeneration of ectopic tissue. We propose a model in which the posterior dominance of classical Hox genes is mirrored by the Parahox genes, providing further evidence of the functional conservation of the Parahox genes. These findings may have implications for further understanding the molecular basis of gastro-duodenal metaplasia and gastro-intestinal transformations such as Barretts esophagus.
OBJECT - The use of intraventricular endoscopy to achieve diagnosis or to resect accessible intraventricular or paraventricular tumors has been described in the literature in both adults and children. Traditionally, these techniques have not been used in patients with small ventricles due to the perceived risk of greater morbidity. The authors review their experience with the effectiveness and safety of endoscopic brain tumor management in children with small ventricles.
METHODS - Between July 2002 and December 2009, 24 children with endoscopically managed brain tumors were identified. Radiological images were reviewed by a radiologist blinded to study goals and clinical setting. Patients were categorized into small-ventricle and ventriculomegaly groups based on frontal and occipital horn ratio. Surgical success was defined a priori and analyzed between groups. Trends were identified in selected subgroups, including complications related to pathological diagnosis and surgeon experience.
RESULTS - Six children had small ventricles and 18 had ventriculomegaly. The ability to accomplish surgical goals was statistically equivalent in children with small ventricles and those with ventriculomegaly (83% vs 89%, respectively, p = 1.00). There were no complications in the small-ventricle cohort, but in the ventriculomegaly cohort there were 2 cases of postoperative hemorrhages and 1 case of infection. All hemorrhagic complications occurred in patients with high-grade tumor histopathological type and were early in the surgeon's endoscopic career.
CONCLUSIONS - Based on our experience, endoscopy should not be withheld in children with intraventricular tumors and small ventricles. Complications appear to be more dependent on tumor histopathological type and surgeon experience than ventricular size.
Constitutive Hedgehog (Hh) signaling underlies several human tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma in skin. Intriguingly, superficial BCCs arise as de novo epithelial buds resembling embryonic hair germs, collections of epidermal cells whose development is regulated by canonical Wnt/beta-catenin signaling. Similar to embryonic hair germs, human BCC buds showed increased levels of cytoplasmic and nuclear beta-catenin and expressed early hair follicle lineage markers. We also detected canonical Wnt/ beta-catenin signaling in epithelial buds and hamartomas from mice expressing an oncogene, M2SMO, leading to constitutive Hh signaling in skin. Conditional overexpression of the Wnt pathway antagonist Dkk1 in M2SMO-expressing mice potently inhibited epithelial bud and hamartoma development without affecting Hh signaling. Our findings uncover a hitherto unknown requirement for ligand-driven, canonical Wnt/ beta-catenin signaling for Hh pathway-driven tumorigenesis, identify a new pharmacological target for these neoplasms and establish the molecular basis for the well-known similarity between early superficial BCCs and embryonic hair germs.
Few autistic brain samples are available for study, limiting investigations into molecular and histopathological abnormalities associated with this common disease. To facilitate distribution of samples, we have constructed a tissue array containing cerebral and cerebellar cores from 5 autistic children, 1 girl with Rett syndrome, and 5 age-matched controls. To demonstrate the utility of this resource, we examined phosphorylation of the S6 ribosomal protein, a signaling event regulated by the genes mutated in tuberous sclerosis and Cowden disease. We hypothesized that the molecular pathways altered in these inherited conditions associated with autism might be dysregulated in sporadic autistic cases as well. However, no consistent alterations in S6 phosphorylation were detected in autistic tissues compared to controls in the brain regions analyzed.
Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.
From 1964 to 1989, we performed operations on 133 patients with cardiac tumors. There were 58 male and 75 female patients ranging in age from three days to 81 years; 101 were adults, and 32 were children (less than 12 years of age). Primary tumors (102 benign and 12 malignant) were found in 114 patients and metastatic tumors in 19. Symptoms included congestive heart failure, arrhythmias, emboli, and chest pain. Diagnosis was accomplished through angiography, echocardiography, computed tomography, and magnetic resonance imaging. Operative treatment encompassed techniques ranging from biopsy to complete excision (including hypothermic circulatory arrest and cardiac autotransplantation) depending on the site of disease and the extent of involvement. Overall operative survival was 91%. Twelve patients died early (within 30 days of operation), and follow-up was obtained for 110 (90.9%) of the remaining 121 survivors (total patient-years of follow-up, 572.8; mean follow-up, 5.2 years). Of the 20 patients who died late, 15 had malignant disease. Operative survival for patients with primary cardiac malignancies and for those with metastatic disease was 83% and 68.4%, respectively, with 3 and 5 patients, respectively, still living. We advocate an aggressive surgical approach, especially in patients with benign tumors, who can expect an excellent outcome. For patients with malignant or metastatic disease, palliation and cure are also possible if aggressive surgical actions are taken.