Background: The indications for Post Mastectomy Radiation Therapy (PMRT) for positive or close margins are unclear. We examined the indications for PMRT in mastectomy patients with close or positive margins and determined patterns for relapse and survival. Methods: The pathology reports of 610 patients treated with a mastectomy from 1999-2012 were reviewed. Of these, 72 patients had a positive or <2 mm margin. Demographic, tumor characteristics, treatments and survival were compared between women treated with and without PMRT. Results: The mean follow up was 4.1 years. Patients who received PMRT were younger (p = 0.03) and more likely to receive chemotherapy (p = 0.03). Patients with lymphovascular invasion (LVI) were more likely to undergo PMRT (p = 0.02). Seven patients who did not receive PMRT recurred. There was no correlation with locoregional failure. The disease free survival was better in the PMRT group (p = 0.03), but the overall survival was the same. Conclusion: We found that women with a close or positive margin who were younger, had LVI, and who received chemotherapy received PMRT. The disease free survival was better in the PMRT cohort, but the overall survival was similar. Long-term follow up of patients is warranted to see if PMRT offers a survival advantage.

Approximately 5% of breast cancer patients develop leptomeningeal metastases over the course of their disease. Though several treatments options are available for these patients, their prognosis is typically considered to be poor. We report a case of leptomeningeal failure after a patient underwent prior radiotherapy, radiosurgery, surgery, chemotherapy, and biologic therapy. This patient experienced a prolonged response after receiving bevacizumab and capecitabine. The literature currently contains several reports regarding the use of systemic therapy to manage leptomeningeal metastases from breast cancer, which we summarize. Finally, we review the relevant effects of the patient's treatment modalities and provide a rationale for the mechanism that led to her prolonged response.

Purpose. Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas. Materials and Methods. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms. Results. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup. Conclusions. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course.

Purpose: To determine the maximum-tolerated dose (MTD) of radiation (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma (GBM), to estimate their progression-free (PFS) and overall survival (OS), and to assess the role of C-11 methionine PET (MET-PET) imaging in predicting recurrence.Experimental Design: Intensity-modulated RT (IMRT) doses of 66 to 81 Gy, assigned to patients by the time-to-event continual reassessment method, were delivered over 6 weeks with concurrent daily temozolomide (75 mg/m(2)) followed by adjuvant cyclic temozolomide (200 mg/m(2) d1-5 q28d x 6 cycles). Treatment was based on gadolinium-enhanced MRI. Pretreatment MET-PET scans were obtained for correlation with eventual sites of failure.Results: A total of 38 patients were analyzed with a median follow-up of 54 months for patients who remain alive. Late CNS grade >= III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). None of 22 patients receiving 75 or less Gy developed RT necrosis. Median OS and PFS were 20.1 (14.0-32.5) and 9.0 (6.0-11.7) months, respectively. Twenty-two of 32 patients with pretreatment MET-PET uptake showed uptake beyond the contrast-enhanced MRI. Patients whose treatment did not include the region of increased MET-PET uptake showed an increased risk of noncentral failure (P < 0.001).Conclusions: Patients with GBM can safely receive standard temozolomide with 75 Gy in 30 fractions, delivered using IMRT. The median OS of 20.1 months is promising. Furthermore, MET-PET appears to predict regions of high risk of recurrence not defined by MRI, suggesting that further improvements may be possible by targeting metabolically active regions. Clin Cancer Res; 18(1); 273-9. (C)2011 AACR.

Purpose: To assess the risk of cervical lymph node metastases after definitive treatment for esthesioneuroblastoma (ENB) that did not include elective neck therapy.Methods and Materials: This was a retrospective analysis of 26 ENB patients treated at the University of Michigan between 1995 and 2007. Tumor stage was Kadish A in 1 patient, B in 19, C in 5, and unknown in 1. Craniofacial or subcranial resection was performed in 24 patients (92%), with negative margins in 22 (92%). Postoperative radiotherapy (RT) to the primary site was given in 12 patients (46%), and 14 patients (54%) had surgery alone. All patients had clinically N0 disease, and no patient underwent elective neck dissection or radiation. Median follow-up was 72 months.Results: Local relapse-free survival was significantly better for patients who received postoperative RT compared with those who had surgery alone: 100% vs. 29% at 5 years, respectively (p = 0.005). Five-year disease-free survival was 87.5% in the RT group vs. 31% in the surgery-alone group (p = 0.05). Regional failure was observed in 7 patients (27%), 6 with Kadish Stage B and 1 with Stage C disease. The most common site of nodal failure was Level II, and 3 patients failed in the contralateral neck. Only 3 patients with regional failure were successfully salvaged.Conclusion: The high rate of regional failures when the neck is not electively treated justifies elective nodal RT in patients with both Kadish Stages B and C. In addition, our experience confirms the beneficial effect on local control of adjuvant RT to the tumor bed. (C) 2011 Elsevier Inc.

Apoptosis-inducing factor (AIF) is an evolutionarily conserved, ubiquitously expressed flavoprotein with NADH oxidase activity that is normally confined to mitochondria. In mammalian cells, AIF is released from mitochondria in response to apoptotic stimuli and translocates to the nucleus where it is thought to bind DNA and contribute to chromatinolysis and cell death in a caspase-independent manner. Here we describe the consequences of inactivating Aif in the early mouse embryo. Unexpectedly, we found that both the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure occur in the absence of AIF, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9 (E9), loss of Aif function causes abnormal cell death, presumably because of reduced mitochondrial respiratory chain complex I activity. Because of this cell death, Aif null embryos fail to increase significantly in size after E9. Remarkably, patterning processes continue on an essentially normal schedule, such that E10 Aif null embryos with only approximately 1/10 the normal number of cells have the same somite number as their wild-type littermates. These observations show that pattern formation in the mouse can occur independent of embryo size and cell number.

In the mouse embryo, the splanchnic mesodermal cells of the anterior heart field (AHF) migrate from the pharynx to contribute to the early myocardium of the outflow tract (OT) and right ventricle (RV). Recent studies have attempted to distinguish the AHF from other precardiac populations, and to determine the genetic and molecular mechanisms that regulate its development. Here, we have used an Fgf8lacZ allele to demonstrate that Fgf8 is expressed within the developing AHF. In addition, we use both a hypomorphic Fgf8 allele (Fgf8neo) and Cre-mediated gene ablation to show that Fgf8 is essential for the survival and proliferation of the AHF. Nkx2.5Cre is expressed in the AHF, primary heart tube and pharyngeal endoderm, while TnT-Cre is expressed only within the specified heart tube myocardium. Deletion of Fgf8 by Nkx2.5Cre results in a significant loss of the Nkx2.5Cre lineage and severe OT and RV truncations by E9.5, while the remaining heart chambers (left ventricle and atria) are grossly normal. These defects result from significant decreases in cell proliferation and aberrant cell death in both the pharyngeal endoderm and splanchnic mesoderm. By contrast, ablation of Fgf8 in the TnT-Cre domain does not result in OT or RV defects, providing strong evidence that Fgf8 expression is crucial in the pharyngeal endoderm and/or overlying splanchnic mesoderm of the AHF at a stage prior to heart tube elongation. Analysis of downstream signaling components, such as phosphorylated-Erk and Pea3, identifies the AHF splanchnic mesoderm itself as a target for Fgf8 signaling.

Cardiac and skeletal muscle critically depend on mitochondrial energy metabolism for their normal function. Recently, we showed that apoptosis-inducing factor (AIF), a mitochondrial protein implicated in programmed cell death, plays a role in mitochondrial respiration. However, the in vivo consequences of AIF-regulated mitochondrial respiration resulting from a loss-of-function mutation in Aif are not known. Here, we report tissue-specific deletion of Aif in the mouse. Mice in which Aif has been inactivated specifically in cardiac and skeletal muscle exhibit impaired activity and protein expression of respiratory chain complex I. Mutant animals develop severe dilated cardiomyopathy, heart failure, and skeletal muscle atrophy accompanied by lactic acidemia consistent with defects in the mitochondrial respiratory chain. Isolated hearts from mutant animals exhibit poor contractile performance in response to a respiratory chain-dependent energy substrate, but not in response to glucose, supporting the notion that impaired heart function in mutant animals results from defective mitochondrial energy metabolism. These data provide genetic proof that the previously defined cell death promoter AIF has a second essential function in mitochondrial respiration and aerobic energy metabolism required for normal heart function and skeletal muscle homeostasis.

SUMMARY University students-whether adult, distance learner, or traditional age-need access to university services and quick accurate answers to their questions beyond traditional “business” hours. Students' busy schedules and changing life patterns dictate that university services meet their needs. At DePaul University in Chicago, student focus groups repeatedly pointed to the need for one central place to get an answer or solve a problem. DePaul Central was created as an information and referral service to satisfy that student need, at the same capitalizing on the value of the librarian skill set.

Members of the cysteine-rich protein (CRP) family are evolutionarily conserved Lin-11, Isl-1, Mac-3 (LIM) domain proteins that have been implicated in cell differentiation. Here we describe the expression pattern of the CRP family member CRP2 in mouse. Unlike other CRP family members, which are expressed primarily in muscle, CRP2 is more broadly expressed. In addition to expression in vascular smooth muscle cells, we also detect CRP2-specific transcripts in mesenchymal derivatives and several epithelia.

Establishing the anterior/posterior (A/P) boundary of individual somites is important for setting up the segmental body plan of all vertebrates. Resegmentation of adjacent sclerotomes to form the vertebrae and selective migration of neural crest cells during the formation of the dorsal root ganglia and peripheral nerves occur in response to differential expression of genes in the anterior and posterior halves of the somite. Recent evidence indicates that the A/P axis is established at the anterior end of the presomitic mesoderm prior to overt somitogenesis in response to both Mesp2 and Notch signaling. Here, we report that mice deficient for paraxis, a gene required for somite epithelialization, also display defects in the axial skeleton and peripheral nerves that are consistent with a failure in A/P patterning. Expression of Mesp2 and genes in the Notch pathway were not altered in the presomitic mesoderm of paraxis(-/-) embryos. Furthermore, downstream targets of Notch activation in the presomitic mesoderm, including EphA4, were transcribed normally, indicating that paraxis was not required for Notch signaling. However, genes that were normally restricted to the posterior half of somites were present in a diffuse pattern in the paraxis(-/-) embryos, suggesting a loss of A/P polarity. Collectively, these data indicate a role for paraxis in maintaining somite polarity that is independent of Notch signaling.

Human MDM2 (hMDM2) inhibits transcriptional activation mediated by wild-type p53 and its tumor-derived mutants. We present evidence to show that hMDM2 interacts with the tumor-derived mutants of p53 and inhibits transcriptional activation of the human c-myc promoter mediated by the tumor-derived mutants of p53 through two domains. These two domains of hMDM2 are able to function independent of each other. Interaction with either of the domains is sufficient for inhibition of mutant p53-mediated transactivation. One of these domains is the same as the wild-type p53 interaction domain of hMDM2, whereas a second domain is situated within amino acid 190 and 276 residues and is specific for mutant p53. hMDM2 does not inhibit transcriptional activation mediated by the transcriptional activator VP16, suggesting that the inhibition is not mediated by inactivation of a general transcription factor. The transactivation and the oligomerization domains of mutant p53 are dispensable for its interaction with hMDM2. Thus, both hMDM2 and p53 recognize each other through unique domains. These observations suggest that forms of hMDM2 incapable of interacting with the wild-type p53, and are often expressed in transformed cells, would inhibit mutant p53-mediated transactivation and antagonize the tumorigenic function of mutant p53. This inhibitory function of hMDM2 may account for infrequent co-occurrence of p53 mutation and hMDM2 overexpression in cancer cells. Our results also suggest distinct mechanisms for wild-type and mutant p53-mediated transcriptional activation.

p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus onco-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and cyc A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53.

Hereditary multiple exostoses (HME) is a genetically heterogeneous disease characterized by the development of bony protuberances at the ends of all long bones. Genetic analyses have revealed HME to be a multigenic disorder linked to three loci on chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes have been cloned and defined as glycosyltransferases involved in the synthesis of heparan sulfate. EST database analysis has demonstrated additional gene family members, EXT-like genes (EXTL1, EXTL2, and EXTL3), not associated with a HME locus. The mouse homologs of EXT1 and EXT2 have also been cloned and shown to be 99% and 95% identical to their human counterparts, respectively. Here, we report the identification of the mouse EXTL1 gene and show it is 74% identical to the human EXTL1 gene. Expression studies of all three mouse EXT genes throughout various stages of embryonic development were carried out and whole-mount in situ hybridization in the developing limb buds showed high levels of expression of all three EXT genes. However, in situ hybridization of sectioned embryos revealed remarkable differences in expression profiles of EXT1, EXT2, and EXTL1. The identical expression patterns found for the EXT1 and EXT2 genes support the recent observation that both proteins form a glycosyltransferase complex. We suggest a model for exostoses formation based on the involvement of EXT1 and EXT2 in the Indian hedgehog/parathyroid hormone-related peptide (PTHrP) signaling pathway, an important regulator of the chondrocyte maturation process.

The NASA/Florida Minority Institution Entrepreneurial Partnership (FMIEP) represents a new infrastructure for technology transfer based on an alliance between the National Aeronautics and Space Administration (NASA)-Kennedy Space Center (KSC), the Technological Research and Development Authority (TRDA), and four Minority Institutions in the State of Florida. This paper describes this partnership, their key activities, and some of the initial results accomplished. The NASA-FMIEP was developed in order to assist in the technological advancement of small businesses through the support of existing federal programs. Many of these programs are underutilized, particularly by small and minority-owned businesses. One of these programs aims to transfer advanced NASA technologies to the private sector. The FMIEP supports Kennedy Space Center by identifying new potential markets for technologies developed at the Center and by developing innovative information technology applications necessary to support the efforts of technology transfer. In addition, the FMIEP';s business thrust includes assisting Kennedy Space Center in promoting the participation by small business in the Technology Outreach Program and the Small Business Innovation Research Program. To date, one NASA technology has been successfully commercialized, seven hundred businesses have been made aware of these federal business-assistance programs, and four companies received important assistance that enabled them to become SBIR winners.

LIM domains are double zinc-finger motifs found in many proteins that play central roles in cell differentiation. Members of the cysteine-rich protein (CRP) family display two LIM domains and are implicated in muscle development. Here we describe the characterization of one member of this family, CRP1, in the mouse. We have isolated and sequenced murine cDNAs that encode CRP1. We have determined by Northern analysis and in situ hybridization that CRP1 expression is developmentally regulated in the embryonic mouse and displays organ specific regulation in adults. The gene encoding CRP1 is expressed in the smooth muscle cells (SMCs) of the dorsal aorta at E9.5, thus illustrating that CRP1 is an early marker for SMC differentiation at that site. As development proceeds, CRP1 transcripts are observed throughout the SMC lineage, with minimal, transient expression detected in skeletal and cardiac muscle. Interestingly, although several markers of mature smooth muscle are already expressed, CRP1 expression in the bladder is not upregulated until the onset of bladder expansion at embryonic day 16.5, at which time its expression becomes very prominent. CRP1 expression persists into adulthood with prominent expression observed in both vascular and visceral smooth muscle. The results reported here define CRP1 as a general marker of smooth muscle lineages. Dev Dyn 1999;214:229–238. © 1999 Wiley-Liss, Inc.