Introduction: Previous stroke studies using fMRI or lesion characterization methods to study the preservation of motor performance have been limited in defining anatomical structure critical for functional performance. This study attempts to overcome this limitation by using voxel-based lesion symptom mapping (VLSM) to identify specific anatomical regions required for preservation of motor function. Methods: Forty-one moderate to moderately-severe stroke subjects (Upper Extremity Fugl-Meyer between 28 and 50, Arm Motor Ability Test > 35) were imaged with a 1mm isotropic T1-weighted volumetric sequence and their motor performance assessed. The T1 volume images were normalized to a symmetric template using SPM5 and oriented so the lesion appeared in the left hemisphere. The lesioned areas were manually segmented on the normalized T1 image. All 3D lesion maps were entered into the VLSM analysis. Areas showing significant correlations with functional performance measures were identified using the false discovery rate corrected at p </= 0.05. Results: The areas most correlated with a decrease in motor performance were at the junction of the corona radiata leading into the corticospinal tract. The Arm Motor Ability Test scores produced the most significant results, while the other measures showed similar anatomical patterns. Conclusion: The use of lesion symptom mapping in conjunction with behavioral measures produced anatomically specific results demonstrating that the area leading from the corticospinal tract to cortical motor areas is critical for maintaining hand motor performance after a stroke. This area may represent the joining of parallel redundant tracts that when damaged, limit recovery potential. Lo, R. Gitelman, D. Levy, R. Hulvershorn, J. Parrish, T. 0 2009-09-06T12:01:18Z 2009-08-27 2009-09-01 %0 Journal Article %A Lo, R. %A Gitelman, D. %A Levy, R. %A Hulvershorn, J. %A Parrish, T. %D 2010 %T Identification of critical areas for motor function recovery in chronic stroke subjects using voxel-based lesion symptom mapping. %J Neuroimage %V 49 %N 1 %P 9-18 %M 19716427 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19716427 %X INTRODUCTION: Previous stroke studies using fMRI or lesion characterization methods to study the preservation of motor performance have been limited in defining anatomical structure critical for functional performance. This study attempts to overcome this limitation by using voxel-based lesion symptom mapping (VLSM) to identify specific anatomical regions required for preservation of motor function. METHODS: Forty-one moderate to moderately severe stroke subjects (upper extremity Fugl-Meyer between 28 and 50, Arm Motor Ability Test >35) were imaged with a 1 mm isotropic T1-weighted volumetric sequence, and their motor performance was assessed. The T1 volume images were normalized to a symmetric template using SPM5 and oriented so the lesion appeared in the left hemisphere. The lesioned areas were manually segmented on the normalized T1 image. All 3D lesion maps were entered into the VLSM analysis. Areas showing significant correlations with functional performance measures were identified using the false discovery rate corrected at p< or =0.05. RESULTS: The areas most correlated with a decrease in motor performance were at the junction of the corona radiata leading into the corticospinal tract. The Arm Motor Ability Test scores produced the most significant results, while the other measures showed similar anatomical patterns. CONCLUSION: The use of lesion symptom mapping in conjunction with behavioral measures produced anatomically specific results demonstrating that the area leading from the corticospinal tract to cortical motor areas is critical for maintaining hand motor performance after a stroke. This area may represent the joining of parallel redundant tracts that, when damaged, limit recovery potential. %+ Feinberg School of Medicine, Northwestern University, 737 N. Michigan Ave., Chicago, IL 60611, USA. 8121 false false 1 NeuroImage Neuroimage 9-18 2010-01-01 ppublish JOURNAL ARTICLE 19716427 In-Process 2009-10-23T06:22:15Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19716427 49 2010 Klippel-Feil syndrome (KFS) is a rare congenital abnormality characterized by a short neck, a low posterior hairline, and limited head movement. Occasionally, patients with KFS may also show signs of deafness, intellectual disability, cardiac malformation, palpebral ptosis, facial nerve paralysis, cleft palate, and scoliosis. Although some researchers have documented this syndrome, scant attention has been paid to craniomaxillofacial manifestations and dental treatment of patients with KFS. The objective of this case report was to describe the planning and execution of dental treatment for a 10-year-old male patient with KFS. de Deus Moura de Lima, M. Ortega, K. L. Araujo, L. C. Soares, M. M. de Magalhaes, M. H. 0 2009-11-07T07:17:49Z 2009-11-06 %0 Journal Article %A de Deus Moura de Lima, M. %A Ortega, K. L. %A Araujo, L. C. %A Soares, M. M. %A de Magalhaes, M. H. %D 2009 %T Dental team management for a patient with Klippel-Feil syndrome: Case report. %J Spec Care Dentist %V 29 %N 6 %P 244-248 %M 19886936 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19886936 %X Klippel-Feil syndrome (KFS) is a rare congenital abnormality characterized by a short neck, a low posterior hairline, and limited head movement. Occasionally, patients with KFS may also show signs of deafness, intellectual disability, cardiac malformation, palpebral ptosis, facial nerve paralysis, cleft palate, and scoliosis. Although some researchers have documented this syndrome, scant attention has been paid to craniomaxillofacial manifestations and dental treatment of patients with KFS. The objective of this case report was to describe the planning and execution of dental treatment for a 10-year-old male patient with KFS. %+ Postgraduate Student, Special Care Dentistry Center, Department of Oral Pathology, University of Sao Paulo, Sao Paulo, Brazil. de Deus Moura de Lima, Marina Ortega, Karem Lopez Araujo, Luis Carlos Arias Soares, Marcelo Melo de Magalhaes, Marina Helena Cury Gallottini 8570 false false 6 Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry Spec Care Dentist 244-248 ppublish Journal Article 19886936 In-Data-Review 2009-11-07T07:17:49Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19886936 29 2009 BACKGROUND: Acute respiratory exacerbations are the most frequent cause of medical visits, hospitalization and death for chronic obstructive pulmonary disease (COPD) patients and, thus, exert a significant social and economic burden on society. OBJECTIVE: To identify the risk factors associated with hospital readmission(s) for acute exacerbation(s) of COPD (AECOPD). METHODS: A review of admission records from three large urban hospitals in Vancouver, British Columbia, identified 310 consecutive patients admitted for an AECOPD between April 1, 2001, and December 31, 2002. Logistic regression analysis was performed to identify risk factors for readmissions following an AECOPD. RESULTS: During the study period, 38% of subjects were readmitted at least once. The mean (+/- SD) duration from the index admission to the first readmission was 5+/-4.08 months. Comparative analysis among the three hospitals identified a significant difference in readmission rates (54%, 36% and 18%, respectively). Logistic regression analysis revealed that preadmission home oxygen use (OR 2.55; 95%CI 1.45 to 4.42; P=0.001), history of a lung infection within the previous year (OR 1.73; 95% CI 1.01 to 2.97; P=0.048), other chronic respiratory disease (OR 1.78; 95% CI 1.06 to 2.99; P=0.03) and shorter length of hospital stay (OR 0.97; 95% CI 0.945 to 0.995; P=0.021) were independently associated with frequent readmissions for an AECOPD. CONCLUSIONS: Hospital readmission rates for AECOPD were high. Only four clinical factors were found to be independently associated with COPD readmission. There was significant variability in the readmission rate among hospitals. This variability may be a result of differences in the patient populations that each hospital serves or may reflect variability in health care delivery at different institutions. Bahadori, K. FitzGerald, J. M. Levy, R. D. Fera, T. Swiston, J. 0 2009-09-30T06:15:47Z 2009-08-27 %0 Journal Article %A Bahadori, K. %A FitzGerald, J. M. %A Levy, R. D. %A Fera, T. %A Swiston, J. %D 2009 %T Risk factors and outcomes associated with chronic obstructive pulmonary disease exacerbations requiring hospitalization. %J Can Respir J %V 16 %N 4 %P e43-e49 %M 19707601 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19707601 %X BACKGROUND: Acute respiratory exacerbations are the most frequent cause of medical visits, hospitalization and death for chronic obstructive pulmonary disease (COPD) patients and, thus, exert a significant social and economic burden on society. OBJECTIVE: To identify the risk factors associated with hospital readmission(s) for acute exacerbation(s) of COPD (AECOPD). METHODS: A review of admission records from three large urban hospitals in Vancouver, British Columbia, identified 310 consecutive patients admitted for an AECOPD between April 1, 2001, and December 31, 2002. Logistic regression analysis was performed to identify risk factors for readmissions following an AECOPD. RESULTS: During the study period, 38% of subjects were readmitted at least once. The mean (+/- SD) duration from the index admission to the first readmission was 5+/-4.08 months. Comparative analysis among the three hospitals identified a significant difference in readmission rates (54%, 36% and 18%, respectively). Logistic regression analysis revealed that preadmission home oxygen use (OR 2.55; 95%CI 1.45 to 4.42; P=0.001), history of a lung infection within the previous year (OR 1.73; 95% CI 1.01 to 2.97; P=0.048), other chronic respiratory disease (OR 1.78; 95% CI 1.06 to 2.99; P=0.03) and shorter length of hospital stay (OR 0.97; 95% CI 0.945 to 0.995; P=0.021) were independently associated with frequent readmissions for an AECOPD. CONCLUSIONS: Hospital readmission rates for AECOPD were high. Only four clinical factors were found to be independently associated with COPD readmission. There was significant variability in the readmission rate among hospitals. This variability may be a result of differences in the patient populations that each hospital serves or may reflect variability in health care delivery at different institutions. %+ Vancouver Coastal Health Research Institute and Respiratory Medicine, Vancouver General Hosptial, Vancouver, Canada. Bahadori, Katayoun FitzGerald, J Mark Levy, Robert D Fera, Tharwat Swiston, John 8418 false false 4 Canadian respiratory journal : journal of the Canadian Thoracic Society Can Respir J e43-e49 ppublish Journal Article 19707601 In-Data-Review 2009-09-30T06:15:47Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19707601 16 2009 Replication-defective adenoviral (Ad) vectors have shown promise as a tool for gene delivery-based therapeutic applications. Their clinical use is however limited by therapeutically suboptimal transduction levels in cell types expressing low levels of Coxsackie-Ad receptor (CAR), the primary receptor responsible for the cell entry of the virus, and by systemic adverse reactions. Targeted delivery achievable with Ad complexed with biodegradable magnetically responsive nanoparticles (MNP) may therefore be instrumental for improving both the safety and efficiency of these vectors. Our hypothesis was that magnetically driven delivery of Ad affinity-bound to biodegradable MNP can substantially increase transgene expression in CAR deficient vascular cells in culture. Fluorescently labeled MNP were formulated from polylactide with inclusion of iron oxide and surface-modified with the D1 domain of CAR as an affinity linker. MNP cellular uptake and GFP reporter transgene expression were assayed fluorimetrically in cultured endothelial and smooth muscle cells using lambda(ex)/lambda(em) of 540 nm/575 nm and 485 nm/535 nm, respectively. Stable vector-specific association of Ad with MNP resulted in formation of MNP-Ad complexes displaying rapid cell binding kinetics following a brief exposure to a high gradient magnetic field with resultant gene transfer levels significantly increased compared to free vector or nonmagnetic control treatment. Multiple regression analysis suggested a mechanism of MNP-Ad mediated transduction distinct from that of free Ad, and confirmed the major contribution of the complexes to the gene transfer under magnetic conditions. The magnetically enhanced transduction was achieved without compromising the cell viability or growth kinetics. The enhancement of adenoviral gene delivery by affinity complexation with biodegradable MNP represents a promising approach with a potential to extend the applicability of the viral gene therapeutic strategies. Chorny, M. Fishbein, I. Alferiev, I. Levy, R. J. 0 2009-09-06T12:01:18Z 2009-06-06 %0 Journal Article %A Chorny, M. %A Fishbein, I. %A Alferiev, I. %A Levy, R. J. %D 2009 %T Magnetically responsive biodegradable nanoparticles enhance adenoviral gene transfer in cultured smooth muscle and endothelial cells. %J Mol Pharm %V 6 %N 5 %P 1380-1387 %M 19496618 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19496618 %X Replication-defective adenoviral (Ad) vectors have shown promise as a tool for gene delivery-based therapeutic applications. Their clinical use is however limited by therapeutically suboptimal transduction levels in cell types expressing low levels of Coxsackie-Ad receptor (CAR), the primary receptor responsible for the cell entry of the virus, and by systemic adverse reactions. Targeted delivery achievable with Ad complexed with biodegradable magnetically responsive nanoparticles (MNP) may therefore be instrumental for improving both the safety and efficiency of these vectors. Our hypothesis was that magnetically driven delivery of Ad affinity-bound to biodegradable MNP can substantially increase transgene expression in CAR deficient vascular cells in culture. Fluorescently labeled MNP were formulated from polylactide with inclusion of iron oxide and surface-modified with the D1 domain of CAR as an affinity linker. MNP cellular uptake and GFP reporter transgene expression were assayed fluorimetrically in cultured endothelial and smooth muscle cells using lambda(ex)/lambda(em) of 540 nm/575 nm and 485 nm/535 nm, respectively. Stable vector-specific association of Ad with MNP resulted in formation of MNP-Ad complexes displaying rapid cell binding kinetics following a brief exposure to a high gradient magnetic field with resultant gene transfer levels significantly increased compared to free vector or nonmagnetic control treatment. Multiple regression analysis suggested a mechanism of MNP-Ad mediated transduction distinct from that of free Ad, and confirmed the major contribution of the complexes to the gene transfer under magnetic conditions. The magnetically enhanced transduction was achieved without compromising the cell viability or growth kinetics. The enhancement of adenoviral gene delivery by affinity complexation with biodegradable MNP represents a promising approach with a potential to extend the applicability of the viral gene therapeutic strategies. %+ The Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. 8129 false false 5 Molecular pharmaceutics Mol Pharm 1380-1387 ppublish JOURNAL ARTICLE 19496618 In-Process 2009-10-27T06:22:06Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19496618 6 2009 Gamble, G. L. Cheville, A. L. 0 2009-09-06T12:00:19Z 2009-03-13 %0 Journal Article %A Gamble, G. L. %A Cheville, A. L. %D 2009 %T Can physical exercise interventions benefit palliative cancer patients? A noble first look. %J J Support Oncol %V 7 %N 1 %P 35-36 %M 19278176 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19278176 %K Caregivers %K Humans %K *Motor Activity %K Neoplasms/economics/*therapy %K *Palliative Care %K Quality of Life %+ Cancer Rehabilitation, Rehabilitation Institute of Chicago, Chicago, IL 60611, USA. ggamble@ric.org Gamble, Gail L Cheville, Andrea L 7439 false false 1 The journal of supportive oncology J Support Oncol Caregivers; Humans; *Motor Activity; Neoplasms/economics/*therapy; *Palliative Care; Quality of Life 35-36 ppublish Comment 19278176 MEDLINE 2009-09-06T12:00:19Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19278176 7 2009 In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underly these changes were not determined. We have used the recently developed knockout mouse models of retinoblastoma to begin to characterize the molecular, cellular and genetic changes associated with retinoblastoma tumor progression and optic nerve invasion. Here we present the isolation and characterization of the first mouse retinoblastoma cell lines with targeted deletions of the Rb family. Our detailed analysis of these cells as they were propagated in culture from the primary tumor show that changes in cadherin-mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago providing a molecular mechanism for these earlier observations. Most importantly, our studies are in agreement with genetic studies on human retinoblastomas suggesting that changes in this pathway are involved in tumor progression. Laurie, N. Mohan, A. McEvoy, J. Reed, D. Zhang, J. Schweers, B. Ajioka, I. Valentine, V. Johnson, D. Ellison, D. Dyer, M. A. 0 2009-10-01T06:13:58Z 2009-09-28 2009-09-30 %0 Journal Article %A Laurie, N. %A Mohan, A. %A McEvoy, J. %A Reed, D. %A Zhang, J. %A Schweers, B. %A Ajioka, I. %A Valentine, V. %A Johnson, D. %A Ellison, D. %A Dyer, M. A. %D 2009 %T Changes in retinoblastoma cell adhesion associated with optic nerve invasion. %J Mol Cell Biol %V 29 %N 23 %P 6268-6282 %M 19786571 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19786571 %X In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underlie these changes were not determined. We used the recently developed knockout mouse models of retinoblastoma to begin to characterize the molecular, cellular, and genetic changes associated with retinoblastoma tumor progression and optic nerve invasion. Here we report the isolation and characterization of the first mouse retinoblastoma cell lines with targeted deletions of the Rb family. Our detailed analysis of these cells as they were propagated in culture from the primary tumor shows that changes in cadherin-mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago, providing a molecular mechanism for these earlier observations. Most importantly, our studies are in agreement with genetic studies on human retinoblastomas, suggesting that changes in this pathway are involved in tumor progression. %+ Department of Developmental Neurobiology, MS 323, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 8422 false false 23 Molecular and cellular biology Mol Cell Biol 6268-6282 2009-12-01 ppublish JOURNAL ARTICLE 19786571 In-Process 2009-11-10T07:18:39Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19786571 29 2009 GFP-expressing Xenopus tadpole made by transplanting a nucleus from a transgenic CMV-GFP blastula into an enucleated GFP(-) egg. The egg was enucleated using a new method, treatment with psoralens and ultraviolet light. See McGarry et al., Developmental Dynamics 238:2614-2621, 2009. Developmental Dynamics, 2009. (c) 2009 Wiley-Liss, Inc. McGarry, T. J. Bonaguidi, M. Lyass, L. Kessler, J. A. Bodily, J. M. Doglio, L. 0 2009-11-21T07:19:57Z 2009-11-18 2009-11-20 %0 Journal Article %A McGarry, T. J. %A Bonaguidi, M. %A Lyass, L. %A Kessler, J. A. %A Bodily, J. M. %A Doglio, L. %D 2009 %T Enucleation of feeder cells and egg cells with psoralens. %J Dev Dyn %V 238 %N 12 %P spc1 %M 19924829 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19924829 %X GFP-expressing Xenopus tadpole made by transplanting a nucleus from a transgenic CMV-GFP blastula into an enucleated GFP(-) egg. The egg was enucleated using a new method, treatment with psoralens and ultraviolet light. See McGarry et al., Developmental Dynamics 238:2614-2621, 2009. Developmental Dynamics, 2009. (c) 2009 Wiley-Liss, Inc. %+ Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 8613 false false 12 Developmental dynamics : an official publication of the American Association of Anatomists Dev Dyn spc1 2009-11-18 aheadofprint JOURNAL ARTICLE 19924829 Publisher 2009-11-21T07:19:57Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19924829 238 2009 BACKGROUND: Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. PROCEDURE: Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). RESULTS: Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3-60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4-9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36-104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. CONCLUSIONS: Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc. Dunkel, I. J. Jubran, R. F. Gururangan, S. Chantada, G. L. Finlay, J. L. Goldman, S. Khakoo, Y. O'Brien, J. M. Orjuela, M. Rodriguez-Galindo, C. Souweidane, M. M. Abramson, D. H. 0 2009-11-14T07:16:23Z 2009-11-11 2009-11-13 %0 Journal Article %A Dunkel, I. J. %A Jubran, R. F. %A Gururangan, S. %A Chantada, G. L. %A Finlay, J. L. %A Goldman, S. %A Khakoo, Y. %A O'Brien, J. M. %A Orjuela, M. %A Rodriguez-Galindo, C. %A Souweidane, M. M. %A Abramson, D. H. %D 2009 %T Trilateral retinoblastoma: Potentially curable with intensive chemotherapy. %J Pediatr Blood Cancer %M 19908299 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19908299 %X BACKGROUND: Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. PROCEDURE: Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). RESULTS: Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3-60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4-9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36-104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. CONCLUSIONS: Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc. %+ Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York; 8590 false false Pediatric blood & cancer Pediatr Blood Cancer 2009-11-11 aheadofprint JOURNAL ARTICLE 19908299 Publisher 2009-11-14T07:16:23Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19908299 2009 We report on a child with chronic granulomatous disease who at the age of 13 years was diagnosed with glioblastoma multiforme of the left thalamus. Therapy included subtotal resection, radiation to the tumor bed (60 Gy), and concomitant chemotherapy with daily thalidomide (250 mg/m), both during radiation and for 5 years thereafter. Currently, she is 9 years from diagnosis and has no evidence of disease. Therapy with thalidomide did not increase her infection complications and provided excellent quality of life. This is the first report of glioblastoma multiforme in a patient with chronic granulomatous disease treated with surgery, radiation, and thalidomide who is a long-term survivor. Aguilera, D. G. Tomita, T. Rajaram, V. Fangusaro, J. Katz, B. Z. Shulman, S. Goldman, S. 0 2009-11-07T07:17:08Z 2009-11-11 2009-11-06 %0 Journal Article %A Aguilera, D. G. %A Tomita, T. %A Rajaram, V. %A Fangusaro, J. %A Katz, B. Z. %A Shulman, S. %A Goldman, S. %D 2009 %T Glioblastoma Multiforme in a Patient With Chronic Granulomatous Disease Treated With Subtotal Resection, Radiation, and Thalidomide: Case Report of a Long-term Survivor. %J J Pediatr Hematol Oncol %M 19887959 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19887959 %X We report on a child with chronic granulomatous disease who at the age of 13 years was diagnosed with glioblastoma multiforme of the left thalamus. Therapy included subtotal resection, radiation to the tumor bed (60 Gy), and concomitant chemotherapy with daily thalidomide (250 mg/m), both during radiation and for 5 years thereafter. Currently, she is 9 years from diagnosis and has no evidence of disease. Therapy with thalidomide did not increase her infection complications and provided excellent quality of life. This is the first report of glioblastoma multiforme in a patient with chronic granulomatous disease treated with surgery, radiation, and thalidomide who is a long-term survivor. %+ Divisions of *Hematology-Oncology and Stem Cell transplantation daggerNeurosurgery section signInfectious Diseases double daggerDepartment of Pathology, Children's Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL. 8569 false false Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology J Pediatr Hematol Oncol 2009-11-11 aheadofprint JOURNAL ARTICLE 19887959 Publisher 2009-11-17T07:20:47Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19887959 2009 Objectives Several drug resistance and secondary mutations have been described in HIV-1 viruses from patients undergoing antiretroviral therapy. In this study, we assessed the impact of the protease substitution T74S on the phenotype and on the replicative fitness in HIV-1 subtypes B and C. Methods HIV-1 molecular clones carrying subtype B or C proteases had these coding regions subjected to site-directed mutagenesis to include T74S alone or in combination with four known protease inhibitor (PI) primary drug resistance mutations. All clones were used in a phenotypic assay to evaluate their susceptibility to most commercially available PIs. The impact of T74S on virus fitness was also assessed for all viruses through head-to-head competitions and oligonucleotide ligation assays to measure the proportion of each virus in culture. Results Viruses of both subtypes carrying T74S did not have their susceptibility altered to any tested PI. Viruses with the four resistance mutations showed strong resistance to most PIs with fold changes ranging from 5 to 300 times compared with their wild-type counterparts. Surprisingly, the addition of T74S to the multiresistant clones restored their susceptibilities to indinavir and ritonavir and partially to lopinavir, close to those of wild-type viruses. Most 74S-containing viruses were more fit than their 74T counterparts. Conclusions Our results suggest that T74S is not a major drug resistance mutation, but it resensitizes multiresistant viruses to certain PIs. T74S is a bona fide accessory mutation, restoring fitness of multidrug-resistant viruses in both subtypes B and C. T74S should be further studied in clinical settings and considered in drug resistance interpretation algorithms. Soares, E. A. Santos, A. F. Gonzalez, L. M. Lalonde, M. S. Tebit, D. M. Tanuri, A. Arts, E. J. Soares, M. A. 0 2009-09-06T11:58:18Z 2009-08-26 2009-08-28 %0 Journal Article %A Soares, E. A. %A Santos, A. F. %A Gonzalez, L. M. %A Lalonde, M. S. %A Tebit, D. M. %A Tanuri, A. %A Arts, E. J. %A Soares, M. A. %D 2009 %T Mutation T74S in HIV-1 subtype B and C proteases resensitizes them to ritonavir and indinavir and confers fitness advantage. %J J Antimicrob Chemother %V 64 %N 5 %P 938-944 %M 19710076 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19710076 %X OBJECTIVES: Several drug resistance and secondary mutations have been described in HIV-1 viruses from patients undergoing antiretroviral therapy. In this study, we assessed the impact of the protease substitution T74S on the phenotype and on the replicative fitness in HIV-1 subtypes B and C. METHODS: HIV-1 molecular clones carrying subtype B or C proteases had these coding regions subjected to site-directed mutagenesis to include T74S alone or in combination with four known protease inhibitor (PI) primary drug resistance mutations. All clones were used in a phenotypic assay to evaluate their susceptibility to most commercially available PIs. The impact of T74S on virus fitness was also assessed for all viruses through head-to-head competitions and oligonucleotide ligation assays to measure the proportion of each virus in culture. RESULTS: Viruses of both subtypes carrying T74S did not have their susceptibility altered to any tested PI. Viruses with the four resistance mutations showed strong resistance to most PIs with fold changes ranging from 5 to 300 times compared with their wild-type counterparts. Surprisingly, the addition of T74S to the multiresistant clones restored their susceptibilities to indinavir and ritonavir and partially to lopinavir, close to those of wild-type viruses. Most 74S-containing viruses were more fit than their 74T counterparts. CONCLUSIONS: Our results suggest that T74S is not a major drug resistance mutation, but it resensitizes multiresistant viruses to certain PIs. T74S is a bona fide accessory mutation, restoring fitness of multidrug-resistant viruses in both subtypes B and C. T74S should be further studied in clinical settings and considered in drug resistance interpretation algorithms. %+ Departamento de Genetica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 5728 false false 5 The Journal of antimicrobial chemotherapy J Antimicrob Chemother 938-944 2009-11-01 ppublish JOURNAL ARTICLE 19710076 In-Process 2009-10-15T06:14:48Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19710076 64 2009 Trypanosoma congolense is one of the most economically important pathogens of livestock in Africa. Culture-derived parasites of each of the three main insect stages of the T. congolense life cycle, i.e., the procyclic, epimastigote and metacyclic stages, and bloodstream stage parasites isolated from infected mice, were used to construct stage-specific cDNA libraries and expressed sequence tags (ESTs or cDNA clones) in each library were sequenced. Thirteen EST clusters encoding different variant surface glycoproteins (VSGs) were detected in the metacyclic library and 26 VSG EST clusters were found in the bloodstream library, 6 of which are shared by the metacyclic library. Rare VSG ESTs are present in the epimastigote library, and none were detected in the procyclic library. ESTs encoding enzymes that catalyze oxidative phosphorylation and amino acid metabolism are about twice as abundant in the procyclic and epimastigote stages as in the metacyclic and bloodstream stages. In contrast, ESTs encoding enzymes involved in glycolysis, the citric acid cycle and nucleotide metabolism are about the same in all four developmental stages. Cysteine proteases, kinases and phosphatases are the most abundant enzyme groups represented by the ESTs. All four libraries contain T. congolense-specific expressed sequences not present in the Trypanosoma brucei and Trypanosoma cruzi genomes. Normalized cDNA libraries were constructed from the metacyclic and bloodstream stages, and found to be further enriched for T. congolense-specific ESTs. Given that cultured T. congolense offers an experimental advantage over other African trypanosome species, these ESTs provide a basis for further investigation of the molecular properties of these four developmental stages, especially the epimastigote and metacyclic stages for which it is difficult to obtain large quantities of organisms. The T. congolense EST databases are available at: http://www.sanger.ac.uk/Projects/T_congolense/EST_index.shtml. The sequence data have been submitted to EMBL under the following accession numbers: FN263376-FN292969. Helm, J. R. Hertz-Fowler, C. Aslett, M. Berriman, M. Sanders, M. Quail, M. A. Soares, M. B. Bonaldo, M. F. Sakurai, T. Inoue, N. Donelson, J. E. 0 2009-09-06T11:58:18Z 2009-06-25 2009-06-30 %0 Journal Article %A Helm, J. R. %A Hertz-Fowler, C. %A Aslett, M. %A Berriman, M. %A Sanders, M. %A Quail, M. A. %A Soares, M. B. %A Bonaldo, M. F. %A Sakurai, T. %A Inoue, N. %A Donelson, J. E. %D 2009 %T Analysis of expressed sequence tags from the four main developmental stages of Trypanosoma congolense. %J Mol Biochem Parasitol %V 168 %N 1 %P 34-42 %M 19559733 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19559733 %X Trypanosoma congolense is one of the most economically important pathogens of livestock in Africa. Culture-derived parasites of each of the three main insect stages of the T. congolense life cycle, i.e., the procyclic, epimastigote and metacyclic stages, and bloodstream stage parasites isolated from infected mice, were used to construct stage-specific cDNA libraries and expressed sequence tags (ESTs or cDNA clones) in each library were sequenced. Thirteen EST clusters encoding different variant surface glycoproteins (VSGs) were detected in the metacyclic library and 26 VSG EST clusters were found in the bloodstream library, 6 of which are shared by the metacyclic library. Rare VSG ESTs are present in the epimastigote library, and none were detected in the procyclic library. ESTs encoding enzymes that catalyze oxidative phosphorylation and amino acid metabolism are about twice as abundant in the procyclic and epimastigote stages as in the metacyclic and bloodstream stages. In contrast, ESTs encoding enzymes involved in glycolysis, the citric acid cycle and nucleotide metabolism are about the same in all four developmental stages. Cysteine proteases, kinases and phosphatases are the most abundant enzyme groups represented by the ESTs. All four libraries contain T. congolense-specific expressed sequences not present in the Trypanosoma brucei and Trypanosoma cruzi genomes. Normalized cDNA libraries were constructed from the metacyclic and bloodstream stages, and found to be further enriched for T. congolense-specific ESTs. Given that cultured T. congolense offers an experimental advantage over other African trypanosome species, these ESTs provide a basis for further investigation of the molecular properties of these four developmental stages, especially the epimastigote and metacyclic stages for which it is difficult to obtain large quantities of organisms. The T. congolense EST databases are available at: http://www.sanger.ac.uk/Projects/T_congolense/EST_index.shtml. The sequence data have been submitted to EMBL under the following accession numbers: FN263376-FN292969. %K Animals %K DNA, Protozoan/genetics %K *Expressed Sequence Tags %K *Gene Expression Profiling %K *Gene Library %K Genes, Protozoan %K Mice %K Multigene Family %K Trypanosoma congolense/*genetics/*growth & development %+ Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Helm, Jared R Hertz-Fowler, Christiane Aslett, Martin Berriman, Matthew Sanders, Mandy Quail, Michael A Soares, Marcelo B Bonaldo, Maria F Sakurai, Tatsuya Inoue, Noboru Donelson, John E 5730 false false 1 Molecular and biochemical parasitology Mol Biochem Parasitol Animals; DNA, Protozoan/genetics; *Expressed Sequence Tags; *Gene Expression Profiling; *Gene Library; Genes, Protozoan; Mice; Multigene Family; Trypanosoma congolense/*genetics/*growth & development 34-42 2009-11-01 ppublish Journal Article 19559733 MEDLINE 2009-10-17T06:19:28Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19559733 168 2009 We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence. Deboer, R. Batjer, H. Marymont, M. Goldman, S. Walker, M. Gottardi-Littell, N. Raizer, J. 0 2009-09-06T11:55:17Z 2009-06-09 2009-06-10 %0 Journal Article %A DeBoer, R. %A Batjer, H. %A Marymont, M. %A Goldman, S. %A Walker, M. %A Gottardi-Littell, N. %A Raizer, J. %D 2009 %T Response of an adult patient with pineoblastoma to vorinostat and retinoic acid. %J J Neurooncol %V 95 %N 2 %P 289-292 %M 19506816 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19506816 %X We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence. %+ Feinberg School of Medicine, Northwestern University, 710 N Lake Shore Drive, Abbott Hall, Room 1123, Chicago, IL 60611, USA. becky.deboer@gmail.com 1683 false false 2 Journal of neuro-oncology J Neurooncol 289-292 2009-11-01 ppublish JOURNAL ARTICLE 19506816 In-Process 2009-10-09T06:13:29Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19506816 95 2009 Before high-grade papillary serous carcinoma (HG-PSC) becomes invasive, it is believed to be a poorly defined short-lived precursor lesion. A recent characterization of serous tubal intraepithelial carcinoma (STIC) and of the p53 signature suggested that HG-PSC may follow a stepwise progression on cellular and molecular levels. High-mobility group AT-hook 2 (HMGA2), an oncofetal protein, is overexpressed in ovarian cancer. To test whether HMGA2 can be another valuable marker for STIC, we examined HMGA2 expression in 3 groups of patients: (1) 24 patients with STIC and its invasive counterpart, HG-PSC of the fallopian tubes, (2) 24 patients with HG-PSC of the ovaries but without STIC (positive control), and (3) 30 patients with cancer and normal fallopian tubes (negative control). We found that HMGA2 was overexpressed in 75% of patients with STIC, was coexpressed with p53 in more than 50% of patients, and was completely negative in the secretory cells of the 30 patients with normal fallopian tubes. Among 7 patients with cells negative for p53 staining, HMGA2 was positive in 5; among 6 patients whose tumor cells were negative for HMGA2 in STIC, 3 were positive for HMGA2 in the invasive component; about 70% of invasive HG-PSC tumor cells were immunoreactive for both HMGA2 and TP53. In invasive carcinoma, HMGA2 overexpression was correlated with p53 (r=0.45), indicating the role of HMGA2 in p53 mediated tumor progression. Our findings of immunoreactivity for HMGA2 may lead to a novel, useful biomarker to complement p53 in the detection of early-stage serous carcinoma. Wei, J. J. Wu, J. Luan, C. Yeldandi, A. Lee, P. Keh, P. Liu, J. 0 2009-11-11T07:23:09Z 2009-10-28 2009-11-10 %0 Journal Article %A Wei, J. J. %A Wu, J. %A Luan, C. %A Yeldandi, A. %A Lee, P. %A Keh, P. %A Liu, J. %D 2009 %T HMGA2: A Potential Biomarker Complement to P53 for Detection of Early-stage High-grade Papillary Serous Carcinoma in Fallopian Tubes. %J Am J Surg Pathol %M 19898227 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898227 %X Before high-grade papillary serous carcinoma (HG-PSC) becomes invasive, it is believed to be a poorly defined short-lived precursor lesion. A recent characterization of serous tubal intraepithelial carcinoma (STIC) and of the p53 signature suggested that HG-PSC may follow a stepwise progression on cellular and molecular levels. High-mobility group AT-hook 2 (HMGA2), an oncofetal protein, is overexpressed in ovarian cancer. To test whether HMGA2 can be another valuable marker for STIC, we examined HMGA2 expression in 3 groups of patients: (1) 24 patients with STIC and its invasive counterpart, HG-PSC of the fallopian tubes, (2) 24 patients with HG-PSC of the ovaries but without STIC (positive control), and (3) 30 patients with cancer and normal fallopian tubes (negative control). We found that HMGA2 was overexpressed in 75% of patients with STIC, was coexpressed with p53 in more than 50% of patients, and was completely negative in the secretory cells of the 30 patients with normal fallopian tubes. Among 7 patients with cells negative for p53 staining, HMGA2 was positive in 5; among 6 patients whose tumor cells were negative for HMGA2 in STIC, 3 were positive for HMGA2 in the invasive component; about 70% of invasive HG-PSC tumor cells were immunoreactive for both HMGA2 and TP53. In invasive carcinoma, HMGA2 overexpression was correlated with p53 (r=0.45), indicating the role of HMGA2 in p53 mediated tumor progression. Our findings of immunoreactivity for HMGA2 may lead to a novel, useful biomarker to complement p53 in the detection of early-stage serous carcinoma. %+ *Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL daggerDepartment of Pathology, New York University School of Medicine, New York, NY double daggerDepartment of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX. 8583 false false The American journal of surgical pathology Am J Surg Pathol 2009-10-28 aheadofprint JOURNAL ARTICLE 19898227 Publisher 2009-11-11T07:23:09Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898227 2009 The mechanisms underlying the timing of the laminar fate decisions during cortical neurogenesis remain poorly understood. Here we show that beta-catenin signaling in cortical neural precursors can regulate the laminar fate of their daughters. In ventricular zone neural precursors, beta-catenin signaling is higher when deep-layer neurons are being generated and lower when upper-layer neurons are being generated. Overactivation of beta-catenin in cortical precursors midway through corticogenesis increased the relative production of deep-layer neurons, while inhibition of signaling increased the relative production of upper-layer neurons. Furthermore, in late-gestation upper-layer precursors, overactive beta-catenin signaling was able to partially restore production of deep-layer neurons. These observations suggest that increased beta-catenin signaling can reset the timing of cortical precursors to promote the production of deep-layer neurons, while inhibition of beta-catenin signaling advances the timing to promote upper-layer production. Mutch, C. A. Funatsu, N. Monuki, E. S. Chenn, A. 0 2009-10-31T06:19:37Z 2009-10-30 %0 Journal Article %A Mutch, C. A. %A Funatsu, N. %A Monuki, E. S. %A Chenn, A. %D 2009 %T Beta-catenin signaling levels in progenitors influence the laminar cell fates of projection neurons. %J J Neurosci %V 29 %N 43 %P 13710-13719 %M 19864583 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19864583 %X The mechanisms underlying the timing of the laminar fate decisions during cortical neurogenesis remain poorly understood. Here we show that beta-catenin signaling in cortical neural precursors can regulate the laminar fate of their daughters. In ventricular zone neural precursors, beta-catenin signaling is higher when deep-layer neurons are being generated and lower when upper-layer neurons are being generated. Overactivation of beta-catenin in cortical precursors midway through corticogenesis increased the relative production of deep-layer neurons, while inhibition of signaling increased the relative production of upper-layer neurons. Furthermore, in late-gestation upper-layer precursors, overactive beta-catenin signaling was able to partially restore production of deep-layer neurons. These observations suggest that increased beta-catenin signaling can reset the timing of cortical precursors to promote the production of deep-layer neurons, while inhibition of beta-catenin signaling advances the timing to promote upper-layer production. %+ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. Mutch, Christopher A Funatsu, Nobuo Monuki, Edwin S Chenn, Anjen 8543 false false 43 The Journal of neuroscience : the official journal of the Society for Neuroscience J Neurosci 13710-13719 2009-10-28 ppublish Journal Article 19864583 In-Process 2009-10-31T06:19:37Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19864583 29 2009 The cystic fibrosis transmembrane conductance regulator (CFTR) gene is driven by a promoter that cannot alone account for the temporal and tissue-specific regulation of the gene. This has led to the search for additional regulatory elements that cooperate with the basal promoter to achieve coordinated expression. We previously identified two alternative upstream exons of the gene that were mutually exclusive with the first exon and one of which showed temporal regulation in the human and sheep lung. We now demonstrate that this alternative splice product generates a stable protein, which initiates translation at an ATG in exon 4 and thus lacks the N-terminus of CFTR. The other splice variant inhibits translation of the protein. In a search for the promoter utilized by the upstream exons, we identified a novel element that contributes to the activity of the basal CFTR promoter in airway epithelial cells, but does not function independently. Finally, we demonstrated that in primary airway cells, skin fibroblasts, and both airway and intestinal cell lines, the CFTR promoter is unmethylated, irrespective of CFTR expression status. Thus methylation is not the main cause of inactivation of CFTR transcription. Lewandowska, M. A. Costa, F. F. Bischof, J. M. Williams, S. H. Soares, M. B. Harris, A. 0 2009-10-28T06:22:33Z 2009-10-23 2009-10-27 %0 Journal Article %A Lewandowska, M. A. %A Costa, F. F. %A Bischof, J. M. %A Williams, S. H. %A Soares, M. B. %A Harris, A. %D 2009 %T Multiple Mechanisms Influence Regulation of the CFTR Gene Promoter. %J Am J Respir Cell Mol Biol %M 19855085 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19855085 %X The cystic fibrosis transmembrane conductance regulator (CFTR) gene is driven by a promoter that cannot alone account for the temporal and tissue-specific regulation of the gene. This has led to the search for additional regulatory elements that cooperate with the basal promoter to achieve coordinated expression. We previously identified two alternative upstream exons of the gene that were mutually exclusive with the first exon and one of which showed temporal regulation in the human and sheep lung. We now demonstrate that this alternative splice product generates a stable protein, which initiates translation at an ATG in exon 4 and thus lacks the N-terminus of CFTR. The other splice variant inhibits translation of the protein. In a search for the promoter utilized by the upstream exons, we identified a novel element that contributes to the activity of the basal CFTR promoter in airway epithelial cells, but does not function independently. Finally, we demonstrated that in primary airway cells, skin fibroblasts, and both airway and intestinal cell lines, the CFTR promoter is unmethylated, irrespective of CFTR expression status. Thus methylation is not the main cause of inactivation of CFTR transcription. %+ Children's Memorial Research Center, Pediatrics, Northwestern University, Feinberg School of Medicine, Human Molecular Genetic Program, Chicago, Illinois, United States. 8531 false false American journal of respiratory cell and molecular biology Am J Respir Cell Mol Biol 2009-10-23 aheadofprint JOURNAL ARTICLE 19855085 Publisher 2009-10-28T06:22:33Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19855085 2009 ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc-metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains, and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and EGF-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities. Liu, H. Shim, A. H. He, X. 0 2009-09-06T11:55:25Z 2009-08-18 2009-08-21 %0 Journal Article %A Liu, H. %A Shim, A. H. %A He, X. %D 2009 %T Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: insights on ADAM function. %J J Biol Chem %V 284 %N 42 %P 29077-29086 %M 19692335 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19692335 %X ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and epidermal growth factor-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities. %+ Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. 1954 false false 42 The Journal of biological chemistry J Biol Chem 29077-29086 2009-10-16 ppublish JOURNAL ARTICLE 19692335 In-Process 2009-10-16T06:14:38Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19692335 284 2009 Fishbein, I. Levy, R. J. 0 2009-10-17T06:20:11Z 2009-10-16 %0 Journal Article %A Fishbein, I. %A Levy, R. J. %D 2009 %T Analytical chemistry: The matrix neutralized. %J Nature %V 461 %N 7266 %P 890-891 %M 19829362 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19829362 Fishbein, Ilia Levy, Robert J 8490 false false 7266 Nature Nature 890-891 2009-10-15 ppublish Journal Article 19829362 In-Process 2009-10-20T06:21:15Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19829362 461 2009 Primary spinal cord tumors represent 2-4% of all neoplasms of the CNS. Primary spinal cord tumors are anatomically separable into two broad categories: intradural intramedullary and intradural extramedullary. Intramedullary tumors are comprised predominantly of gliomas (infiltrative astrocytomas and ependymomas). Resective surgery can usually be accomplished with spinal ependymomas owing to separation of tumor from spinal cord and, when complete, require no further therapy. By contrast, spinal cord gliomas infiltrate the myelon and, consequently, surgery is nearly always incomplete. Involved-field radiotherapy is most often administered after partial resection. Intradural extramedullary tumors are either peripheral nerve sheath tumors (neurofibromas or schwanommas) or meningiomas. In either instance, complete resection may be accomplished and is often curative. Radiotherapy is reserved for rare malignant variants and for patients in whom surgery is contraindicated. Chemotherapy is administered for recurrent primary spinal cord tumors without other options, that is, reoperation or re-irradiation. Problematic, however, is the lack of clinical trials in general for these CNS tumors and for spinal cord tumors in particular. Consequently, treatment is similar to that for intracranial tumors with a similar histology. Early recognition of the signs and symptoms of primary spinal cord tumors allows for early treatment, potentially minimizes neurologic morbidity and improves outcome. Primary treatment is surgery in essentially all spinal cord tumors, and predictors of outcome include preoperative functional status, histological grade of tumor and extent of surgical resection. Grimm, S. Chamberlain, M. C. 0 2009-10-18T06:19:26Z 2009-10-17 %0 Journal Article %A Grimm, S. %A Chamberlain, M. C. %D 2009 %T Adult primary spinal cord tumors. %J Expert Rev Neurother %V 9 %N 10 %P 1487-1495 %M 19831838 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19831838 %X Primary spinal cord tumors represent 2-4% of all neoplasms of the CNS. Primary spinal cord tumors are anatomically separable into two broad categories: intradural intramedullary and intradural extramedullary. Intramedullary tumors are comprised predominantly of gliomas (infiltrative astrocytomas and ependymomas). Resective surgery can usually be accomplished with spinal ependymomas owing to separation of tumor from spinal cord and, when complete, require no further therapy. By contrast, spinal cord gliomas infiltrate the myelon and, consequently, surgery is nearly always incomplete. Involved-field radiotherapy is most often administered after partial resection. Intradural extramedullary tumors are either peripheral nerve sheath tumors (neurofibromas or schwanommas) or meningiomas. In either instance, complete resection may be accomplished and is often curative. Radiotherapy is reserved for rare malignant variants and for patients in whom surgery is contraindicated. Chemotherapy is administered for recurrent primary spinal cord tumors without other options, that is, reoperation or re-irradiation. Problematic, however, is the lack of clinical trials in general for these CNS tumors and for spinal cord tumors in particular. Consequently, treatment is similar to that for intracranial tumors with a similar histology. Early recognition of the signs and symptoms of primary spinal cord tumors allows for early treatment, potentially minimizes neurologic morbidity and improves outcome. Primary treatment is surgery in essentially all spinal cord tumors, and predictors of outcome include preoperative functional status, histological grade of tumor and extent of surgical resection. %+ University of Washington, Department of Neurology/Division of Neuro-Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 825 Eastlake Avenue E, POB 19023, MS G4940, Seattle, WA 98109-1023, USA. Grimm, Sean Chamberlain, Marc C 8493 false false 10 Expert review of neurotherapeutics Expert Rev Neurother 1487-1495 2009-10-01 ppublish Journal Article 19831838 In-Process 2009-10-20T06:19:57Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19831838 9 2009 Recognition of the ability of CD4(+)FoxP3(+) T cells (Treg) to influence the generation of peripheral immune responses has engendered enthusiasm for the development of strategies utilizing these cells to regulate immune responses in clinically important settings including transplantation, autoimmunity and cancer. A number of studies have reported effective regulation utilizing ex-vivo expansion approaches and subsequent transfer of Treg populations in experimental models. This commentary discusses recently emerging strategies to activate and expand Treg cells in situ which include antibodies, antigen presenting cells and the use of IL2 / anti-IL2 antibody complex. The development of reagents which can stimulate and / or remove Treg cells in situ would represent an important advance towards facilitating new opportunities to harness this compartment for the augmentation of 'wanted' or suppression of 'unwanted' immune responses. Simultaneous targeting of multiple molecules on Treg cells may ultimately enable more effective control of this regulatory sector. Shatry, A. Chirinos, J. Gorin, M. A. Jones, M. Levy, R. B. 0 2009-09-16T06:16:25Z 2009-08-03 2009-09-15 %0 Journal Article %A Shatry, A. %A Chirinos, J. %A Gorin, M. A. %A Jones, M. %A Levy, R. B. %D 2009 %T Targeting Treg cells in situ: emerging expansion strategies for (CD4(+)CD25(+)) regulatory T cells. %J Biol Blood Marrow Transplant %V 15 %N 10 %P 1239-1243 %M 19747630 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19747630 %X Recognition of the ability of CD4(+)FoxP3(+) T cells (Treg) to influence the generation of peripheral immune responses has engendered enthusiasm for the development of strategies utilizing these cells to regulate immune responses in clinically important settings including transplantation, autoimmunity and cancer. A number of studies have reported effective regulation utilizing ex-vivo expansion approaches and subsequent transfer of Treg populations in experimental models. This commentary discusses recently emerging strategies to activate and expand Treg cells in situ which include antibodies, antigen presenting cells and the use of IL2 / anti-IL2 antibody complex. The development of reagents which can stimulate and / or remove Treg cells in situ would represent an important advance towards facilitating new opportunities to harness this compartment for the augmentation of 'wanted' or suppression of 'unwanted' immune responses. Simultaneous targeting of multiple molecules on Treg cells may ultimately enable more effective control of this regulatory sector. %+ Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA. Shatry, Alwi Chirinos, Jackeline Gorin, Michael A Jones, Monica Levy, Robert B 8280 false false 10 Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Biol Blood Marrow Transplant 1239-1243 2009-10-01 ppublish Journal Article 19747630 In-Process 2009-09-16T06:16:25Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19747630 15 2009 The cell nucleus must be inactivated or destroyed in order to generate feeder layers for cultured cells or to prepare recipient egg cells for nuclear transfer. Existing enucleation techniques are either cumbersome or employ toxic chemicals. Here we report a new method to enucleate cells by treatment with a psoralen and long-wave ultraviolet light. The technique is >90% efficient and causes little cytoplasmic damage to the treated cell. We have used psoralen treatment to enucleate a wide variety of cells, including eggs, sperm, HeLa cells, and fibroblasts. Colonies of human embryonic stem cells (hESCs) and human keratinocyte precursors grown on psoralen-treated feeders are indistinguishable from those grown on gamma-irradiated or mitomycin C-treated cells. Psoralen enucleation provides a rapid, simple, and non-toxic method to generate feeder cells. The technique is also useful for nuclear transfer studies in species with large eggs whose cleavage divisions are not regulated by cell-cycle checkpoints. Developmental Dynamics, 2009. (c) 2009 Wiley-Liss, Inc. McGarry, T. J. Bonaguidi, M. Lyass, L. Kessler, J. A. Bodily, J. M. Doglio, L. 0 2009-09-06T11:55:49Z 2009-08-26 %0 Journal Article %A McGarry, T. J. %A Bonaguidi, M. %A Lyass, L. %A Kessler, J. A. %A Bodily, J. M. %A Doglio, L. %D 2009 %T Enucleation of feeder cells and egg cells with psoralens. %J Dev Dyn %V 238 %N 10 %P 2614-2621 %M 19705441 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19705441 %X The cell nucleus must be inactivated or destroyed in order to generate feeder layers for cultured cells or to prepare recipient egg cells for nuclear transfer. Existing enucleation techniques are either cumbersome or employ toxic chemicals. Here we report a new method to enucleate cells by treatment with a psoralen and long-wave ultraviolet light. The technique is >90% efficient and causes little cytoplasmic damage to the treated cell. We have used psoralen treatment to enucleate a wide variety of cells, including eggs, sperm, HeLa cells, and fibroblasts. Colonies of human embryonic stem cells (hESCs) and human keratinocyte precursors grown on psoralen-treated feeders are indistinguishable from those grown on gamma-irradiated or mitomycin C-treated cells. Psoralen enucleation provides a rapid, simple, and non-toxic method to generate feeder cells. The technique is also useful for nuclear transfer studies in species with large eggs whose cleavage divisions are not regulated by cell-cycle checkpoints. %+ Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. t-mcgarry@northwestern.edu 2687 false false 10 Developmental dynamics : an official publication of the American Association of Anatomists Dev Dyn 2614-2621 2009-10-01 ppublish JOURNAL ARTICLE 19705441 In-Process 2009-10-06T06:14:40Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19705441 238 2009