Publications by authors named "Fabrizio D"

55 Publications

General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study.

Hum Pathol 2017 12 24;70:84-91. Epub 2017 Oct 24.

Albany Medical College, Albany, NY 12208, USA; Foundation Medicine, Inc. Cambridge, MA 02141, USA.

Hepatoblastoma (HBL) is a hepatic malignancy of infants and young children, which is often cured by combinations of surgery and chemotherapy. Management of refractory and metastatic HBL is challenging. Comprehensive genomic profiling was performed on 31 refractory and metastatic HBL using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. Tumor mutation burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA). Activating CTNNB1 mutation was the most frequent GA seen in 19 (61%) of cases. All 3 (100%) mixed epithelial and mesenchymal HBL harbored CTNNB1 mutation. The small cell undifferentiated subtype showed SMARCB1 loss in both cases. There was no significant further correlation of GA with histologic subtype. In addition to the potential targeting of CTNNB1, other rarely identified possible targetable GA included ERBB4 (6%) and FBXW7, SRC and BRCA2 (each at 3%). The mean TMB was 3.5 mut/Mb, the median was 1.7 mut/Mb. There were 2 HBL with ≥10 mut/Mb. No alterations in TP53 were identified, and alterations in the DNA repair pathways were rare. Refractory and metastatic HBL is characterized by a general paucity of GA and is dominated by frequent CTNNB1 mutation and overall low TMB. Although potentially targetable GA are seen on occasion in HBL and a small number of cases have high TMB with potential to respond to immune checkpoint inhibitors, advanced HBL will remain a treatment challenge.
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http://dx.doi.org/10.1016/j.humpath.2017.10.007DOI Listing
December 2017

Comprehensive Analysis of Hypermutation in Human Cancer.

Cell 2017 Nov 19;171(5):1042-1056.e10. Epub 2017 Oct 19.

Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
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http://dx.doi.org/10.1016/j.cell.2017.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849393PMC
November 2017

Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies.

Ann Oncol 2017 Oct;28(10):2539-2546

Division of Medical Oncology, University of Colorado School of Medicine, Aurora, USA. Electronic address:

Background: Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease.

Patients And Methods: From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously.

Results: The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial-myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen.

Conclusions: Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.
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http://dx.doi.org/10.1093/annonc/mdx399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834110PMC
October 2017

Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

Oncologist 2017 12 14;22(12):1478-1490. Epub 2017 Sep 14.

Foundation Medicine, Inc., Morrisville, North Carolina and Cambridge, Massachusetts, USA

Background: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making.

Materials And Methods: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]).

Results: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. was most frequently altered (48%; 60/125), and missense (17.6%; 22/125), loss of function (8.8%; 11/125), and (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including , , , , and fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were (49%; 77/157), (37.6%; 59/157), (24.2%; 38/157), (22.2%; 35/157), and (21.7%; 34/157). Interestingly, most mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic , , , and fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in , and genes (78% of cases).

Conclusion: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.

Implications For Practice: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.
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http://dx.doi.org/10.1634/theoncologist.2017-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728033PMC
December 2017

Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity.

Antimicrob Agents Chemother 2017 08 25;61(8). Epub 2017 Jul 25.

Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, Massachusetts, USA.

A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.
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http://dx.doi.org/10.1128/AAC.00508-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527662PMC
August 2017

First-in-human trial of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab in advanced cancer patients.

JCI Insight 2017 Apr 20;2(8). Epub 2017 Apr 20.

Drug Development Program, Sarah Cannon Research Institute at HealthONE, Presbyterian/St. Luke's Medical Center, Denver, Colorado, USA.

Background: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC).

Methods: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder.

Results: Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI).

Conclusion: Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.

Trial Registration: clinicaltrials.gov NCT02095054FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).
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http://dx.doi.org/10.1172/jci.insight.90380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396533PMC
April 2017

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Genome Med 2017 04 19;9(1):34. Epub 2017 Apr 19.

Foundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.

Background: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.

Methods: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.

Results: We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.

Conclusions: These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.
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http://dx.doi.org/10.1186/s13073-017-0424-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395719PMC
April 2017

Genomic analysis of 63,220 tumors reveals insights into tumor uniqueness and targeted cancer immunotherapy strategies.

Genome Med 2017 02 24;9(1):16. Epub 2017 Feb 24.

Foundation Medicine, Inc, 150 2nd St, Cambridge, MA, 02141, USA.

Background: The integration of genomics with immunotherapy has potential value for cancer vaccine development. Given the clinical successes of immune checkpoint modulators, interest in cancer vaccines as therapeutic options has been revived. Current data suggest that each tumor contains a unique set of mutations (mutanome), thus requiring the creation of individualized cancer vaccines. However, rigorous analysis of non-individualized cancer immunotherapy approaches across multiple cancer types and in the context of known driver alterations has yet to be reported. We therefore set out to determine the feasibility of a generalizable cancer vaccine strategy based on targeting multiple neoantigens in an HLA-A/B subtype-directed manner.

Methods: A cancer gene-focused, hybrid capture-based genomic analysis was performed on 63,220 unique tumors. Neoantigens were predicted using a combined peptide processing and MHC-I binding prediction tool (IEDB) for all recurrent (>10 tumors) missense alterations and non-frameshift indels for the two most common HLA-A/B subtypes in North American/European populations.

Results: Despite being overwhelmingly unique overall, many mutanomes (~45%) contain at least one mutation from a set of ten mutations chosen to maximize the number of unique tumors. This held true for tumors driven by KRAS G12C (n = 1799), PIK3CA E545K (n = 1713), or EGFR L858R (n = 478) alterations, which define distinct sample subsets. We therefore hypothesized that sets of carefully selected mutations/neoantigens may allow the development of broadly applicable semi-universal cancer vaccines. To test the feasibility of such an approach, antigen processing and MHC-I binding prediction was applied for HLA subtypes A*01:01/B*08:01 and A*02:01/B*44:02. In tumors with a specific HLA type, 0.7 and 2.5% harbored at least one of a set of ten neoantigens predicted to bind to each subtype, respectively. In comparison, KRAS G12C-driven tumors produced similar results (0.8 and 2.6% for each HLA subtype, respectively), indicating that neoantigen targets still remain highly diverse even within the context of major driver mutations.

Conclusions: This "best case scenario" analysis of a large tumor set across multiple cancer types and in the context of driver alterations reveals that semi-universal, HLA-specific cancer vaccine strategies will be relevant to only a small subset of the general population. Similar analysis of whole exome/genome sequencing, although not currently feasible at scale in a clinical setting, will likely uncover further diversity.
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http://dx.doi.org/10.1186/s13073-017-0408-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324279PMC
February 2017

Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.

Cancer Immunol Res 2016 11 26;4(11):959-967. Epub 2016 Sep 26.

Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. ©2016 AACR.
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http://dx.doi.org/10.1158/2326-6066.CIR-16-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134329PMC
November 2016

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor.

MAbs 2011 Jan-Feb;3(1):38-48. Epub 2011 Jan 1.

Oncology Drug Discovery, Bristol-Myers Squibb Company, Princeton, NJ, USA.

Engineered domains of human fibronectin (Adnectins™) were used to generate a bispecific Adnectin targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR), two transmembrane receptors that mediate proliferative and survival cell signaling in cancer. Single-domain Adnectins that specifically bind EGFR or IGF-IR were generated using mRNA display with a library containing as many as 10 ( 13) Adnectin variants. mRNA display was also used to optimize lead Adnectin affinities, resulting in clones that inhibited EGFR phosphorylation at 7 to 38 nM compared to 2.6 μM for the parental clone. Individual, optimized, Adnectins specific for blocking either EGFR or IGF-IR signaling were engineered into a single protein (EI-Tandem Adnectin). The EI-Tandems inhibited phosphorylation of EGFR and IGF-IR, induced receptor degradation, and inhibited down-stream cell signaling and proliferation of human cancer cell lines (A431, H292, BxPC3 and RH41) with IC 50 values ranging from 0.1 to 113 nM. Although Adnectins bound to EGFR at a site distinct from those of anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, like the antibodies, the anti-EGFR Adnectins blocked the binding of EGF to EGFR. PEGylated EI-Tandem inhibited the growth of both EGFR and IGF-IR driven human tumor xenografts, induced degradation of EGFR, and reduced EGFR phosphorylation in tumors. These results demonstrate efficient engineering of bispecific Adnectins with high potency and desired specificity. The bispecificity may improve biological activity compared to monospecific biologics as tumor growth is driven by multiple growth factors. Our results illustrate a technological advancement for constructing multi-specific biologics in cancer therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038010PMC
http://dx.doi.org/10.4161/mabs.3.1.14168DOI Listing
July 2011

FEF75 in asthma management.

Eur Ann Allergy Clin Immunol 2007 Dec;39(10):333-6

Paediatric Allergist, G.P. ASL Milan, Italy.

Rationale: Diagnosis of asthma is based on the presence of symptoms (clinical diagnosis) supported by lung function measurements, such as forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) variability. Recently, it has been reported that the forced expiratory flow at 25-75 of the pulmonary volume might be considered as a possible marker of early bronchial impairment in patients with allergic rhinitis.

Objectives: The aim of this retrospective study was to identify the most reliable spirometric parameter for the follow up of intermittent allergic asthma.

Methods: Data from 108 outpatients with intermittent allergic asthma was studied. The spirometric parameters before and after 1 week of short aerosol therapy were analyzed. Patients were divided into three groups according to basal FEV1 values: those with all spirometric values normal, those with reduced FEV1 and those with normal FEV1 but reduced FEF75.

Results: There was a good correlation between the spirometric parameters analysed. FEF75 showed a greater significant reduction than FEV1 and PEF. Moreover, 26 of 38 patients with normal FEV1 (68 %) showed a reduction in FEF75. No significant differences were observed between FEV1 and PEF. After short aerosol therapy, FEV1 improved in 93% of patients, but many (61%) still had a reduced FEF75 value, thus the correlation between the two parameters decreased (from r= 0.68 to r = 0.40).

Conclusions: On the basis of these observations, FEF75 should be reconsidered a usefull spirometric parameter for allergic asthma follow up.
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December 2007

Growth factors in plastic surgery.

Aesthetic Plast Surg 2005 Jul-Aug;29(4):295-9

1718 1426 Buenos Aires, Buenos Aires, Argentina.

Recent advances in molecular biology and tissue engineering [9] have provided useful tools for improving surgery in general and plastic surgery in particular [11]. Advancing knowledge of cell function and easier ways to obtain active substances or even cells with specific activity have led to more frequent use of many surgical procedures. The active substances that participate in the restoration of damaged tissues are known as growth factors (fundamentally contained in platelets), cytokines, chemokines [16], and similar factors such as interleukins and tissue necrosis factors. Platelets, monocytes, and lymphocytes (T helper cells) as well as neutrophils and astrocytes are involved in the process. As potential cells, stem cells [15,23] also can be used, if obtained from the same patient. The authors used cells with well-known functions, which when added to the surgical procedures, seemed to promote the healing process and the restoration of damaged tissues. The simplest, most effective, and least expensive techniques were selected from trials and feasibility studies for wider use in all types of surgical procedures.
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http://dx.doi.org/10.1007/s00266-004-0054-0DOI Listing
December 2005

DRAGON, a bone morphogenetic protein co-receptor.

J Biol Chem 2005 Apr 25;280(14):14122-9. Epub 2005 Jan 25.

Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)beta superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGFbeta ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGFbeta signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGFbeta ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling.
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http://dx.doi.org/10.1074/jbc.M410034200DOI Listing
April 2005

Reconstitution and analysis of soluble inhibin and activin receptor complexes in a cell-free system.

J Biol Chem 2004 Dec 8;279(51):53126-35. Epub 2004 Oct 8.

Program in Membrane Biology and the Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Activins and inhibins compose a heterogeneous subfamily within the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors with critical biological activities in embryos and adults. They signal through a heteromeric complex of type II, type I, and for inhibin, type III receptors. To characterize the affinity, specificity, and activity of these receptors (alone and in combination) for the inhibin/activin subfamily, we developed a cell-free assay system using soluble receptor-Fc fusion proteins. The soluble activin type II receptor (sActRII)-Fc fusion protein had a 7-fold higher affinity for activin A compared with sActRIIB-Fc, whereas both receptors had a marked preference for activin A over activin B. Although inhibin A and B binding was 20-fold lower compared with activin binding to either type II receptor alone, the mixture of either type II receptor with soluble TGF-beta type III receptor (TbetaRIII; betaglycan)-Fc reconstituted a soluble high affinity inhibin receptor. In contrast, mixing either soluble activin type II receptor with soluble activin type I receptors did not substantially enhance activin binding. Our results support a cooperative model of binding for the inhibin receptor (ActRII.sTbetaRIII complex) but not for activin receptors (type II + type I) and demonstrate that a complex composed of activin type II receptors and TbetaRIII is both necessary and sufficient for high affinity inhibin binding. This study also illustrates the utility of this cell-free system for investigating hypotheses of receptor complex mechanisms resulting from crystal structure analyses.
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http://dx.doi.org/10.1074/jbc.M408090200DOI Listing
December 2004

DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties.

J Neurosci 2004 Feb;24(8):2027-36

Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.

DRG11, a transcription factor expressed in embryonic dorsal root ganglion (DRG) and dorsal horn neurons, has a role in the development of sensory circuits. We have used a genomic binding strategy to screen for the promoter region of genes regulated by DRG11. One gene with a promoter region binding to the DNA binding domain of DRG11 encodes a novel membrane-associated [glycosyl-phosphatidylinositol (GPI)-anchored] protein that we call DRAGON. DRAGON expression is transcriptionally regulated by DRG11, and it is coexpressed with DRG11 in embryonic DRG and spinal cord. DRAGON expression in these areas is reduced in DRG11 null mutants. DRAGON is expressed, however, in the neural tube before DRG11, and unlike DRG11 it is expressed in the brain and therefore must be regulated by other transcriptional regulatory elements. DRAGON shares high sequence homology with two other GPI-anchored membrane proteins: the mouse ortholog of chick repulsive guidance molecule (mRGM), which is expressed in the mouse nervous system in areas complementary to DRAGON, and DRAGON-like muscle (DL-M), the expression of which is restricted to skeletal and cardiac muscle. A comparative genomic analysis indicates that the family of RGM-related genes--mRGM, DRAGON, and DL-M--are highly conserved among mammals, zebrafish, chick, and Caenorhabditis elegans but not Drosophila. DRAGON, RGM, and DL-M mRNA expression in the zebrafish embryo is similar to that in the mouse. Neuronal cell adhesion assays indicate that DRAGON promotes and mRGM reduces adhesion of mouse DRG neurons. We show that DRAGON interacts with itself homophilically. The dynamic expression, ordered spatial localization, and adhesive properties of the RGM-related family of membrane-associated proteins are compatible with specific roles in development.
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http://dx.doi.org/10.1523/JNEUROSCI.4115-03.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730385PMC
February 2004

The influence of noncognitive factors on the Mini-Mental State Examination in older Mexican-Americans: findings from the Hispanic EPESE. Established Population for the Epidemiologic Study of the Elderly.

J Clin Epidemiol 1999 Nov;52(11):1095-102

Center on Aging, University of Texas Medical Branch, Galveston 77555-0460, USA.

Mini-Mental State Examination data from the Hispanic Established Population for the Epidemiologic Study of the Elderly baseline survey, a population-based study of community-dwelling Mexican Americans aged 65 and older, were used to examine the relationship between cognitive impairment, sociodemographics, and health-related characteristics. The rate of cognitive impairment found in this group of older Mexican Americans, using the conventional cut point of 23/24 on the MMSE, was 36.7%. Using a more conservative cut point of 17/18 indicated an overall rate of severe cognitive impairment of 6.7%. Rates of impairment varied significantly with age, education, literacy, marital status, language of interview, and immigrant status and were associated with high and moderate levels of depressive symptoms, and history of stroke. Importantly, although education was strongly related to poor cognitive performance, it was not a significant predictor of severe cognitive impairment. Multivariate analyses further indicated that as a screen for cognitive impairment in older Mexican Americans, the MMSE is strongly influenced by these noncognitive factors. Scores may reflect test bias, secondary to cultural differences or the level of education in this population.
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http://dx.doi.org/10.1016/s0895-4356(99)00100-6DOI Listing
November 1999

Correlates of prescription and over-the-counter medication usage among older Mexican Americans: the Hispanic EPESE study. Established Population for the Epidemiologic Study of the Elderly.

J Am Geriatr Soc 1998 Oct;46(10):1228-34

Department of Family Practice, University of Texas Health Science Center at San Antonio, USA.

Objectives: To determine the prevalence rates of prescription and over-the-counter (OTC) medication usage among community-dwelling older Mexican Americans.

Design: Cross-sectional survey of a regional probability sample of older Mexican Americans.

Setting: The 1992-1997 Hispanic Established Population for the Epidemiologic Study of the Elderly (H-EPESE), a probability sample of noninstitutionalized Mexican Americans, age 65 and over, living in the five Southwestern states of Texas, New Mexico, Colorado, Arizona, and California.

Participants: 2899 persons, age 65 and over, considered Mexican American, using appropriate weighting procedures to produce regional estimates.

Outcome Measures: Use of prescription and OTC medication within the last 2 weeks before the survey confirmed by in-home review of medication containers.

Results: Medication users consumed a mean of 2.9 prescription and 1.3 OTC medications. Over half (58.9%, n = 1,798) of the participants used at least one prescribed medication, and 31.3% (n = 847) used at least one OTC medication within the 2 weeks before their participation in the study. Factors associated with both prescription and OTC medication usage were self-perceived health and number of co-morbid conditions. Factors associated only with prescription medication usage included female gender, alcohol usage, ADL dependency, and presence of additional insurance. Structural assimilation was associated only with OTC medication usage.

Conclusions: These data show lower prevalence rates of prescription medication usage among Mexican American older men and lower rates of OTC medication usage in older Mexican Americans of both genders than previously reported in other ethnic groups. This may reflect differences in time and geographic location of the Hispanic EPESE relative to other EPESE studies, ethnic differences in access to care as reflected by insurance in addition to Medicare, ethnic differences in survival, especially among males, or ethnic differences in medication preferences.
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http://dx.doi.org/10.1111/j.1532-5415.1998.tb04538.xDOI Listing
October 1998

Herpes-type virus in cultured leukocytes from chimpanzees.

J Natl Cancer Inst 1968 Jan;40(1):181-92

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January 1968