Publications from 2012
Induction of Group IVC Phospholipase A2 in Allergic Asthma: Transcriptional Regulation by TNF-α in Bronchoepithelial Cells, Justin S. Bickford, Kimberly J. Newsom, John-David Herlihy, Christian Mueller, Benjamin Keeler, Xiaolei Qiu, Jewell N. Walters, Nan Su, Shannon M. Wallet, Terence R. Flotte, and Harry S. Nick
Gene transfer in the lung using recombinant adeno-associated virus, Alisha Gruntman, Christian Mueller, Terence R. Flotte, and Guangping Gao
rAAV9 airway delivery results in effective knockdown of mutant alpha 1-antitrypsin in the liver while upregulating wildtype alpha 1-antitrypsin in the lung, Alisha Gruntman, Christian Mueller, Qiushi Tang, Lina Song, James M. Wilson, Terence R. Flotte, and Maria P. Limberis
Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy, Allison M. Keeler, Thomas J. Conlon, Glenn Walter, Huadong Zeng, Scott A. Shaffer, Fu Dungtao, Kirsten E. Erger, Travis L. Cossette, Qiushi Tang, Christian Mueller, and Terence R. Flotte
Cell and gene therapy for genetic diseases: inherited disorders affecting the lung and those mimicking sudden infant death syndrome, Allison M. Keeler and Terence R. Flotte
Codon Optimization for Alpha 1-Antitrypsin Disease, Timothy Menz, Qiushi Tang, Lina Song, Christian Mueller, and Terence R. Flotte
Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles, Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith S. Blomenkamp, Jeffrey H. Teckman, Lina Song, Phillip D. Zamore, and Terence R. Flotte
Production and discovery of novel recombinant adeno-associated viral vectors, Christian Mueller, Li Zhong, Dmitry Ratner, Miguel Sena-Esteves, and Guangping Gao
A patient with asthma seeks medical advice, Brian P. O'Sullivan, Robert G. Zwerdling, and Ted M. Kremer
A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis, Michael S. Stalvey, Ran D. Anbar, Michael W. Konstan, Joan R. Jacobs, Bert Bakker, Barbara Lippe, and David E. Geller
Long-term, efficient inhibition of microRNA function in mice using rAAV vectors, Jun Xie, Stefan L. Ameres, Randall H. Friedline, Jui-Hung Hung, Yu Zhang, Qing Xie, Li Zhong, Qin Su, Ran He, Mengxin Li, Huapeng Li, Xin Mu, Hongwei Zhang, Jennifer A. Broderick, Jason K. Kim, Zhiping Weng, Terence R. Flotte, Phillip D. Zamore, and Guangping Gao
Publications from 2011
Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method, Jeffrey D. Chulay, Guo-Jie Ye, Darby L. Thomas, David R. Knop, Janet M. Benson, Julie A. Hutt, Gensheng Wang, Margaret Humphries, and Terence R. Flotte
The role of gene and cell therapy in the era of health care reform, Walter H. Ettinger and Terence R. Flotte
Sendai virus vectors. Pushing the envelope in the lung, Terence R. Flotte
Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results, Terence R. Flotte, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Roberto Calcedo, Farshid Rouhani, Martha Campbell-Thompson, Anthony T. Yachnis, Robert A. Sandhaus, Noel G. McElvaney, Christian Mueller, Louis M. Messina, James M. Wilson, Mark L. Brantly, David R. Knop, Guo-jie Ye, and Jeffrey D. Chulay
No immune responses by the expression of the yeast Ndi1 protein in rats, Mathieu Marella, Byoung Boo Seo, Terence R. Flotte, Akemi Matsuno-Yagi, and Takao Yagi
N-glycosylation augmentation of the cystic fibrosis epithelium improves Pseudomonas aeruginosa clearance, Ashley T. Martino, Christian Mueller, Sofia Braag, Pedro E. Cruz, Martha Campbell-Thompson, Shouguang Jin, and Terence R. Flotte
Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses, Christian Mueller, Sofia A. Braag, Allison M. Keeler, Craig Hodges, Mitchell Drumm, and Terence R. Flotte
Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice, Bharath D. Nath, Ivan Levin, Timea Csak, Jan Petrasek, Christian Mueller, Karen Kodys, Donna Catalano, Pranoti Mandrekar, and Gyongyi Szabo
Using hyperpolarized 3He MRI to evaluate treatment efficacy in cystic fibrosis patients, Yanping Sun, Brian P. O'Sullivan, John P. Roche, Ronn P. Walvick, Austin Reno, Dawn Baker, Joey Mansour, and Mitchell Albert
MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression, Jun Xie, Qing Xie, Hongwei Zhang, Stefan L. Ameres, Jui-Hung Hung, Qin Su, Ran He, Xin Mu, Seemin Seher Ahmed, Soyeon Park, Hiroki Kato, Chengjian Li, Christian Mueller, Craig C. Mello, Zhiping Weng, Terence R. Flotte, Phillip D. Zamore, and Guangping Gao
Publications from 2010
IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia, S. M. Buff, H. Yu, J. N. McCall, S. M. Caldwell, T. W. Ferkol, Terence R. Flotte, and I. L. Virella-Lowell
Dual reporter comparative indexing of rAAV pseudotyped vectors in chimpanzee airway, Terence R. Flotte, Anne C. Fischer, Jason Goetzmann, Christian Mueller, Liudmila Cebotaru, Ziying Yan, Lilli Wang, James M. Wilson, William B. Guggino, and John F. Engelhardt
Cystic fibrosis newborn screening: using experience to optimize the screening algorithm, Jaime E. Hale, Richard B. Parad, Henry L. Dorkin, Robert Gerstle, Allen Lapey, Brian P. O'Sullivan, L. Terry Spencer, William Yee, and Anne Marie Comeau
Characterization of a recombinant adeno-associated virus type 2 Reference Standard Material, Martin Lock, Susan McGorray, Alberto Auricchio, Eduard Ayuso, E. Jeffrey Beecham, Veronique Blouin-Tavel, Fatima Bosch, Mahuya Bose, Barry J. Bryne, Tina Caton, John A. Chiorini, Abdelwahed Chtarto, K. Reed Clark, Thomas Conlon, Christophe Darmon, Monica Doria, Anne Douar, Terence R. Flotte, Joyce D. Francis, Achille Francois, Mauro Giacca, Michael T. Korn, Irina Korytov, Xavier Leon, Barbara Leuchs, Gabriele Lux, Catherine Melas, Hiroaki Mizukami, Philippe Moullier, Marcus Muller, Keiya Ozawa, Tina Philipsberg, Karine Poulard, Christina Raupp, Christel Riviere, Sigrid D. Roosendaal, Richard Jude Samulski, Steven M. Soltys, Richard Surosky, Liliane Tenenbaum, Darby L. Thomas, Bart van Montfort, Gabor Veres, J. Fraser Wright, Yili Xu, Olga Zelenaia, Lorena Zentilin, and Richard O. Snyder
Autoimmunity in a genetic disease-a cautionary tale, Melissa J. Moore and Terence R. Flotte
Modulation of Exaggerated-IgE Allergic Responses by Gene Transfer-mediated Antagonism of IL-13 and IL-17e., Christian Mueller, Allison M. Keeler, Sofia Braag, Timothy Menz, Qiushi Tang, and Terence R. Flotte
In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors, Christian Mueller, M. S. Strayer, Jeffrey Sirninger, Sofia A. Braag, Francisco Branco, Jean-Pierre Louboutin, Terence R. Flotte, and David S. Strayer
Cystic Fibrosis: Diagnosis, Sweat Testing, and Newborn Screening, Brian P. O'Sullivan
Inhaled aztreonam, Brian P. O'Sullivan, Uma Yasothan, and Peter Kirkpatrick
Cystic Fibrosis, Michael S. Stalvey, Christian Mueller, and Terence R. Flotte
Publications from 2009
Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy, Mark L. Brantly, Jeffrey D. Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L. Terry Spencer, Farshid Rouhani, Thomas J. Conlon, Roberto Calcedo, Michael R. Betts, Carolyn Spencer, Barry J. Bryne, James M. Wilson, and Terence R. Flotte
Oropharyngeal flora in healthy infants: observations and implications for cystic fibrosis care, David Carlson, Elizabeth McKeen, Michael Mitchell, Brenda B. Torres, Richard B. Parad, Anne Marie Comeau, and Brian P. O'Sullivan
Cystic fibrosis pulmonary guidelines: airway clearance therapies, Patrick A. Flume, Karen A. Robinson, Brian P. O'Sullivan, Jonathan D. Finder, Robert L. Vender, Donna-Beth Willey-Courand, Terry B. White, and Bruce C. Marshall
Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery, Rejean Liqun Wang, Thomas J. McLaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott A. Loiler, Christian Mueller, and Terence R. Flotte
The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr-/- -dependent allergy mouse model, Christian Mueller, Sofia A. Braag, A. T. Martino, Qiushi Tang, M. Campbell-Thompson, and Terence R. Flotte
The clinical approach to lung disease in patients with cystic fibrosis, Brian P. O'Sullivan and Patrick Flume
Cystic fibrosis, Brian P. O'Sullivan and Steven D. Freedman
Pulmonary Manifestations of Systemic Vasculitis, Brian P. O'Sullivan and Ted M. Kremer
Murine model for cystic fibrosis bone disease demonstrates osteopenia and sex-related differences in bone formation, Troy D. Pashuck, Sarah E. Franz, Molly K. Altman, Clive H. Wasserfall, Mark A. Atkinson, Thomas J. Wronski, Terence R. Flotte, and Michael S. Stalvey
Endocrine parameters of cystic fibrosis: back to basics, Michael S. Stalvey and Terence R. Flotte
Defective acid sphingomyelinase pathway with Pseudomonas aeruginosa infection in cystic fibrosis, Hong Yu, Youssef H. Zeidan, Bill X. Wu, Russell W. Jenkins, Terence R. Flotte, Yusuf A. Hannun, and Isabel Virella-Lowell
Publications from 2008
Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD, Stuart G. Beattie, Eric Goetzman, Thomas Conlon, Sean Germain, Glenn Walter, Martha Campbell-Thompson, Dietrich Matern, Jerry Vockley, and Terence R. Flotte
Recombinant adeno-associated virus-mediated gene delivery of long chain acyl coenzyme A dehydrogenase (LCAD) into LCAD-deficient mice, Stuart G. Beattie, Eric Goetzman, Qiushi Tang, Thomas Conlon, Martha Campbell-Thompson, Dietrich Matern, Jerry Vockley, and Terence R. Flotte
Cystic fibrosis transmembrane regulator missing the first four transmembrane segments increases wild type and DeltaF508 processing, Liudmila Cebotaru, Neerag Vij, Igor Ciobanu, Jerry Wright, Terence R. Flotte, and William B. Guggino
Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics, Artur V. Cideciyan, Tomas S. Aleman, Sanford L. Boye, Sharon B. Schwartz, Shalesh Kaushal, Alejandro J. Roman, Ji-Jing Pang, Alexander Sumaroka, Elizabeth A. M. Windsor, James M. Wilson, Terence R. Flotte, Gerald A. Fishman, Elise Heon, Edwin M. Stone, Barry J. Bryne, Samuel G. Jacobson, and William W. Hauswirth
In utero efficacy of cystic fibrosis gene therapy: difficult studies, positive or negative, Terence R. Flotte
Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees, Terence R. Flotte, Jason Goetzmann, James Caridi, Joseph Paolillo, Thomas J. Conlon, Mark Potter, Christian Mueller, and Barry J. Bryne
Recombinant adeno-associated virus-mediated global anterograde delivery of glial cell line-derived neurotrophic factor to the spinal cord: comparison of rubrospinal and corticospinal tracts in the rat, Kevin D. Foust, Terence R. Flotte, Paul J. Reier, and Ronald J. Mandel
Neonatal intraperitoneal or intravenous injections of recombinant adeno-associated virus type 8 transduce dorsal root ganglia and lower motor neurons, Kevin D. Foust, Amy Poirier, Christina A. Pacak, Ronald J. Mandel, and Terence R. Flotte
Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial, William W. Hauswirth, Tomas S. Aleman, Shalesh Kaushal, Artur V. Cideciyan, Sharon B. Schwartz, Lili Wang, Thomas J. Conlon, Sanford L. Boye, Terence R. Flotte, Barry J. Bryne, and Samuel G. Jacobson
Intensive care management of the patient with cystic fibrosis, Ted M. Kremer, Robert G. Zwerdling, Peter H. Michelson, and Brian P. O'Sullivan
Clinical gene therapy using recombinant adeno-associated virus vectors, Christian Mueller and Terence R. Flotte
Gene therapy for cystic fibrosis, Christian Mueller and Terence R. Flotte
Partial correction of the CFTR-dependent ABPA mouse model with recombinant adeno-associated virus gene transfer of truncated CFTR gene, Christian Mueller, Daniel M. Torrez, Sofia Braag, Ashley Martino, Tracy Clarke, Martha Campbell-Thompson, and Terence R. Flotte
By the sweat of our brows: how salty should a person be, Brian P. O'Sullivan and Robert G. Zwerdling
Towards a rAAV-based gene therapy for ADA-SCID: from ADA deficiency to current and future treatment strategies, Jared N. Silver and Terence R. Flotte
CFTR mutations impart elevated immune reactivity in a murine model of cystic fibrosis related diabetes, Michael S. Stalvey, Todd M. Brusko, Christian Mueller, Clive H. Wasserfall, Desmond A. Schatz, Mark A. Atkinson, and Terence R. Flotte
Publications from 2007
Progress and prospects: gene therapy clinical trials (part 1), B. L. Alexander, R. R. Ali, E.W.F. Alton, J. W. Bainbridge, S. Braun, S. H. Cheng, Terence R. Flotte, H. B. Gaspar, M. Grez, U. Griesenbach, M. G. Kaplitt, M. G. Ott, R. Seger, M. Simons, A. Z. Thrasher, and S. Yla-Herttuala
Potential utility of plasma fatty acid analysis in the diagnosis of cystic fibrosis, Ibrahim Batal, Mhd-Bassel Ericsoussi, Joanne E. Cluette-Brown, Brian P. O'Sullivan, Steven D. Freedman, Juanito E. Savaille, and Michael Laposata
Adeno-associated viral vector-mediated interleukin-10 prolongs allograft survival in a rat kidney transplantation model, B. Chen, M. H. Kapturczak, R. Joseph, J. F. George, M. Campbell-Thompson, Clive H. Wasserfall, Mark A. Atkinson, C. C. Tisher, Terence R. Flotte, A. Argarwal, and S. Chen
Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report, Anne Marie Comeau, Frank J. Accurso, Terry B. White, Preston W. Campbell, Gary Hoffman, Richard B. Parad, Benjamin S. Wilfond, Margaret Rosenfeld, Marci K. Sontag, John H. Massie, Philip M. Farrell, and Brian P. O'Sullivan
In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA, Pedro E. Cruz, Christian Mueller, Travis L. Cossette, Alexandra Golant, Qiushi Tang, Stuart G. Beattie, Mark Brantly, Martha Campbell-Thompson, Keith S. Blomenkamp, Jeffrey H. Teckman, and Terence R. Flotte
The promise of gene therapy for the treatment of alpha-1 antitrypsin deficiency, Pedro E. Cruz, Christian Mueller, and Terence R. Flotte
In vivo expression of human ATP:cob(I)alamin adenosyltransferase (ATR) using recombinant adeno-associated virus (rAAV) serotypes 2 and 8, Kirsten E. Erger, Thomas J. Conlon, Nicole A. Leal, Robert Zori, Thomas A. Bobik, and Terence R. Flotte
Gene therapy: the first two decades and the current state-of-the-art, Terence R. Flotte
Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health, Patrick A. Flume, Brian P. O'Sullivan, Karen A. Robinson, Christopher H. Goss, Peter J. Mogayzel Jr., Donna Beth Willey-Courand, Janet Bujan, Jonathan Finder, Mary Lester, Lynne Quittell, Randall Rosenblatt, Robert L. Vender, Leslie Hazle, Kathy Sabadosa, and Bruce Marshall
Cystic fibrosis heterozygotes do not have increased platelet activation, Inge Tarnow, Alan D. Michelson, Andrew L. Frelinger III, Matthew Dean Linden, YouFu Li, Marsha L. Fox, Marc R. Barnard, and Brian P. O'Sullivan
Publications from 2006
Enhanced IgE allergic response to Aspergillus fumigatus in CFTR-/- mice, Christian Mueller, Sofia A. Braag, John-David Herlihy, Clive H. Wasserfall, Sarah E. Chesrown, Harry S. Nick, Mark A. Atkinson, and Terence R. Flotte
The inflammatory role of platelets in cystic fibrosis, Brian P. O'Sullivan and Alan D. Michelson
Early pulmonary manifestation of cystic fibrosis in children with the DeltaF508/R117H-7T genotype, Brian P. O'Sullivan, Robert G. Zwerdling, Henry L. Dorkin, Anne Marie Comeau, and Richard B. Parad
Cystic fibrosis transmembrane conductance regulator deficiency exacerbates islet cell dysfunction after beta-cell injury, Michael S. Stalvey, Christian Mueller, Desmond A. Schatz, Clive H. Wasserfall, Martha L. Campbell-Thompson, Douglas W. Theriaque, Terence R. Flotte, and Mark A. Atkinson
Publications from 2005
Communications systems and their models: Massachusetts parent compliance with recommended specialty care after positive cystic fibrosis newborn screening result, Anne Marie Comeau, Richard B. Parad, Robert Gerstle, Brian P. O'Sullivan, Henry L. Dorkin, Mark Dovey, Kenan Haver, Thomas Martin, and Roger B. Eaton
Frequency of laboratory test utilization in the intensive care unit and its implications for large-scale data collection efforts, Joseph J. Frassica
Platelet activation in cystic fibrosis, Brian P. O'Sullivan, Matthew D. Linden, Andrew L. Frelinger III, Marc R. Barnard, Michele Spencer-Manzon, James E. Morris, Raneem O. Salem, Michael Laposata, and Alan D. Michelson
Sweat testing infants detected by cystic fibrosis newborn screening, Richard B. Parad, Anne Marie Comeau, Henry L. Dorkin, Mark Dovey, Robert Gerstle, Thomas Martin, and Brian P. O'Sullivan
Publications from 2004
Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections, Anne Marie Comeau, Richard B. Parad, Henry L. Dorkin, Mark Dovey, Robert Gerstle, Kenan Haver, Allen Lapey, Brian P. O'Sullivan, David A. Waltz, Robert G. Zwerdling, and Roger B. Eaton
Frequency of laboratory test utilization in the intensive care unit and its implications for large scale data collection efforts, Joseph J. Frassica
Association of cystic fibrosis with abnormalities in fatty acid metabolism, Steven D. Freedman, Paola G. Blanco, Munir M. Zaman, Julie C. Shea, Mario Ollero, Isabel K. Hopper, Deborah A. Weed, Andres Gelrud, Meredith M. Regan, Michael Laposata, Juan G. Alvarez, and Brian P. O'Sullivan
Use of nasopharyngoscopy in the evaluation of children with noisy breathing, Brian P. O'Sullivan, Lenna Finger, and Robert G. Zwerdling
Survey of breast-feeding practices and outcomes in the cystic fibrosis population, Eliza M. Parker, Brian P. O'Sullivan, Julie C. Shea, Meredith M. Regan, and Steven D. Freedman
Functional characterization of a recombinant adeno-associated virus 5-pseudotyped cystic fibrosis transmembrane conductance regulator vector, Jeffrey Sirninger, Christian Mueller, Sofia A. Braag, Qiushi Tang, Hungwen Yue, Carol Detrisac, Thomas Ferkol, William B. Guggino, and Terence R. Flotte
Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line, Isabel Virella-Lowell, John-David Herlihy, Barry Liu, Cecilia Lopez, Pedro Cruz, Christian Mueller, Henry V. Baker, and Terence R. Flotte
Interleukin 8 secretion from monocytes of subjects heterozygous for the deltaF508 cystic fibrosis transmembrane conductance regulator gene mutation is altered, Munir M. Zaman, Andres Gelrud, Omer Junaidi, Meredith M. Regan, Michel Warny, Julie C. Shea, Ciaran Kelly, Brian P. O'Sullivan, and Steven D. Freedman
Publications from 2002
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-2002. An eight-year-old girl with fever, hemoptysis, and pulmonary consolidations, Brian P. O'Sullivan, Lori A. Erickson, and John L. Niles
Publications from 2001
Situs inversus totalis and corrected transposition of the great arteries [I,D,D] in association with a previously unreported vascular ring, B. Feingold, Brian P. O'Sullivan, Pedro J. del Nido, and Phyllis Pollack
Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications, Patricia M. Joseph, Brian P. O'Sullivan, Allen Lapey, Henry L. Dorkin, Joseph Oren, Rosemary Balfour, Michael A. Perricone, Martin Rosenberg, Samuel C. Wadsworth, Alan E. Smith, Judith A. St. George, and David P. Meeker
Asthma, Brian P. O'Sullivan
Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium, Michael A. Perricone, James E. Morris, Karen Pavelka, Malinda S. Plog, Brian P. O'Sullivan, Patricia M. Joseph, Henry L. Dorkin, Allen Lapey, Rosemary Balfour, David P. Meeker, Alan E. Smith, Samuel C. Wadsworth, and Judith A. St. George
A novel approach in treating recurrent bilateral hepaticojejunostomy biliary strictures post-liver transplantation: Successful use of Simpson's atherectomy device, Amar Rajadhyaksha, Ducksoo Kim, Ravi Chari, Joseph J. Frassica, William A. Primack, and Eliezer Katz
Publications from 1998
Tracheal bronchus: a cause of prolonged atelectasis in intubated children, Brian P. O'Sullivan, Joseph J. Frassica, and Shawn M. Rayder