David C Seldin

Beverly Hospital, Boston MA, Beverly, Massachusetts, United States

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Publications (155)832.39 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of AL amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5mg/m2/day for 4 days, lenalidomide 10mg/day for 21 days and dexamethasone 20-40mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled; of which 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12/14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6/14) and 7% (n=1/14) respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367.
    Haematologica 11/2012; · 5.94 Impact Factor
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    ABSTRACT: Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp1 pathway similarly required Ras signaling activation, we tested whether Blimp1 plays a role in TGF-β1-mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp1 and then Snail expression; whereas, BMP5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1-induced EMT via repression of BMP5 in breast cancer.
    Cancer Research 10/2012; · 9.28 Impact Factor
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    ABSTRACT: Familial amyloidoses are a group of inherited disorders that cause deposition of misfolded amyloidogenic proteins in various tissues, resulting in organ dysfunction. Point mutations in the coding region of seven different genes are known to cause clinically significant systemic amyloid disease. We describe a new mutation in exon 2 of the lysozyme gene associated with amyloidosis (ALys) in a 61-year-old woman with a 7-year history of non-bloody, watery diarrhea, and weight loss. Biopsies of the duodenum and stomach were positive for amyloid deposits in the lamina propria and blood vessels. Direct DNA sequencing of the lysozyme gene revealed a single base nucleotide transversion from T to A at the first position of codon 54, resulting in replacement of Tyr by Asn in the mature lysozyme protein (pTyr54Asn). Immunoblot analysis of amyloid fibrils extracted from a fat tissue sample confirmed lysozyme as the amyloid protein. Clinically, the phenotype associated with this lysozyme mutation featured chronic abdominal pain, diarrhea, weight loss, malabsorption, and sicca syndrome. There was no associated nephropathy as has been reported for other ALys mutations. We describe a new mutant lysozyme that presents with abdominal discomfort, diarrhea, weight loss, and sicca syndrome.
    Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 09/2012; · 2.51 Impact Factor
  • Journal of clinical pathology 08/2012; 65(11):1052-5. · 2.43 Impact Factor
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    ABSTRACT: Amyloid deposits are often found in the bone marrow in patients with Immunoglobulin light chain (AL) amyloidosis. We sought to determine whether this affects stem cell collection or engraftment after high-dose melphalan and autologous stem cell transplantation (HDM-SCT). We reviewed data on 361 patients with AL amyloidosis who had Congo red staining of pretreatment bone marrow biopsy specimens and underwent HDM-SCT between July 1994 and December 2011. We analyzed data on stem cell yield, days of stem cell collection, and days to neutrophil and platelet engraftment posttransplantation. Bone marrow amyloid deposits were found in 65% of patients (n = 233). There were no significant differences in median number of stem cells collected and days to neutrophil or platelet engraftment between patients with bone marrow amyloid deposits and those without these deposits. Thus, our data indicate that although amyloid involvement of the bone marrow is common, it does not negatively affect stem cell mobilization or neutrophil and platelet engraftment after HDM-SCT.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2012; · 3.15 Impact Factor
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    ABSTRACT: Background. Amyloidosis of the gastrointestinal tract, with biopsy-proven disease, is rare. We review a series of patients who presented with biopsy proven gastrointestinal amyloidosis and report clinical characteristics, treatments, and survival. Design and Methods This is a retrospective review of data prospectively collected from January 1998 to December 2011 in a tertiary referral center; 2,334 patients with all types of amyloidosis were evaluated during this time. Results. 76 patients (3.2%) had biopsy-proven amyloid involvement of the gastrointestinal tract. The median age was 61 years (range 34 - 79). Systemic amyloidosis with dominant gastrointestinal involvement was present in 60 (79%) patients. Amyloidosis localized to the gastrointestinal tract without evidence of an associated plasma cell dyscrasia or other organ involvement comprised 16 (21%) patients. Of the 60 systemic cases, 50 (83%) had immunoglobulin light-chain, 5 (8%) familial lysozyme, 3 (5%) wild type transthyretin, and 2 (3%) mutant transthyretin amyloidosis. The most frequent symptoms for all patients were weight loss in 33 (45%) and gastrointestinal bleeding in 27 (36%). Incidental identification of amyloidosis on routine endoscopic surveillance played a role in the diagnosis of 7 patients with systemic immunoglobulin light-chain, and 4 patients with immunoglobulin light-chain localized to the gastrointestinal tract. Amyloid protein subtyping was performed in 12 of the cases of localized disease, and all had lambda light chain disease. Of the 50 patients with systemic immunoglobulin light-chain amyloidosis, 45 patients were treated with anti-plasma cell therapy. The median survival has not been reached for this group. For the 16 patients with localized gastrointestinal amyloidosis, supportive care was the mainstay of treatment; none received anti plasma cell therapy. All 16 are alive at a median follow-up of 36 months (range 1-143). Conclusions. Patients with biopsy-proven gastrointestinal amyloidosis often present with weight loss and bleeding. In localized cases, all that underwent typing were due to λ light chain amyloidosis and none progressed to systemic disease during the period of follow-up. Most patients with systemic disease had immunoglobulin light-chain, and their tolerance of therapy and median survival were excellent. Although a rare manifestation of amyloidosis, staining for amyloid should be considered in patients undergoing gastrointestinal biopsy who have unexplained chronic gastrointestinal symptoms.
    Haematologica 06/2012; · 5.94 Impact Factor
  • Xiaozhong Shi, David C Seldin, Daniel J Garry
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    ABSTRACT: Previous studies have established that Foxk1 (forkhead box k1) plays an important role in skeletal muscle regeneration. Foxk1 regulates the cell-cycle progression of myogenic progenitors by repressing the cell-cycle inhibitor gene p21. However, the underlying mechanism is not well understood. In the present study, we report the identification of Sds3 (suppressor of defective silencing 3) as an adaptor protein that recruits the Sin3 [SWI (switch)-independent 3]-HDAC (histone deacetylase) repression complex and binds Foxk1. Using GST (glutathione transferase) pull-down assays, we defined the interaction between the Foxk1 FHA (forkhead-associated domain) domain and phospho-Thr(49) in Sds3. We demonstrated that the transcriptional repression of Foxk1 is dependent on the Sin3-Sds3 repression complex, and knockdown of Sds3 results in cell-cycle arrest. We further identified the protein kinase CK2 as the protein kinase for Sds3 Thr(49) and demonstrated that the protein kinase activity of CK2 is required for proper cell-cycle progression. Analysis of CK2 mutant mice reveals perturbation of skeletal muscle regeneration due to the dysregulation of cell-cycle kinetics. Overall, these studies define a CK2-Sds3-Foxk1 cascade that modulates gene expression and regulates skeletal muscle regeneration.
    Biochemical Journal 06/2012; 446(3):349-57. · 4.65 Impact Factor
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    ABSTRACT: A 41-year-old woman with immunoglobulin light chain (AL) systemic amyloidosis with cardiac and gastrointestinal involvement developed multiple arterial and venous thromboembolic complications. Treatment with unfractionated heparin was complicated by life-threatening gastrointestinal bleeding. Work up for hereditary thrombophilia was unrevealing. Treatment with cyclophosphamide, bortezomib and dexamethasone combination regimen led to hematologic response without further thromboembolic complications. While thromboembolic complications have been reported in AL amyloidosis and cardiac involvement, this unique case highlights the complexity of the disease, the various pathogenic mechanisms at play and the difficult management decisions necessary in caring for these complex patients. A literature review of thrombembolic complications in patients with amyloidosis is presented.
    Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2012; 19(3):156-60. · 2.51 Impact Factor
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    ABSTRACT: This manuscript summarizes the recommendations that emerged from the first Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis (AL), a meeting sponsored by the Amyloidosis Foundation in order to develop a consensus of experts on a modern framework for clinical trial design and drug development in AL. Recent diagnostic and technical advances in AL, and updated consensus guidelines for assessing hematologic and organ responses, enable us to define study populations, appropriate endpoints, and other criteria for all phases of clinical research. This manuscript provides a framework for the design and conduct of systematic collaborative clinical research in AL in order to encourage more rapid testing of therapies and to expedite new drug development and approval.Leukemia accepted article preview online, 5 April 2012; doi:10.1038/leu.2012.100.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; · 10.16 Impact Factor
  • David C Seldin, Vaishali Sanchorawala
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    ABSTRACT: Potentially effective and life-saving treatment for patients with systemic amyloidosis relies on the astute clinician recognizing the signs and symptoms, histochemical identification of fibrils, and accurate diagnosis of amyloid type. In this issue of Blood, Brambilla et al report a new methodology for accomplishing the key third step in this process.
    Blood 02/2012; 119(8):1795-6. · 9.78 Impact Factor
  • Vaishali Sanchorawala, David C Seldin
    Oncology (Williston Park, N.Y.) 02/2012; 26(2):164, 166, 169. · 3.19 Impact Factor
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    ABSTRACT: Systemic AL amyloidosis results from the aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) usually produced by a plasma cell clone in the bone marrow. AL is the most rapidly fatal of the systemic amyloidoses, as amyloid fibrils can rapidly accumulate in tissues including the heart, kidneys, autonomic or peripheral nervous systems, gastrointestinal tract, and liver. Chemotherapy is used to eradicate the cellular source of the amyloidogenic precursor. Currently, there are no therapies that target the process of LC aggregation, fibril formation, or organ damage. We developed transgenic mice expressing an amyloidogenic λ6 LC using the cytomegalovirus (CMV) promoter to circumvent the disruption of B cell development by premature expression of recombined LC. The CMV-λ6 transgenic mice develop neurologic dysfunction and Congophilic amyloid deposits in the stomach. Amyloid deposition was inhibited in vivo by the antibiotic doxycycline. In vitro studies demonstrated that doxycycline directly disrupted the formation of recombinant LC fibrils. Furthermore, treatment of ex vivo LC amyloid fibrils with doxycycline reduced the number of intact fibrils and led to the formation of large disordered aggregates. The CMV-λ6 transgenic model replicates the process of AL amyloidosis and is useful for testing the antifibril potential of orally available agents.
    Blood 12/2011; 118(25):6610-7. · 9.78 Impact Factor
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    ABSTRACT: Amyloid light chain (AL) amyloidosis is a lethal disorder characterized by the pathologic deposition of clonal plasma cell-derived, fibrillogenic immunoglobulin light chains in vital organs. Current chemotherapeutic regimens are problematic in patients with compromised organ function and are not effective for all patients. Here, a platform of computer-based prediction and preclinical mouse modeling was used to begin development of a complementary, immunotherapeutic approach for AL amyloidosis. Three peptide/MHC I-binding algorithms identified immunogenic peptides from three AL plasma cell-associated proteins: (1) amyloidogenic λ6 light chains, (2) CYP1B1, a universal tumor antigen hyper-expressed in AL plasma cells and (3) B lymphocyte-induced maturation protein 1 (Blimp-1), a transcription factor required for plasma cell differentiation. The algorithms correctly predicted HLA-A(*)0201-binding native and heteroclitic peptides. In HLA-A2 transgenic mice, these peptides, given individually or in combination, induced potent CTL which kill peptide-loaded human lymphoma cells and/or lymphoma cells producing target protein. Blimp-1 peptide-immunized mice exhibited a reduced percentage of splenic, lymph node and bone marrow plasma cells and a decrease in the absolute number of splenic plasma cells demonstrating (1) presentation of target peptide by endogenous plasma cells and (2) appropriate CTL homing to lymphoid organs followed by killing of target plasma cells. These studies suggest that AL amyloidosis, with its relatively low tumor cell burden, may be an attractive target for peptide-based multivalent vaccines.
    Immunology and Cell Biology 09/2011; 90(5):528-39. · 3.93 Impact Factor
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    ABSTRACT: Bone marrow plasma cells (BMPCs) were purified using anti-CD138 immunomagnetic beads, from aspirates obtained with permission of the Boston University Medical Campus Institutional Review Board, from patients with immunoglobulin light chain (AL) amyloidosis and from controls. Expression levels of MicroRNAs (miRNAs) were compared by microarray; 10 were found to be increased more than 1.5-fold. These results were confirmed using stem-loop RT-qPCR for the most highly upregulated miRNAs, miR-148a, miR-26a, and miR-16. miR-16, a micro-RNA linked to other hematopoietic diseases, was significantly increased in the AL group at diagnosis, and also in treated patients with persistent monoclonal plasma cells in the bone marrow, but not in patients who achieved a hematologic remission after therapy. miR-16 can be derived from the miR-16-1/mirR-15, a cluster on chromosome 13 or the miR-16-2/miR-15b cluster on chromosome 3. The expression of miR-15b was much higher than miR-15a in both AL and control BMPC, suggesting that miR-16 in plasma cells is mainly derived from miR-16-2/miR-15b. The anti-apoptosis gene BCL-2, a putative target mRNA that can be downregulated by miR-16, was expressed in BMPCs from AL patients, despite elevated levels of miR-16. Our data suggests that miRNAs are dysregulated in clonal plasma cells in AL amyloidosis and may be potentially useful as biomarkers of disease.
    Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 09/2011; 18(3):128-35. · 2.51 Impact Factor
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    ABSTRACT: Not applicable for letter to the editor.
    Haematologica 08/2011; 96(12):1890-2. · 5.94 Impact Factor
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    ABSTRACT: Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.
    Blood 08/2011; 118(16):4346-52. · 9.78 Impact Factor
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    ABSTRACT: The CK2 α and α' catalytic gene products have overlapping biochemical activity, but in vivo, their functions are very different. Deletion of both alleles of CK2α leads to mid-gestational embryonic lethality, while deletion of both alleles of CK2α' does not interfere with viability or development of embryos; however, adult CK2α'-/-males are infertile. To further elucidate developmental roles of CK2, and analyze functional overlap between the two catalytic genes, mice with combined knockouts were bred. Mice bearing any two CK2 catalytic alleles were phenotypically normal. However, inheritance of a single CK2α allele, without either CK2α' allele, resulted in partial embryonic lethality. Such mice that survived through embryogenesis were smaller at birth than littermate controls, and weighed less throughout life. However, their cardiac function and lifespan were normal. Fibroblasts derived from CK2α+/-CK2α'-/- embryos grew poorly in culture. These experiments demonstrate that combined loss of one CK2α allele and both CK2α' alleles leads to unique abnormalities of growth and development.
    Molecular and Cellular Biochemistry 07/2011; 356(1-2):227-31. · 2.33 Impact Factor
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    ABSTRACT: CK2 is a highly conserved serine-threonine kinase involved in biological processes such as embryonic development, circadian rhythms, inflammation, and cancer. Biochemical experiments have implicated CK2 in the control of several cellular processes and in the regulation of signal transduction pathways. Our laboratory is interested in characterizing the cellular, signaling, and molecular mechanisms regulated by CK2 during early embryonic development. For this purpose, animal models, including mice deficient in CK2 genes, are indispensable tools. Using CK2α gene-deficient mice, we have recently shown that CK2α is a critical regulator of mid-gestational morphogenetic processes, as CK2α deficiency results in defects in heart, brain, pharyngeal arch, tail bud, limb bud, and somite formation. Morphogenetic processes depend upon the precise coordination of essential cellular processes in which CK2 has been implicated, such as proliferation and survival. Here, we summarize the overall phenotype found in CK2α (-/- ) mice and describe our initial analysis aimed to identify the cellular processes affected in CK2α mutants.
    Molecular and Cellular Biochemistry 07/2011; 356(1-2):209-16. · 2.33 Impact Factor
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    ABSTRACT: Amyloidotic cardiomyopathy (ACMP) occurs in the setting of rare genetic diseases, blood dyscrasias, chronic infection and inflammation, and advanced age. Cardiologists are on the front lines of diagnosis of ACMP when evaluating patients with unexplained dyspnea, congestive heart failure, or arrhythmias. Noninvasive detection of diastolic cardiac dysfunction and unexplained left ventricular hypertrophy should be followed by biopsy to demonstrate the presence of amyloid deposits and appropriate genetic, biochemical, and immunologic testing to accurately define the type of amyloid. Growing numbers of treatment options exist for these diseases, and timely diagnosis and institution of therapy is essential for preservation of cardiac function.
    Heart Failure Clinics 07/2011; 7(3):385-93.
  • Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:122-4. · 2.51 Impact Factor

Publication Stats

4k Citations
832.39 Total Impact Points

Institutions

  • 1998–2014
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1993–2013
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Genetics
      Boston, Massachusetts, United States
  • 2002–2012
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2001–2012
    • Boston University
      • • Section of Hematology and Medical Oncology
      • • Renal Section
      • • Department of Medicine
      Boston, MA, United States
  • 2010
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1998–2009
    • University of Massachusetts Medical School
      • • Department of Medicine
      • • Program in Molecular Medicine
      Worcester, Massachusetts, United States
  • 2003
    • CSU Mentor
      Long Beach, California, United States
  • 2000
    • Dana-Farber Cancer Institute
      • Department of Cancer Biology
      Boston, MA, United States