David C Seldin

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

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Publications (160)861.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Immunoglobulin light chain (AL) amyloidosis can be treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Risk factors for infections may include hyposplenism, hypogammaglobulinemia, treatment-related neutropenia, melphalan-induced mucositis, and nosocomial exposures. METHODS AND DESIGN: A review of 493 patients with AL amyloidosis undergoing treatment with HDM/SCT from August 1994 to August 2009 was performed. The objectives were to determine the rate and types of infections following HDM/SCT, to identify factors associated with microbiologically documented infections, and to assess the contribution of infections to all-cause treatment-related mortality (TRM; defined as deaths within 100 days of SCT). RESULTS: Microbiologically documented infections after HDM/SCT occurred in 24% (n = 119) of patients. TRM was 10% (n = 48) overall, and 21% (n = 25) in patients who had a documented infection. Thus, the relative risk of TRM in a patient with a documented infection was 3.42 (95% confidence interval [CI] 2.02-5.79). Infections were caused by gram-positive bacteria in 51%, anaerobic bacteria in 16%, gram-negative bacteria in 13%, and fungi in 9% of cases. Serum creatinine >2 mg/dL was associated with increased risk of post-SCT infection (38% vs. 21%, P = 0.0007) with an odds ratio of 2.27 (95% CI 1.40-3.68). No significant association for infection was found for age, gender, cardiac involvement, prior steroid therapy, dose of melphalan, multiorgan involvement, days to neutrophil engraftment, or dose of CD34 + cells infused. CONCLUSION: Serum creatinine >2 mg/dL is a risk factor for infections in patients with AL amyloidosis undergoing HDM/SCT. The relative risk of TRM in a patient with a documented infection was increased >3-fold. A broad spectrum of infections, similar to that in other SCT patients, is seen in this population in the early post-SCT period.
    Transplant Infectious Disease 12/2012; · 1.98 Impact Factor
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    ABSTRACT: AL cardiomyopathy leading to heart failure (HF) represents a significant cause of morbidity and mortality in systemic amyloidosis. However, the paucity of robust in vivo models of AL-induced cardiac dysfunction has limited our ability to probe the mechanisms of AL heart disease. To address this problem, we have developed a model of AL HF in zebrafish embryos by injection of in vitro transcribed mRNA encoding amyloidogenic light chain (aLC) into fertilized oocytes. We demonstrate that expression of aLC causes cardiomyopathy in developing zebrafish without significantly impairing extracardiac development. The cardiac ventricle of embryos expressing aLC exhibit impaired contractility, smaller size, and increased myocardial thickness which result in congestion and edema, features paralleling the clinical manifestations of amyloid cardiomyopathy. Phosphorylated p38, a marker of oxidative stress, was increased in response to aLC expression. No evidence of amyloid fibril deposition was identified. Thus, expression of aLC mRNA in zebrafish results in cardio toxic effects without fibril deposition. This is consistent with prior evidence indicating that aLC oligomers mediate cardiac dysfunction in vitro. This model will allow exploration of amyloid pathophysiology and testing of interventions to reduce and reverse the deleterious effects of amyloidosis on myocardial function.
    Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 12/2012; 19(4):191-6. · 2.51 Impact Factor
  • Blood 11/2012; 120(22):4445-6. · 9.78 Impact Factor
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    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: The establishment of the dorso-ventral axis is a fundamental process that occurs after fertilization. Dorsal axis specification in frogs starts immediately after fertilization, and depends upon activation of Wnt/β-catenin signaling. The protein kinase CK2α can modulate Wnt/β-catenin signaling and is necessary for dorsal axis specification in Xenopus laevis. Our previous experiments show that CK2α transcripts and protein are animally localized in embryos, overlapping the region where Wnt/β-catenin signaling is activated. Here we determined whether the animal localization of CK2α in the embryo is preceded by its localization in the oocyte. We found that CK2α transcripts were detected from stage I, their levels increased during oogenesis, and were animally localized as early as stage III. CK2α transcripts were translated during oogenesis and CK2α protein was localized to the animal hemisphere of stage VI oocytes. We cloned the CK2α 3'UTR and showed that the 2.8 kb CK2α transcript containing the 3'UTR was enriched during oogenesis. By injecting ectopic mRNAs, we demonstrated that both the coding and 3'UTR regions were necessary for proper CK2α transcript localization. This is the first report showing the involvement of coding and 3'UTR regions in animal transcript localization. Our findings demonstrate the pre-localization of CK2α transcript and thus, CK2α protein, in the oocyte. This may help restrict CK2α expression in preparation for dorsal axis specification.
    Human genetics & embryology : current research. 05/2012; Suppl 4(1):11328.
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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

Publication Stats

4k Citations
861.84 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