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Omar Abdel-Wahab

Publications and source records attributed to Omar Abdel-Wahab.

7 recordsLinked to original sources
PubMed2025

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape.

An emerging hallmark of many human diseases is transcription of typically silenced repetitive DNA containing pathogen-associated molecular patterns (PAMPs). These PAMPs engage the innate immune system via pattern recognition receptors (PRRs)-a phenomenon known as viral mimicry. We propose a statistical physics framework to quantify viral mimicry by measuring "selective forces" that enrich PAMPs compared to a genome-wide reference distribution. We validate our predictions by identifying repeats that bind different PRRs and show potential viral mimics in different repeat families across eukaryotic genomes, suggesting shared mechanisms drive emergence and retention. We propose two non-exclusive evolutionary hypotheses. The first "repeat-centric" hypothesis posits PAMPs are integral to the repeat life cycle and are therefore enriched as they mediate repeat expansion. The second "organism-centric" hypothesis proposes viral mimicry functions as a cell-intrinsic feedback mechanism for sensing and reacting to transcriptional dysregulation, which provides a selective pressure to maintain PAMPs in genomes.

Humans↗
PubMed2006

Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature.

BACKGROUND: Intravenous immune globulin (IVIG) has been approved by the Food and Drug Administration (FDA) for use in 6 conditions: immune thrombocytopenic purpura (ITP), primary immunodeficiency, secondary immunodeficiency, pediatric HIV infection, Kawasaki disease, prevention of graft versus host disease (GVHD) and infection in bone marrow transplant recipients. However, most usage is for off-label indications, and for some of these comprehensive guidelines have been published. STUDY DESIGN AND METHODS: We retrospectively reviewed all approved IVIG transfusions at Massachusetts General Hospital in 2004 to identify the current usage pattern and completed a literature review. RESULTS: IVIG was most commonly used in the treatment of chronic neuropathy, which included chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy. For such patients, the annual cost of IVIG can exceed 50,000 dollars per patient. Other common indications were the treatment of hypogammaglobulinemia, ITP, renal transplant rejection, myasthenia gravis, Guillain-Barre syndrome, necrotizing fasciitis, autoimmune hemolytic anemia, and Kawasaki disease. IVIG was administered in a variety of other indications each representing <3% of the total treated patients. CONCLUSION: Only a few indications account for most of the usage for IVIG. Reports concerning IVIG continue to grow at a tremendous pace but few high-quality randomized controlled trials have been reported. Randomized trials are especially needed for conditions such as CIDP, which consume large quantities of product.

Boston↗
PubMed2005

Cotransfection of DC with TLR4 and MART-1 RNA induces MART-1-specific responses.

BACKGROUND: Cotransfection of dendritic cells (DC) with MART-1 and constitutively active TLR4 (caTLR4) RNA enhances the maturation of DC. MATERIALS AND METHODS: Immature DC were cotransfected with RNA constructs encoding MART-1 and caTLR4, and CTL responses were analyzed. RESULTS: Cotransfection of DC with MART-1 + caTLR4 enhanced the expression of CD80 and CD83 surface markers and increased the secretion of cytokines IL-6, IL-12, and TNFalpha. Neither the native nor the A27L-modified MART-1 RNA could induce significant DC maturation or cytokine secretion. More importantly, DC cotransfected with caTLR4 + MART-1 RNA induced MART-1-specific CTL responses of a higher magnitude than DC transfected with either the native or A27L MART-1 RNA. When the MART-1 RNA-transfected DC were treated with DC-maturing cytokines, the induced CTL were less frequent and less lytic than those induced with MART-1 + caTLR4. A 2- to 100-fold increase in MART-1 tetramer+ cells and 2- to 10-fold increases in IFNgamma secretion and cytotoxicity were seen in CTL induced with MART-1 + caTLR4 compared to CTL induced with either MART-1 or A27L RNA. CTL induced with the mixed RNA displayed high percentages of CD8+ cells coexpressing CD45RA, CD56, and 2B4 antigens. Transfection with caTLR4 alone induced DC maturation, but did not induce lytic CTL, suggesting that CTL responses were induced solely by MART-1 epitopes. CONCLUSIONS: caTLR4 increases the CTL-inducing capacity of DC generating a lytic response specific for the accompanying antigen. These results demonstrate the possibility of enhancing the immunogenicity of the native MART-1 and other RNA derived from weakly immunogenic tumors in DC-based immunotherapy.

Antigens, Neoplasm↗
PubMed2004

In-transit melanoma: the role of alkylating-agent resistance in regional therapy.

BACKGROUND: Regional perfusion treatments for melanoma, using the alkylating agent melphalan, show variable responses in magnitude and duration. Surprisingly, the potential contribution of alkylating-agent resistance mechanisms to diminish tumor responses, especially the crucial cellular detoxifying system formed by glutathione (GSH) and its associated enzyme glutathione-S-transferase (GST), has remained unexplored. Objectives of this study were to characterize GSH levels and GST activity in melanoma of patients undergoing regional perfusion and examine the effect of melphalan concentration in both an in vitro human melanoma cell line and in the extremity melanoma of an in vivo rodent limb infusion model. STUDY DESIGN: Human in-transit melanoma, muscle, subcutaneous tissue, and skin (n = 9) and metastatic regional lymph nodes (n = 7) were evaluated for GSH level and GST activity. Effects of increasing melphalan exposure on GSH and GST were studied in an in vitro human melanoma cell line. A survival human melanoma xenograft model of isolated limb infusion using increasing dosages of melphalan was used, with evaluation of GSH and GST in the recurrent tumor. RESULTS: GSH levels in human in-transit lesions and muscle were significantly higher than that of skin and subcutaneous tissue. Four of 9 patients had tumor-to-muscle GSH ratio > 1. A strong correlation was seen between in vitro melphalan dose and resultant GSH level and GST activity. In vivo recurrent tumor GSH levels correlated with increasing melphalan infusion dose. CONCLUSIONS: A GSH-based resistance pathway may play a role in effecting response and toxicity to regional melphalan perfusion.

Animals↗
PubMed2004

Modulation of resistance to regional chemotherapy in the extremity melanoma model.

BACKGROUND: The presence of resistance to chemotherapy is associated with poor tumor response and patient survival in a variety of tumors. Attempts to modulate resistance in conjunction with systemic chemotherapy have been limited by the toxicity of combined therapy, particularly gastrointestinal or hematopoetic toxicity. This study explored systemic modulation of resistance in conjunction with intra-arterial regional therapy to determine if tumor responses to melphalan could be improved with acceptable toxicity. METHODS: Using a nude rat human xenograft model of extremity melanoma,we analyzed tumors for glutathione (GSH), the main protein in the melphalan resistance pathway. Modulation of GSH was performed with intraperitoneal buthionine sulfoximine (BSO). In parallel, BSO-modulated and nonmodulated animals underwent survival studies after regional intra-arterial perfusion with melphalan or saline. Rats were monitored daily for tumor growth and toxicity. RESULTS: BSO depleted tumor GSH levels by 71.8% with minimal toxicity. Survival studies using increasing melphalan concentrations demonstrated similar tumor growth. The combined use of modulator and chemotherapeutic agent showed a significant tumor growth delay as compared to control and drug-alone group without enhanced toxicity. CONCLUSIONS: Modulation of resistance in conjunction with regional chemotherapy allows for improved tumor responses with minimal toxicity. These results demonstrate that BSO can potentiate the cytotoxic effects of regional melphalan therapy in the setting of extremity melanoma.

Animals↗