Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of non-Hodgkin's lymphoma (NHL) has doubled over the past two decades in the US and most other westernized countries. While improved cancer reporting, changes in lymphoma classification, and increases in AIDS-associated lymphomas have contributed to the startling escalation of disease incidence, these factors are estimated to account for only about 50% of the increase in observed incidence. The elucidation of etiologic factors and their mechanistic role in the pathogenesis of this malignancy are critical to advancements in disease prevention and treatment. Current evidence suggests that factors/conditions that precipitate either chronic antigenic stimulation or immunosuppression may provide a preferential milieu for development of NHL. High rates of lymphoma have been observed among individuals with autoimmune disease, organ transplants, and primary or acquired immunodeficiencies. Ultraviolet radiation, previously demonstrated to have an immunosuppressive effect, has also been suggested as a possible risk factor for NHL. Several pathogens have been linked to the risk of lymphoma, including Epstein-Barr virus, human immunodeficiency virus, human T-cell lymphotropic virus-1, Helicobacter pylori, hepatitis C, and simian virus 40. Whether these microbes are responsible for specific genetic mutations that initiate tumor growth, antigenic stimulation leading to B-cell proliferation, and increased potential of random cell replication errors, or immunosuppression, which thereby promotes tumor growth, has not been clearly delineated. Other exogenous factors which have been implicated in lymphomagenesis are chemicals and agricultural exposures, hair dyes, and blood transfusions. We must build on our current knowledge regarding the etiology of NHL in order that prevention, treatment, and ultimately, cure of this malignancy becomes a reality.
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PMID:The epidemiology of non-Hodgkin's lymphoma. 1532 22

Human cells have developed innate immunity, exploiting several means to block virus infection, and viruses have evolved diverse strategies to resist these. We show here that the human immunodeficiency virus 1 (HIV-1) could neither progressively infect engrafted human leukemic T cells nor repress their growth in NOG mice. However, ED-40515(-) cells infected with HIV-1 before inoculation were found to significantly delay the onset of tumor growth and increased the survival period of NOG mice. ED-40515(-) tumor cells showed resistance to HIV-1 which was apparently correlated with the down-regulation of CD4 and CXCR4 molecules in NOG mice. Serum from three different mouse strains, including NOG, retained a suppressive effect on the CD4 molecule of ED-40515(-) cells in vitro. ED-40515(-) cells obtained from mice re-expressed CD4 and CXCR4 molecules upon in vitro culture and were again successfully infected with HIV-1. These findings indicate that HIV-1 may initially successfully delay or regress tumor growth in NOG mice, but eventually fails to do so because of the evolution of HIV-resistant cells due to a rapid down-modulation of CD4 and CXCR4. Our data also demonstrated that some unknown soluble factor(s) present in mouse serum was responsible for conferring resistance to HIV infection to human T cells.
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PMID:Mouse serum factor(s) down-modulate the CD4 and CXCR4 molecules on human T cells conferring resistance to HIV infection in NOG mice. 1565 27

Suicide gene therapy using the herpes simplex virus thymidine kinase (TK) gene in combination with ganciclovir (GCV) has been shown to produce therapeutic, but limited, efficacy because of poor gene transfer efficiency and reduced bystander effect. Here we report that fusion of TK to an eight-amino acid peptide from the basic domain of the human immunodeficiency virus (HIV) Tat protein significantly increases the cytotoxic efficacy of the TK/GCV system in pancreatic cancer cells. We demonstrate that Tat8-TK protein is released from the intracellular compartment of Tat8-TK-expressing cells to the extracellular medium after GCV treatment. Interestingly, we show that this conditioned medium is then able to mediate cytotoxicity of wildtype cultures, suggesting the internalization of the Tat8-TK protein. Moreover, a strong antitumoral effect of Tat8-TK/GCV treatment could be achieved by two different in vivo approaches. Tumors injected with NIH 3T3/Tat8-TK cells attached to microcarriers (MC+Tat8-TK) and treated with GCV led to a 35.6% reduction in the initial tumor volume and to 50% tumor eradication. Furthermore, electrogene transfer of TK or Tat8-TK followed by administration of high doses of GCV led to an overall statistically significant reduction in tumor growth. However, the reduction in initial tumor volume was statistically significant only for the Tat8-TK group (59.5% reduction). Moreover, in this group 50% complete tumor eradication was achieved. When moderate doses of GCV were administered, the overall reduction in tumor growth was statistically significant only in the Tat8-TK group. Therefore, our results suggest that fusion of TK to the Tat8 peptide enhances TK/GCV suicide gene therapy.
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PMID:Tat8-TK/GCV suicide gene therapy induces pancreatic tumor regression in vivo. 1639 Feb 69

The clinical success of suicide gene therapy using herpes simplex virus type 1 thymidine kinase (TK) is largely dependent on the capacity of this enzyme to effectively induce the death of bystander cells. We have shown that fusion of TK to an 11-amino acid peptide from the basic domain of the human immunodeficiency virus type 1 Tat protein (Tat11) imparts cell membrane-translocating ability to the enzyme and significantly increases its cytotoxic activity. Here we report on the efficacy of this strategy in two different mouse models of adoptive tumorigenesis, based on the implantation of human Kaposi sarcoma (KS-IMM) cells in nude mice or of B16F10 melanoma cells in syngeneic C57BL/6J mice. Experiments were performed by the subcutaneous injection of mixtures of unmodified tumor cells containing different fractions of TK or Tat11-TK producing cells followed by animal treatment with ganciclovir (GCV). In both systems we consistently found that mice bearing tumors containing Tat11-TK cells displayed significantly retarded tumor growth and prolonged survival as compared with mice inoculated with cells expressing unmodified TK. Collectively, these results demonstrate that fusion of Tat11 to TK imparts remarkable intercellular trafficking capability to the enzyme. This modification of TK might constitute an important step in the optimization of TK suicide gene strategy for gene therapy of cellular proliferation.
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PMID:Fusion of the human immunodeficiency virus type 1 tat protein transduction domain to thymidine kinase increases bystander effect and induces enhanced tumor killing in vivo. 1639 Feb 70

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis.
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PMID:Prolactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis. 1697 51

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein that induces apoptosis utilizing both insulin-like growth factor receptor (IGF)-dependent and -independent mechanisms. We investigated the effects of IGFBP-3 on tumor growth and angiogenesis utilizing a human CaP xenograft model in severe-combined immunodeficiency mice. A 16-day course of IGFBP-3 injections reduced tumor size and increased apoptosis and also led to a reduction in the number of vessels stained with CD31. In vitro, IGFBP-3 inhibited both vascular endothelial growth factor- and IGF-stimulated human umbilical vein endothelial cells vascular network formation in a matrigel assay. This action is primarily IGF independent as shown by studies utilizing the non-IGFBP-binding IGF-1 analog Long-R3. Additionally, we used a fibroblast growth factor-enriched matrigel-plug assay and chick allantoic membrane assays to show that IGFBP-3 has potent antiangiogenic actions in vivo. Finally, overexpression of IGFBP-3 or the non-IGF-binding GGG-IGFBP-3 mutant in Zebrafish embryos confirmed that both IGFBP-3 and the non-IGF-binding mutant inhibited vessel formation in vivo, indicating that the antiangiogenic effect of IGFBP-3 is an IGF-independent phenomenon. Together, these studies provide the first evidence that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis providing an additional mechanism by which it exerts its tumor suppressive effects and further supporting its development for clinical use in the therapy of patients with prostate cancer.
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PMID:Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis. 1698 36

T lymphoma invasion and metastasis 1 (Tiam1) is a metastasis-related gene of T lymphoma that is also involved in the metastasis of a variety of other cancers. In this study, we tested the hypothesis that Tiam1 is a determinant of proliferation and metastasis in colorectal cancer, and we examined the effect of the inhibition of Tiam1 expression on proliferation and metastasis. We succeeded in establishing the Tiam1 knockdown colorectal cancer cell line using human immunodeficiency virus lentivirus-mediated RNA interference (RNAi) and found that the silencing of Tiam1 resulted in the effective inhibition of in vitro cell growth and of the invasive ability of colorectal cancer cells. Using an orthotopic xenograft model in nude mice, we confirmed that Tiam1 silencing could reduce tumor growth by subcutaneous injection and could suppress lung and liver metastases of colorectal cancer cells. Our results suggest that Tiam1 truly plays a causal role in the metastasis of colorectal cancer and that RNAi-mediated silencing of Tiam1 may provide an opportunity to develop a new treatment strategy for colorectal cancer.
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PMID:Lentivirus-mediated silencing of Tiam1 gene influences multiple functions of a human colorectal cancer cell line. 1713 23

The use of pharmacologically active short peptide sequences is a better option in cancer therapeutics than the full-length protein. Here we report one such 44-mer peptide sequence of SMAR1 (TAT-SMAR1 wild type, P44) that retains the tumor suppressor activity of the full-length protein. The protein transduction domain of human immunodeficiency virus, type 1, Tat protein was used here to deliver the 33-mer peptide of SMAR1 into the cells. P44 peptide could efficiently activate p53 by mediating its phosphorylation at serine 15, resulting in the activation of p21 and in effect regulating cell cycle checkpoint. In vitro phosphorylation assays with point-mutated P44-derived peptides suggested that serine 347 of SMAR1 was indispensable for its activity and represented the substrate motif for the protein kinase C family of proteins. Using xenograft nude mice models, we further demonstrate that P44 was capable of inhibiting tumor growth by preventing cellular proliferation. P44 treatment to tumor-bearing mice prevented the formation of poorly organized tumor vasculature and an increase in hypoxia-inducible factor-1alpha expression, both being signatures of tumor progression. The chimeric TAT-SMAR1-derived peptide, P44, thus has a strong therapeutic potential as an anticancer drug.
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PMID:SMAR1-derived P44 peptide retains its tumor suppressor function through modulation of p53. 1722 33

The human immunodeficiency virus type 1 (HIV-1) viral protein R (vpr) gene is an evolutionarily conserved gene among the primate lentiviruses. Several functions are attributed to Vpr including the ability to cause cell death, cell cycle arrest, apoptosis and DNA damage. The Vpr domain responsible for DNA damage as well as the mechanism(s) through which Vpr induces this damage is unknown. Using site-directed mutagenesis, we identified the helical domain II within Vpr (aa 37-50) as the region responsible for causing DNA damage. Interestingly, Vpr Delta(37-50) failed to cause cell cycle arrest or apoptosis, to induce Ku70 or Ku80 and to suppress tumor growth, but maintained its capability to activate the HIV-1 LTR, to localize to the nucleus and to promote nonhomologous end-joining. In addition, our cytogenetic data indicated that helical domain II induced chromosomal aberrations, which mimicked those induced by cisplatin, an anticancer agent. This novel molecular mimicry function of Vpr might lead to its potential therapeutic use as a tumor suppressor.
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PMID:Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin. 1765 96

A short peptide, corresponding to the nuclear localization signal of the human immunodeficiency virus-1 Tat protein, Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg, was modified by adding a cysteine residue at the COOH terminus. The peptide was mixed with a reporter plasmid, and then with cationic lipids, to form a tripartite complex, DNA/peptide/lipid (DPL). Various cell lines were treated with the DPL complex and compared for transfection efficiency with those of the conventional DNA/lipid (DL) complex. With the simple inclusion of the peptide, the DPL complex showed much enhanced transfection. Meanwhile, the plasmid DNA mixed only with the peptide exhibited some improvement but with much lower transfection than the DPL complex. When the DPL complex was formed with various cationic lipids, the DOSPA/DOPE exhibited superior transfection efficiency than the other cationic lipids tested at the optimal ratio of 1:3:5 (w:w:w) in many cell types. At the optimal ratio of the DPL components, transfection efficiency was routinely shown to be approximately 10-fold higher for reporter gene expression than that of the conventional DL complex. Furthermore, when subcutaneous tumors of a colon cancer cell line (SW480) were treated intratumorally with antisense oligos, k-ras-RiAS, delivered as a DPL complex, tumor growth was markedly suppressed. This study shows that the DPL complex, which is easy to formulate by ordered mixing, can be employed for a much enhanced cellular uptake of a transgene both in vitro and in vivo.
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PMID:Marked transfection enhancement by the DPL (DNA/peptide/lipid) complex. 1778 72


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