Biomedical subjects

S F Wen

Publications and source records attributed to S F Wen.

At least 19 recordsLinked to original sources

PubMed2003

Characterization of adenovirus p21 gene transfer, biodistribution, and immune response after local ocular delivery in New Zealand white rabbits.

Previous studies suggest that local gene therapy with rAd-p21(WAF1/Cip-1) [. Arch. Ophthalmol. 120, (2002) 941-949] may provide an effective adjunctive anti-proliferative treatment to prevent glaucoma surgery failure. To further investigate rAd-p21 in this indication, we have characterized several parameters of local gene delivery to conjunctiva including, vector delivery and transgene expression in target tissue, inflammatory response, biodistribution to non-target tissues, and immune response. Quantitative PCR and RT-PCR assays were employed to evaluate rAd-p21 dissemination and gene transfer following a single subconjunctival injection. In target tissue, significant levels of rAd-p21 DNA were found in 6/6 animals 1 and 4 days after injection. rAd-p21 DNA and RNA could be detected in the un-injected contralateral eye but at levels that were 10000-100000 lower than in the injected eye. Expression of human p21 transgene in conjunctival fibroblasts was confirmed by immunohistochemistry. Biodistribution of rAd-p21 following subconjunctival injection was substantially limited to ocular tissue. In 1/6 rabbits, rAd-p21 DNA was found in whole blood, liver, and spleen at levels that were barely detectable. All non-target organs were negative on day 4. In contrast, in a rabbit injected intravenously as a positive control, all blood samples and tissues samples were positive. rAd-p21 delivery to conjunctiva followed by filtration surgery caused an early acute inflammatory response, which by day 14 was indistinguishable from placebo-treated eyes. Neutralizing anti-adenovirus antibodies were detected following administration of rAd-p21 to conjunctiva, however, vector delivery and transgene expression were unaffected in a subsequent administration to the contralateral eye in the same animal. These results show that local delivery to conjunctiva may be a suitable delivery mode for ocular gene therapy.

Adenoviridae↗

PubMed2001

Specific depletion of human anti-adenovirus antibodies facilitates transduction in an in vivo model for systemic gene therapy.

Recombinant adenoviral (rAd) vectors are capable of mediating high-efficiency gene transfer in vivo. Under conditions requiring systemic administration, however, the use of rAd vectors can be problematic due to the presence of circulating anti-adenovirus antibodies developed either through natural infection or during the course of treatment. We developed a passive immunization model in SCID/Beige mice to assess the effect of human and mouse anti-adenovirus antibodies on systemic administration of a rAd vector expressing beta-galactosidase (rAd-betagal). In this model, the in vitro neutralizing activity of human or mouse antibodies used for passive immunization correlated well with inhibition of transduction of the liver following i.v. administration of rAd-betagal. Depletion of antibodies to individual adenovirus structural proteins (hexon, penton, fiber) by affinity chromatography demonstrated that antibodies to each of the three virion components contributed to neutralization of infectivity in vitro and to inhibition of transduction in vivo. Depletion of antibodies against all three structural proteins from human or mouse immune serum prior to passive immunization restored in vivo transduction activity to levels comparable to those obtained with nonimmune serum. Our data suggest that depletion of both murine and human anti-adenoviral antibodies can restore transduction in vivo during systemic rAd gene therapy in hosts previously exposed to adenovirus.

Adenoviridae↗

PubMed2001

Interferon alpha2b gene delivery using adenoviral vector causes inhibition of tumor growth in xenograft models from a variety of cancers.

A recombinant adenovirus expressing human interferon alpha2b driven by the cytomegalovirus promoter, IACB, was shown to produce and secrete biologically active protein in vitro and in vivo. Intravenous administration of IACB in Buffalo rats resulted in circulating levels of biologically active human interferon at 70,000 international units/mL for up to 15 days. Distribution of interferon protein after IACB administration was different from that seen with the subcutaneous delivery of interferon protein. Higher levels of interferon protein were observed in liver and spleen after IACB delivery compared to protein delivery. The antitumor efficacy of IACB, as measured by suppression of tumor growth, was tested in athymic nude mice bearing established human tumor xenografts from different types of human cancer. Subcutaneous tumors most responsive to the intratumoral administration of IACB ranked as U87MG (glioblastoma) and K562 (chronic myelogenous leukemia), followed by Hep 3B (hepatocellular carcinoma) and LN229 cells (glioblastoma). Intravenous administration of IACB in animals bearing U87MG or Hep 3B xenografts was also effective in suppressing tumor growth, although to a lesser extent than the intratumoral administration. IACB was also tested in a metastatic model in beige/SCID mice generated with H69 (small cell lung carcinoma) cells and was found to prolong survival in tumor-bearing animals. This suggested that interferon gene delivery can be effective in suppressing tumor growth in a wide variety of cells.

Adenoviridae↗

PubMed2001

Ex vivo purging by adenoviral p53 gene therapy does not affect NOD-SCID repopulating activity of human CD34+ cells.

Co-incubation of a replication-deficient, recombinant adenovirus carrying the wild-type p53 gene (rAd-p53) and hematopoietic stem cell (HSC) products from patients with breast cancer can significantly reduce tumor cell contamination. Whereas this approach provides a powerful tumor cell purging strategy, potential detrimental effects on the HSC population have not been investigated. The ability of human HSC to reconstitute hematopoiesis in severe combined immunodeficient (SCID) mice and to undergo secondary transplantation provides the only nonclinical measure of self-renewing, stem cell function. The objective of this study was to investigate whether co-incubation with rAd-p53 compromised the SCID repopulating activity (SRA) of HSC. Granulocyte colony-stimulating factor-mobilized human CD34+ cells were co-cultured with rAd-p53 at our targeted clinical dose, and the ability of these cells to establish multilineage hematopoiesis in sublethally irradiated, nonobese diabetic (NOD)-SCID mice was investigated. The persistence of human cells in the mice was investigated by flow cytometry, granulocyte-macrophage colony-forming unit assay, and polymerase chain reaction of human Alu sequences. Further, limiting dilution analysis provided a quantitative comparison between the SRA of CD34+ cells co-incubated with rAd-p53 and control CD34+ cells (no rAd-p53 co-incubation). We conclude that co-incubation with rAd-p53 has little effect on the SRA of HSC.

Adenoviridae↗

PubMed2001

Intratumoral spread and increased efficacy of a p53-VP22 fusion protein expressed by a recombinant adenovirus.

In vitro experiments have demonstrated intercellular trafficking of the VP22 tegument protein of herpes simplex virus type 1 from infected cells to neighboring cells, which internalize VP22 and transport it to the nucleus. VP22 also can mediate intercellular transport of fusion proteins, providing a strategy for increasing the distribution of therapeutic proteins in gene therapy. Intercellular trafficking of the p53 tumor suppressor protein was demonstrated in vitro using a plasmid expressing full-length p53 fused in-frame to full-length VP22. The p53-VP22 chimeric protein induced apoptosis both in transfected tumor cells and in neighboring cells, resulting in a widespread cytotoxic effect. To evaluate the anti-tumor activity of p53-VP22 in vivo, we constructed recombinant adenoviruses expressing either wild-type p53 (FTCB) or a p53-VP22 fusion protein (FVCB) and compared their effects in p53-resistant tumor cells. In vitro, treatment of tumor cells with FVCB resulted in enhanced p53-specific apoptosis compared to treatment with equivalent doses of FTCB. However, in normal cells there was no difference in the dose-related cytotoxicity of FVCB compared to that of FTCB. In vivo, treatment of established tumors with FVCB was more effective than equivalent doses of FTCB. The dose-response curve to FVCB was flatter than that to FTCB; maximal antitumor responses could be achieved using FVCB at doses 1 log lower than those obtained with FTCB. Increased antitumor efficacy was correlated with increased distribution of p53 protein in FVCB-treated tumors. This study is the first demonstration that VP22 can enhance the in vivo distribution of therapeutic proteins and improve efficacy in gene therapy.

Adenoviruses, Human↗

PubMed2000

Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models.

SCH58500 (ACN53) is a replication-deficient, type 5 adenovirus (Ad) expressing human wild-type p53 tumor suppressor. It is currently undergoing clinical trials as a cancer therapeutic. Many SCH58500 clinical trials incorporate an arm comparing traditional chemotherapy against chemotherapy combined with SCH58500. Paclitaxel was chosen for combination therapy in the preclinical study reported here due to its extensive use as a first-line therapy in ovarian cancer, its synergy with SCH58500 in preclinical cancer models, and its activation of p53-independent apoptosis, which might result in a "lowered threshold" for tumor cell death. SCID mice bearing human tumor xenografts were dosed with intratumoral vehicle, control Ad vector, or SCH58500, with or without paclitaxel. Real-time quantitative reverse transcriptase polymerase chain reaction assays were developed and validated to quantitate expression of p53, the p53 downstream effector gene p21, and the apoptosis-related genes, bax, bcl-2, and survivin. Protein expression was confirmed using immunohistochemical assays for p53 and p21. Only tumors injected with SCH58500 had detectable levels of exogenous p53 DNA and mRNA. After SCH58500 treatment, 3-11-fold elevations of p21 expression were observed in tumor xenografts containing nonfunctional p53 (MDA-MB-468, MDA-MB-231, MIAPaCa2, DU-145, and SK-OV-3), but no change in p21 mRNA in wild-type p53 PA-1 tumors. Immunohistochemical assays confirmed induction of p21 protein in MDAMB-468 and SK-OV-3 cells, but not in PA-1 cells. Ad vector alone or paclitaxel alone had no effect on p21 mRNA levels in most tumors. However, paclitaxel suppressed p21 expression induced by SCH58500 4-fold in DU-145 and SK-OV-3 tumors. Paclitaxel also affected expression of the housekeeping gene gapdh. There was no consistent pattern to the changes in bax, bcl-2, or survivin after SCH58500 treatment with or without paclitaxel between tumor types, although there were consistent responses within individual tumor lines. The mRNA ratios for bax/bcl-2 and bax/survivin were also not informative across tumor types. Of the genes examined, only p21 gave a predictable response 24 hours after p53 gene therapy and therefore, p21 expression may be useful for confirming SCH58500 activity in human tumor biopsies.

Adenoviridae↗

PubMed1999

Ethanol improves adenovirus-mediated gene transfer and expression to the bladder epithelium of rodents.

OBJECTIVES: Replication deficient adenoviral vectors (rAds) are used as gene delivery systems that can efficiently transduce a variety of tissues and may be appropriate vectors to develop gene therapeutics for many urologic applications. However, the bladder epithelium has been shown to be highly resistant to transgene expression after intracystic administration. A potential explanation for this low gene transfer efficiency may be the protective structure of the urothelium. Since this protective barrier can be disrupted by organic solvents, we assessed whether ethanol co-administration can enhance adenovirus-mediated transgene expression. METHODS: Normal and bladder tumor-bearing rats received a single intracystic administration of rAd encoding beta-galactosidase (rAd-beta gal) or p53 (rAd-p53). rAd was administered in a saline solution or in solutions with increasing concentrations of ethanol. Transgene expression was evaluated in the bladder tissues. RESULTS: A dramatic increase in urothelial beta-galactosidase transgene expression was achieved by rAd-beta gal administered in a 22% ethanol solution. Transgene expression was enhanced in normal urothelium and in superficial bladder tumors. p53 transgene expression was similarly enhanced. CONCLUSIONS: Co-administration of 22% ethanol enhanced local rAd-mediated transgene expression in the normal and neoplastic bladder epithelium in rodents. Improvement of rAd-mediated transgene expression is progress toward local gene delivery to the urothelium and may enable local gene therapy for superficial bladder cancer or other bladder diseases.

Adenoviridae↗

PubMed1998

p53 gene therapy in a rat model of hepatocellular carcinoma: intra-arterial delivery of a recombinant adenovirus.

p53 tumor suppressor gene therapy has been proposed for cancers characterized by inactivation of p53 function, and successful therapy will require efficient strategies for gene delivery. To maximize transgene expression in tumors, a clinical strategy has been proposed to treat neoplasms in the liver via hepatic artery administration of a recombinant adenovirus encoding wild-type p53 (rAd-p53). We have developed a syngeneic rat model using a p53mut hepatocellular carcinoma cell line (McA-RH7777) that results in multifocal liver tumor nodules to provide experimental support for this strategy. Treatment of McA-RH7777 cells with rAd-p53 in vitro resulted in efficient transgene expression, growth suppression, and apoptosis. Intrahepatic artery dosing with rAd-p53 or an adenovirus encoding beta-galactosidase (rAd-betagal) increased transgene expression in tumor tissue and decreased systemic exposure when compared with i.v. dosing. Daily hepatic artery dosing of rAd-p53 suppressed tumor growth when compared with untreated rats or animals treated with rAd-betagal. These data demonstrate the potential for arterial gene delivery to tumors using recombinant adenoviruses, and support continued investigation of rAd-p53 gene therapy for liver malignancies.

Adenoviridae↗

PubMed1998

Hyperkalemic renal tubular acidosis induced by trimethoprim/sulfamethoxazole in an AIDS patient.

A patient with the acquired immunodeficiency syndrome (AIDS) and sickle cell anemia presented to the University of Wisconsin Hospital on two separate occasions with pneumocystis carinii pneumonia (PCP). On both occasions he was treated with high-dose intravenous trimethoprim/sulfamethoxazole (TMP/SMX). Several days into each treatment course he developed hyperkalemia and systemic acidosis consistent with hyperkalemic renal tubular acidosis (RTA). The abnormalities resolved in the first instance with the addition of amphotericin B while continuing TMP/SMX, and in the second upon discontinuation of the TMP/SMX. While an increasing number of cases with TMP/SMX-induced hyperkalemia have been reported, hyperkalemic RTA is an uncommon complication of TMP/SMX therapy, occurring in patients with predisposing factors for acidosis such as aldosterone defects, medullary dysfunction and renal insufficiency.

AIDS-Related Opportunistic Infections↗

PubMed1997

Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes.

Transfer of "anti-HIV-1 genes" into hematopoietic stem cells of human immunodeficiency virus-1 (HIV-1)-infected individuals may be a potent therapeutic approach to render mature cells arising from transduced stem cells resistant to the destructive events associated with HIV-1 infection. To determine the feasibility of gene therapy for acquired immunodeficiency syndrome in individuals already infected with HIV-1, granulocyte colony-stimulating factor mobilized peripheral blood CD34+ cells were isolated from HIV-1-infected individuals and transduced with retroviral vectors containing three different anti-HIV-1-genes: the Rev binding domain of the Rev Responsive Element (RRE decoy) (L-RRE-neo), a double hammerhead ribozyme vector targeted to cleave the tat and rev transcripts (L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a control, a vector mediating only neomycin resistance (LN) was used. After 3 days of transduction on allogeneic stroma in the presence of stem cell factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected, and then challenged with HIV-1(JR-FL) and a primary HIV-1 isolate. Compared with the control cultures, the L-RRE-neo-, L-TR/TAT-neo-, and L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1 replication after challenge with HIV-1(JR-FL) and the primary HIV-1 isolate. Growth of the hematopoietic cells in long-term bone marrow culture was not perturbed by the presence of any of the anti-HIV-1 genes. This study shows that anti-HIV-1 genes can be introduced into CD34+ cells from individuals already infected with HIV-1, and strongly inhibit HIV-1 replication in primary monocytes derived from the CD34+ progenitors.

Binding Sites↗

PubMed1997

Nephrotoxicities of nonsteroidal anti-inflammatory drugs.

While the relative incidence of serious nephrotoxicities in the population consuming nonsteroidal anti-inflammatory drugs (NSAIDs) is very low, the frequency of adverse events in patients at risk has considerably increased due to the rising popularity of the use of the drugs in recent years. Under normal conditions, NSAIDs have relatively little effect on the kidney because of low renal production of prostaglandins. However, in the presence of renal hypoperfusion in which local synthesis of vasodilator prostaglandins is increased to protect the glomerular hemodynamics and to maintain appropriate renal tubular transport of fluid and electrolytes, inhibition of prostaglandin synthesis by NSAIDs can lead to vasoconstrictive acute renal failure as well as fluid and electrolyte disorders such as sodium retention and resistance to diuretics, hyponatremia and hyperkalemia. Conditions that increase the risk for NSAID-induced nephrotoxicities include volume depletion from diuretics and other causes, edematous states such as congestive heart failure and cirrhosis of the liver, old age and underlying renal disease, especially in the presence of renal functional impairment. In addition, renal parenchymal diseases may develop in susceptible patients taking NSAIDs. These include acute tubulointerstitial nephritis, frequently associated with nephrotic syndrome, and chronic progressive renal disease, with or without renal papillary necrosis. Rare cases of vasculitis and glomerulonephritis have also been reported. Finally, NSAIDs may aggravate hypertension by interacting with antihypertensive drugs, especially with diuretics and beta-blockers. Withdrawal of NSAIDs in patients at risk can frequently reverse or improve the nephrotoxicities. It is recommended that physicians be aware of the clinical settings that increase the risk for NSAID-induced nephrotoxicities and take preventive or therapeutic measures accordingly.

Animals↗

PubMed1996

Wild-type and mutant retinoblastoma protein in paraffin sections.

Inactivation of the retinoblastoma susceptibility (RB) gene plays a role in the pathogenesis of a variety of human malignancies. Recently, it has become feasible to study RB expression in archival tissues, and it is expected that immunohistochemical studies on routinely processed tumors will further elucidate the biologic and clinical significance of RB mutations. Our study was designed to address two issues that are critical for the interpretation of such studies, i.e., whether mutant RB protein (pRB) can reliably be distinguished from normal pRB and whether there are significant differences in the performance characteristics of various anti-RB antibodies. We studied cell blocks of 26 mutant RB cell lines (11 lines without any RB expression, nine lines expressing truncated mRNA/pRB, six lines carrying missense mutations) with five different anti-RB monoclonal antibodies, using a recently described procedure that includes an antigen retrieval step. The specific staining pattern for pRB was nuclear. Cytoplasmic staining was found to be nonspecific and could be strong. Some truncated and all full-length mutant pRBs localized to the nucleus, creating positive nuclear staining that might be indistinguishable from the staining pattern of cells carrying wild-type RB. The five antibodies tested showed significant differences in sensitivity, specificity, and background reactivity. Our data suggest that a significant subset of mutant pRB has preserved nuclear translocation capacity, that not all anti-RB antibodies are equally suitable for immunohistochemical analysis of RB expression, and that any such analysis is bound to include a certain, albeit probably small, number of positive stains, despite the absence of functional pRB.

Humans↗

PubMed1995

Estimation of PCNA mRNA stability in cell cycle by a serum-deprivation method.

A simple scheme was developed to study the mRNA stability of the proliferating cell nuclear antigen (PCNA) gene during cellular transition from the G1/S boundary to a quiescent state. By this scheme, CHO.K1 cells were grown to about 80% confluence and then serum-starved for 40 h for synchronization in a quiescent state. The quiescent cells were serum-stimulated for a period of time (between 8 h and 12 h) and then grown in serum-free medium until being harvested for further analyses. The cellular PCNA mRNA level was analyzed by Northern blotting. As compared with that in cells which were continuously incubated in serum-containing medium, the decline of the mRNA level, after reaching the peak, in these serum-deprived cells was virtually devoid of mRNA synthesis. Thus, this mRNA decay was taken for the measurement of mRNA stability. The advantage of the scheme is that, unlike the treatment of transcription inhibitors, it does not prevent the cells from completing the rest of the cell cycle before returning to the resting state, and so the mRNA stability observed is cell cycle dependent. In contrast with the previous report that the stability of PCNA mRNA in quiescent cells is less by severalfold than that in S phase cells, our study shows that the mRNA stability of PCNA remained constant during the cellular transition from G1/S boundary to quiescent state.

Animals↗

PubMed1995

Characterization of a new human glioblastoma cell line that expresses mutant p53 and lacks activation of the PDGF pathway.

We have established and characterized a new glioblastoma cell line, termed GT9, from a biopsy sample of a female adult patient with glioblastoma multiforme. The line has now undergone over 60 passages and has been successfully cultured after cryopreservation. Immunofluorescence analyses with a panel of monoclonal antibodies were positive for glial fibrillary acidic protein and vimentin, and negative for neurofilament, galactocerebroside, and fibronectin, a pattern typical of glial cells. Based on a tetraploid, the composite karyotype of GT9 cells included the loss of chromosome 10, gain of chromosome 7, and the presence of double minute chromosomes, three of the most common karyotypic abnormalities in glioblastoma. Sequence analysis of p53 cDNA revealed a homozygous double mutation at codon 249 (commonly mutated in aflatoxin-associated hepatocellular carcinoma) and codon 250. Moreover, there was a complete absence of wild-type p53. However, unlike the majority of human glioblastomas previously described, the expression of platelet-derived growth factor-B (PDGF-B), a potent mitogenic autocrine factor, was low in GT9 cells. The expression and phosphorylation of c-Jun and Jun-B, downstream mediators of the PDGF pathway, were also low. Thus, deregulation of the PDGF pathway does not appear to be involved in the pathogenesis of the GT9 glioblastoma. Conversely, Jun-D, a negative regulator of cell growth, was also low. In addition, Phosphorylated Egr-1, a recently reported suppressor of PDGF-B/v-sis-transformed cells, was also low, suggesting that the lack of activation of the PDGF pathway was not due to these suppressive mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Syndrome of flank pain and acute renal failure after binge drinking and nonsteroidal anti-inflammatory drug ingestion.

The binge drinking of alcohol combined with the ingestion of a nonsteroidal anti-inflammatory drug (NSAID) is a recently described cause of reversible acute renal failure. The pathogenetic mechanisms leading to acute tubular necrosis in this setting include the initial compromise in renal perfusion due to alcohol-induced extracellular volume contraction and the superimposed renal hemodynamic alterations induced by the NSAID that interfere with the renal autoregulation. Although alcohol may also cause rhabdomyolysis leading to acute tubular necrosis, this is usually not apparent in these cases. Previously, only three such cases have been reported but the incidence is likely to be higher in view of the prevalence of alcohol and NSAID use. Herein is presented another patient in whom the features of flank pain and acute renal failure in association with binge drinking and NSAID ingestion constitute a characteristic syndrome.

Abdominal Pain↗

PubMed1994

Retinoblastoma protein monoclonal antibodies with novel characteristics.

We have developed a family of monoclonal antibodies directed against the retinoblastoma gene product (p110RB). One of these monoclonal antibodies, 3C8, binds p110RB near the C-terminal end of the protein (aa886-aa905). It was characterized by immunoblotting, ELISA, fluorescence-activated flow cytometry and immunohistostaining. It was shown to be useful for the detection of p110RB in formalin-fixed and paraffin-embedded tissue sections. Because 3C8 binds outside of regions shown to be involved in p110RB interactions with other cellular proteins, it may be an especially useful reagent for the reliable detection of p110RB in tumor cells, and for the isolation by affinity chromatography of p110RB complexes with other cellular proteins.

Animals↗

PubMed1994

Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer.

We have constructed recombinant human adenoviruses that express wild-type human p53 under the control of either the Ad 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. Each construct replaces the Ad 5 E1a and E1b coding sequences necessary for viral replication with the p53 cDNA and MLP or CMV promoter. These p53/Ad recombinants are able to express p53 protein in a dose-dependent manner in infected human cancer cells. Tumor suppressor activity of the expressed p53 protein was assayed by several methods. [3H]Thymidine incorporation assays showed that the recombinant adenoviruses were capable of inhibiting DNA synthesis in a p53-specific, dose-dependent fashion. Ex vivo treatment of Saos-2 tumor cells, followed by injection of the treated cells into nude mice, led to complete tumor suppression using the MLP/p53 recombinant. Following a single injection of CMV/p53 recombinant adenovirus into the peritumoral space surrounding an in vivo established tumor derived from a human small cell lung carcinoma cell line (NIH-H69), we were able to detect p53 mRNA in the tumors at 2 and 7 days post-injection. Continued treatment of established H69 tumors with MLP/p53 recombinant led to reduced tumor growth and increased survival time compared to control treated animals. These results indicate that recombinant adenoviruses expressing wild-type p53 may be useful vectors for gene therapy of human cancer.

Adenoviruses, Human↗

PubMed1994

Antineutrophil cytoplasmic autoantibody--associated glomerulonephritis: potentially reversible disease.

Renal vasculitis frequently presents itself as rapidly progressive glomerulonephritis, but its diagnosis may be hampered by the difficulty in demonstrating classic vasculitic lesions in renal biopsy specimens. Early diagnosis of renal vasculitis has been greatly enhanced by the advent of antineutrophil cytoplasmic autoantibodies (ANCA). On indirect immunofluorescence microscopy, cytoplasmic ANCA (C-ANCA) show cytoplasmic staining of alcohol-fixed neutrophils and are directed against proteinase 3 in the primary granules of neutrophils. Perinuclear ANCA (P-ANCA) show perinuclear staining due to redistribution of granular antigens, and are specific for myeloperoxidase in the primary granules of the vasculitic patients. C-ANCA are most frequently associated with Wegener's granulomatosis and P-ANCA, with "idiopathic" necrotizing and crescentic glomerulonephritis (renal-limited disease). Patients with microscopic polyarteritis may be associated with either P-ANCA or C-ANCA and there is a considerable overlap between Wegener's granulomatosis and microscopic polyarteritis in both clinical features and serologic patterns. ANCA are not only the markers for vasculitis but may also play a role in the pathogenesis by activating the neutrophils to attack target blood vessels. There is also a crude correlation between ANCA titer and the activity of vasculitis. ANCA-associated vasculitis responds well to steroid and/or cyclophosphamide therapy. Renal failure in these patients is frequently reversible if treated early. Long-term patient and kidney survival rates are good with proper treatment and are far better than those of the other causes of rapidly progressive glomerulonephritis. Potential morbidity of steroid and immunosuppressive therapy should be reduced by the use of low effective doses and by close clinical observation and management.

Antibodies, Antineutrophil Cytoplasmic↗