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PubMed2000

Role of alpha v integrins during angiogenesis.

Angiogenesis depends on specific molecular interactions between vascular cells and components of the extracellular matrix. This review focuses on the recent advances in the understanding of the mechanism of action of integrins and integrin antagonists during angiogenesis. For example, angiogenesis induced with vascular endothelial growth/permeability factor but not with basic fibroblast growth factor (bFGF) depends on integrin avb5 and Src kinase activity. In contrast, bFGF-induced angiogenesis requires integrin avb3 and functions independently of Src. Recent studies document a role for integrins and growth factor regulation of Src family kinases during angiogenesis. We also discuss the effect of av integrin antagonists on angiogenesis during tumor growth, inflammatory disease, and retinopathy and summarize recent clinical progress in using av integrin antagonists.

Animals↗
PubMed2000

Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix.

Hypoxia stimulates angiogenesis, the formation of new blood vessels. This study evaluates the direct effect of hypoxia (1% oxygen) on the angiogenic response of human microvascular endothelial cells (hMVECs) seeded on top of a 3-dimensional fibrin matrix. hMVECs stimulated with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor (VEGF) together with tumor necrosis factor-alpha (TNF-alpha) formed 2- to 3-fold more tubular structures under hypoxic conditions than in normoxic (20% oxygen) conditions. In both conditions the in-growth of capillary-like tubular structures into fibrin required cell-bound urokinase-type plasminogen activator (uPA) and plasmin activities. The hypoxia-induced increase in tube formation was accompanied by a decrease in uPA accumulation in the conditioned medium. This decrease in uPA level was completely abolished by uPA receptor-blocking antibodies. During hypoxic culturing uPA receptor activity and messenger RNA (mRNA) were indeed increased. This increase and, as a consequence, an increase in plasmin formation contribute to the hypoxia-induced stimulation of tube formation. A possible contribution of VEGF-A to the increased formation under hypoxic conditions is unlikely because there was no increased VEGF-A expression detected under hypoxic conditions, and the hypoxia-induced tube formation by FGF-2 and TNF-alpha was not inhibited by soluble VEGFR-1 (sVEGFR-1), or by antibodies blocking VEGFR-2. Furthermore, although the alpha(v)-integrin subunit was enhanced by hypoxia, blocking antibodies against alpha(v)beta(3)- and alpha(v)beta(5)-integrins had no effect on hypoxia-induced tube formation. Hypoxia increases uPA association and the angiogenic response of human endothelial cells in a fibrin matrix; the increase in the uPA receptor is an important determinant in this process. (Blood. 2000;96:2775-2783)

Antigens, CD↗
PubMed2000

An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand.

Identification of receptor activator of nuclear factor-kappaB (RANK) and RANK-ligand (RANKL) has provided new insights into the osteoclast differentiation pathway. Osteoclast precursor cells were isolated using monoclonal antibodies against c-Fms and RANK, and the effect of adherence on the in vitro differentiation and proliferation of these cells was examined in 2 different types of stromal-cell-free culture systems: a semisolid culture medium (a nonadherent system) and a liquid culture medium (an adherent system). Osteoclast precursor cells were not able to differentiate into mature osteoclasts efficiently in the semisolid culture system. Trimerized RANKL enhanced osteoclast differentiation in semisolid cultures, but not to the extent seen when cells were allowed to adhere to plastic. Initial precursor cells were capable of differentiating into macrophages or osteoclasts. Once these cells were transferred to adherent conditions, striking differentiation was induced. Multinuclear cells were observed even after they had displayed phagocytic activity, which suggests that cell adhesion plays an important role in the differentiation of osteoclast precursor cells. Integrins, especially the arginine-glycine-aspartic acid (RGD)-recognizing integrins alpha(v) and beta(3), were needed for osteoclast-committed precursor cells to proliferate in order to form multinuclear osteoclasts, and the increase in cell density affected the formation of multinuclear cells. A model of osteoclast differentiation with 2 stages of precursor development is proposed: (1) a first stage, in which precursor cells are bipotential and capable of anchorage-independent growth, and (2) a second stage, in which the further proliferation and differentiation of osteoclast-committed precursor cells is anchorage-dependent. (Blood. 2000;96:4335-4343)

Animals↗
PubMed2001

Combined targeting of adenoviruses to integrins and epidermal growth factor receptors increases gene transfer into primary glioma cells and spheroids.

Adenoviral-mediated gene transfer is suboptimal in human glioma and limits in vivo gene therapy approaches. There is a need for targeted vectors able to enhance gene transfer into the tumor as well as to lower the viral load in the surrounding normal tissues. We evaluated primary human tumor samples by immunohistochemistry and fluorescence-activated cell sorter for expression of the Coxsackie-adenovirus receptor and other antigens with potential utility to redirect adenoviruses (Ads) to gliomas. In the majority of the samples, Coxsackie-adenovirus receptor expression was low. This correlated with inefficient gene transfer in vitro. Epidermal growth factor receptor (EGFR) and alpha(v)beta5 integrins were often highly, but heterogeneously, expressed. We hypothesized that these receptors, overexpressed in tumor but not in normal brain, could serve as independent binding sites for alternative pathways of infection with targeted Ads. We examined this, using Ads that expressed the luciferase reporter gene under the cytomegalovirus promoter. Targeting to the EGFR was performed with a single-chain bispecific antibody directed against the human EGFR and against the fiber knob of the Ad. Targeting to the alpha(v) integrins was performed by insertion of an integrin-binding sequence, RGD-4C, in the HI-loop of the Ad. Increased luciferase gene transfer in primary glioma cells was observed in 8 of 13 samples with EGFR-targeting (2-11 times enhancement; median, 6) and in all of the samples with RGD-targeting (2-42 times enhancement; median, 12). Combining the two targeting motifs further enhanced the gene transfer in primary glioma cells in an additive manner (3-56 times; median, 20). The double-targeted Ads also strongly augmented gene transfer into organotypic glioma spheroids. Conversely, gene transfer into normal brain explants was reduced dramatically using Ads targeted to the tumor. Our findings demonstrate the feasibility and benefit of binding multiple ligands to the adenoviral fiber knob. These vectors have a great potential for clinical use in the context of tumors that are usually heterogeneous for target antigen expression at the single-cell level.

Adenoviridae↗
PubMed2001

Polarity and developmental regulation of two PDZ proteins in the retinal pigment epithelium.

PURPOSE: Identification of binding partners for ezrin, an actin-binding protein crucial for morphogenesis of apical microvilli and basolateral infoldings in RPE cells. METHODS: Rat eyes, rat primary RPE, the rat RPE-J cell line, and a clonal line of RPE-J cells transfected with human ezrin cDNA were analyzed by immunofluorescence microscopy and immunoblot. Immunofluorescence localization of two ezrin-binding proteins was performed in cryosections of rat eyes of various ages and in monolayers extracted with the detergent Triton X-100 and fixed in paraformaldehyde. The interaction of both proteins with ezrin and gluthathione-S-transferase (GST)-ezrin fusion proteins was analyzed by SDS-PAGE and immunoblot. RESULTS: Immunofluorescence microscopy of adult rat eyes detected a polarized distribution of ERM (ezrin, radixin, and moesin)-binding phosphoprotein of 50 kDa (EBP50) at the apical microvilli and synaptic-associated protein of 97 kDa (SAP97) at the basolateral surface of RPE cells, which overlapped with ezrin. These two PDZ (postsynaptic density protein [PSD-95]/disc large [DLG]-A/ZO-1) domain proteins had a similar polarized distribution and high resistance to detergent extractability, indicative of cytoskeletal association, both in primary cultures of rat RPE and in a clonal RPE-J cell line expressing high levels of transfected ezrin. RPE cell lysates from rat retinas of various postnatal ages revealed increasing levels of EBP50 and SAP97 compared with alphav integrin, a protein expressed at constant adult levels from birth. GST pull-down and immunoprecipitation experiments demonstrated a direct interaction between EBP50 and SAP97 and ezrin. CONCLUSIONS: The data indicate that EBP50 localizes at the apical microvilli, whereas SAP97 localizes at the basolateral surface of RPE cells, probably through a direct interaction with ezrin.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Abnormal pattern of integrin expression at the implantation window in endometrium from fertile women treated with clomiphene citrate and users of intrauterine device.

UNLABELLED: Determine quantitative expression of endometrial integrins that reflect receptivity during implantation window in fertile women treated with clomiphene citrate (CC), and in intrauterine device users (IUD) as compared to fertile controls. Comparative study of the quantitative expression of a1, a4, av and b3 integrins in epithelial and stromal cells in mid-secretory endometrium of CC treated fertile women, IUD users and controls. All subjects included in this study had regular and ovulatory menstrual cycles. SUBJECTS: Ten women treated with a daily dose of 50 mg of CC. Six women T-Cu device users and nine fertile controls. Age ranges for all groups were similar, 29-41 years old (mean 36.3). Tissue samples were taken at the mid-secretory phase or implantation window. A histological dating of the endometrial biopsies was assessed according to Noyes criteria. Ovulation was assessed by repeated transvaginal ultrasonography. The expression of a1, a4, aV and b3 integrins in dispersions of epithelial (EEC) and stromal (ESC) cells isolated from endometrial biopsies was quantitatively determined by flow cytometry using specific monoclonal antibodies. Immunohistochemistry was also used to detect integrin expression. Biopsies from CC-treated women had a high incidence of out-of-phase endometria. Interestingly, CC-treated women over-expressed a1, aV and b3-ESC integrins and under-expressed b3-EEC subunit (P<0.05). IUD users over-expressed the a1-EEC and under-expressed a4-ESC (P<0.05) at the time of the implantation window. CC treatment in fertile women provokes a high frequency of out-of-phase endometrium and desynchronises the expression of endometrial integrins at the implantation window. The epithelial b3 integrin was under-expressed in all CC-treated patients. The T-Cu intrauterine device alters endometrial receptivity by a different mechanism independent of the expression of the epithelial b3 integrin. However, both CC and IUD use alter the expression of some epithelial and stromal integrins during the implantation window.

Adult↗
PubMed2002

Myelin proteolipid protein forms a complex with integrins and may participate in integrin receptor signaling in oligodendrocytes.

Myelination of axons in the CNS by oligodendrocytes is a process critical to rapid and efficient impulse conduction. A new role for the myelin proteolipid protein (PLP), the most abundant protein of CNS myelin, has been identified, in studies showing PLP interaction with signaling proteins in oligodendrocytes. In particular, these studies suggest that the PLP protein may be involved in signaling through integrins in oligodendrocytes. Stimulation of muscarinic acetylcholine receptors on oligodendrocytes induced formation of a tripartite complex containing PLP, calreticulin, and alpha(v)-integrin. PLP interacted directly with the cytoplasmic domain of the alpha(v)-integrin. Complex formation was mediated by phospholipase C and Ca2+ binding to the high affinity binding site on calreticulin. This complex appears important for binding of fibronectin to oligodendrocytes. These data establish a novel function for PLP as a part of the integrin signaling complex in oligodendrocytes and suggest that neurotransmitter-mediated integrin receptor signaling may be involved in myelinogenesis.

Animals↗
PubMed2002

Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy.

The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. AdDelta24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of AdDelta24 was expanded toward alphav integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-Delta24RGD). We show that Ad5-Delta24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-Delta24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-Delta24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 10(7) plaque-forming units Ad5-Delta24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-Delta24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-Delta24RGD infection decreased viability of glioma cells more effectively than Ad5-Delta24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-Delta24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 10(6) plaque-forming units Ad5-Delta24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-Delta24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-Delta24RGD in combination with radiation therapy for treatment of these highly malignant tumors.

Adenoviridae↗
PubMed2003

Participation of fibroblasts in MMP-2 binding and activation on the surface of oral squamous cell carcinoma cells.

The effect of fibroblasts on the activation of matrix metalloproteinase-2 (MMP-2) in oral squamous cell carcinoma (SCC) cells was examined. The plasma membrane of SCC cells failed to bind and activate latent MMP-2. However, treatment of SCC cells with fibroblast-conditioned medium (fibroblast-CM) led to the enhancement of the binding and activation of latent MMP-2 on the cell surface. Moreover, fibroblasts induced the expression of membrane type 1 MMP (MT1-MMP) in SCC cells. MMP-2 activated on the cell surface bound to the surface of SCC cells via alphav integrins. These findings suggest that fibroblasts might facilitate the invasion of SCC cells by increasing the proteolytic activity on the surfaces of SCC cells.

Carcinoma, Squamous Cell↗
PubMed2003

CpG oligodeoxynucleotides enhance the capacity of adenovirus-mediated CD154 gene transfer to generate effective B-cell lymphoma vaccines.

Activation of CD40 by CD154 induces antigen-presenting cells (APC) to express immune costimulatory molecules, thereby enhancing their APC activity. Oligonucleotides (ODN), containing immunostimulatory DNA sequences (ISS) with nonmethylated CpG dinucleotides in a defined motif, also can induce similar changes in APC. In this study, we examined whether infection with recombinant adenovirus (Ad) encoding CD154 and/or treatment with ISS-ODN could enhance the capacity of A20 murine B lymphoma cells to function as APCs capable of inducing a syngeneic antilymphoma immune response. High-level expression of CD154 after infection with Ad-CD154 induced up-regulation of immune costimulatory molecules on A20 cells, as did incubation with ISS-ODN. Treatment of A20 cells with ISS-ODN also enhanced surface expression of alphav integrins, making them significantly more susceptible to Ad infection than nontreated A20 cells. In syngeneic mixed-lymphocyte reactions with BALB/c splenocytes, A20 cells activated with ISS-ODN and then transduced with Ad-CD154 were significantly more effective APCs than Ad-CD154 transduced cells, which, in turn, were significantly more effective than A20 cells treated with ISS-ODN alone. Also, injection of mice with ISS-activated, Ad-CD154-infected cells induced significantly better A20-specific immune responses against A20 cells, as assessed via enzyme-linked immunospot analysis in vitro and immune prophylaxis against subsequent challenge with A20 lymphoma cells in vivo. These data demonstrate that CpG-containing oligonucleotides can serve as an adjuvant for Ad-mediated gene therapy of B-cell malignancies.

Adenoviridae↗
PubMed2003

Alpha v integrin inhibitors and cancer therapy.

Recent gene disruption experiments have suggested that targeting the alpha v integrins (cell surface adhesion and signaling receptors) to prevent tumor progression can result in different outcomes depending on the strategy. Nevertheless, two alpha v binding antagonists have made their way to the clinic in the oncology field; both Vitaxin, a humanized antibody, and cilengitide, a cyclic peptide mimicking the RGD ligand recognition peptidic domain common to alpha v integrin ligands, are in phase II clinical trials. This year, development of another peptidic inhibitor was initiated. This review questions whether companies are reluctant to propose small synthetic heterocyclic inhibitors as successors to peptide-derived agents with better pharmacokinetics and oral bioavailability. Is this class of compounds immediably flawed like the platelet alpha IIb beta 3 oral antagonists? Tentative answers are provided in this review following description of the lead compounds and the rationale for their use as cancer treatments, imaging agents or drug targeting vectors.

Animals↗
PubMed1994

Alpha v integrins mediate the rise in intracellular calcium in endothelial cells on fibronectin even though they play a minor role in adhesion.

We have investigated which integrins mediate the elevation of intracellular calcium ([Ca2+]i) triggered by spreading of endothelial cells on fibronectin (FN). Specific anti-integrin monoclonal antibodies immobilized on glass surfaces were used as agonists to trigger cell spreading. These experiments demonstrated that an antibody to alpha v could induce the rise in [Ca2+]i, whereas two antibodies to alpha 5 beta 1 were inactive, despite their ability to induce cell spreading and elevation of intracellular pH. Antibodies in solution were then used as agonists to block association of specific integrins with FN. These experiments also showed that alpha v integrin(s) but not alpha 5 beta 1 mediated the rise in [Ca2+]i in cells spreading on FN. Adhesion assays in the presence of function-blocking anti-integrin antibodies and affinity chromatography on FN columns of surface-labeled cell extracts were carried out to characterize the integrins that bind to FN. Both methods showed that alpha v integrin(s) and alpha 5 beta 1 participate in FN binding; however, the contribution from alpha v integrin(s) was much less than that of alpha 5 beta 1. These results demonstrate that two receptors for FN on the same cells can trigger distinct intracellular signaling pathways and, furthermore, that an integrin whose contribution to adhesion is barely detectable can have a major effect on cellular responses. The results also suggest that the specificity for activation of the calcium signaling pathway resides primarily in the integrin alpha subunit.

Antibodies↗
PubMed1993

Modulation of integrins expression during human osteoblasts "in vitro" differentiation.

We here report the modulation of the adhesion of cultured human osteoblasts on Laminin during the acquisition of differentiated phenotype. We also show that interference with the differentiation program caused by treatment with Retinoic acid of the cultures, causes changes of the capability to adhere to Laminin and type I Collagen. The younger or dedifferentiated cells have lower capability to bind to Laminin or Collagen. The maturation associated changes are specific for the adhesion to the above substrata and do not involve the adhesion to FN or plastic. The alpha subunit(s) of the integrin receptor(s) for these proteins is likely to be responsible for the modulation adhesion to Laminin and Collagen.

Cell Adhesion↗
PubMed1995

Localization of the alpha v subfamily of integrins and their putative ligands in synovial lining cell layer.

OBJECTIVE: The lining cell layer of the synovium proliferates strongly in rheumatoid arthritis. It has been suggested that it has a central role in the destruction of cartilage. We have analyzed the structure of the extracellular matrix and the adhesion molecules of normal, osteoarthritic and rheumatoid lining cell layer. METHODS: We localized the alpha v integrin subunit and its 4 putative partner beta subunits in synovial samples by using indirect immunofluorescence. The specimens were also analyzed by confocal microscopy. Indirect immunofluorescence was also used to analyze the ligands of alpha v integrins, namely fibronectin and vitronectin. RESULTS: The alpha v integrin was abundant in the lining cell layer of normal and osteoarthritic synovia, whereas it was not expressed in the proliferating rheumatoid lining cell layers. A similar expression pattern was found for beta 5 subunit, suggesting that it is the major partner for alpha v. However, also some alpha v beta 1 and alpha v beta 3 heterodimers may be present. The confocal microscopy revealed the presence of both alpha v beta 5 positive and negative lining cells. The putative ligands for alpha v integrins, namely fibronectin and vitronectin were found in the lining cell layer of all the synovial specimens. CONCLUSION: In spite of the proliferation of the lining cell layer in rheumatoid inflammation, the extracellular matrix stays very similar to that in normal and osteoarthritic synovium, whereas the pattern of the adhesion receptors is completely altered.

Aged↗
PubMed1995

Human mast cells derived from fetal liver cells cultured with stem cell factor express a functional CD51/CD61 (alpha v beta 3) integrin.

Human fetal livers contain progenitor cells that become mast cells after 4 weeks of culture with recombinant human stem cell factor. Expression of cell surface CD29 (beta 1), CD18 (beta 2), CD61 (beta 3), and beta 5 integrins was investigated on such cells by flow cytometry and adhesion measurements. High surface expression of CD49e, CD51, and CD61 along with kit was apparent by 4 weeks of culture, whereas expression of each at day 0 was low to undetectable. CD29 and CD49d were detected on cells from day 0 to 4 weeks of culture; CD49b, CD49c, CD49f, CD18, and CD54 expression was negligible. The fetal liver-derived mast cells spontaneously adhered to vitronectin. No evidence for degranulation was found during vitronectin-dependent adhesion. Adhesion occurred in part through the CD61/CD51 receptor. No evidence for adhesion to vitronectin through CD29 and beta 5 integrins was obtained. Almost all of the vitronectin-adherent cells expressed CD51, CD61, kit, and tryptase, and exhibited metachromasia with toluidine blue. Thus, among the fetal liver-derived cells, developing mast cells were selectively adherent to vitronectin. These mast cells and the other cell types present also adhere spontaneously to fibronectin and to laminin, this adhesion being partially inhibited by antibodies against CD61 and CD29 integrins. In conclusion, human mast cells acquire functional vitronectin receptors as they develop from fetal liver progenitors under the influence of rhSCF. This may be important for the recruitment, localization, and retention of developing mast cells.

Amino Acid Sequence↗
PubMed1996

Analysis of integrin expression on oligodendrocytes during axo-glial interaction by using rat-mouse xenocultures.

To analyze the expression of cell-surface molecules on neurons or glia during myelination, we have developed a xenotypic coculture system in which mouse oligodendrocytes interact with rat dorsal root ganglion neurons. The axo-glial interactions in these cultures promote oligodendrocyte precursor cell proliferation, survival, and differentiation as in vivo, thus supporting the validity of the xenocultures as a model system to study myelination in which the molecules on the neurons or the glia can be distinguished using species-specific antibodies. We examined the expression of integrins, the major family of cell-surface extracellular matrix receptors, on oligodendrocytes during the early stages of myelination and found that, unlike Schwann cells, oligodendrocytes do not express alpha 6 beta 4 in association with myelin sheath formation. The pattern of integrin expression observed on oligodendrocytes in these cultures is similar to that seen in oligodendrocytes that differentiate in purified cultures, and it comprises alpha 6 beta 1, alpha v beta 5, and an as yet uncharacterized alpha v-associated beta subunit of 80 kDa. Changes in integrin expression associated with differentiation, therefore, do not depend on axonal contact, and beta 4 is not required for myelin sheath formation, although its expression may contribute to the individual properties of oligodendrocytes and Schwann cells.

Animals↗
PubMed1996

Gradient of RGD-dependent entry of adenoviral vector in nasal and intrapulmonary epithelia: implications for gene therapy of cystic fibrosis.

The efficiency with which adenoviral vectors infect airway epithelial cells in vivo is unclear despite extensive preclinical and clinical studies. Our hypothesis is that gene transfer is limited by vector internalization which is mediated by binding of a fiber with a cellular receptor and the RGD motif of the penton base of the virus with cellular alpha v beta integrin. Experiments in mice demonstrate an anatomical gradient of susceptibility to adenoviral vector-mediated gene transfer with epithelia of proximal structures, such as nose and trachea, much less infectable than the distal noncartilaginous airway. Throughout the airway, gene transfer is dependent on RGD-mediated interactions which are rate limiting in the distal lung. A panel of tissues from cystic fibrosis and non-cystic fibrosis patients was analyzed for expression of alpha v beta 5 integrin which is capable of mediating RGD-dependent uptake of vector. Luminal epithelial cells of the nose and trachea were void of alpha v beta 5 expression whereas abundant expression of this integrin was present in virtually all epithelial cells of distal conducting airway. These findings could explain difficulties we and others have had in correcting the functional deficit of cystic fibrosis nasal epithelia and suggest that gene transfer efficiency may be greater in distal human lung.

Adenoviruses, Human↗