North Atlantic climate far more predictable than models imply.

Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.

Full-length dystrophin gene transfer to the mdx mouse in utero.

In utero gene therapy for genetic diseases, such as muscular dystrophies, offers potential advantages over postnatal treatment including vector delivery at the earliest point in the disease and treatment prior to full maturation of the immune system. This study examines in utero gene delivery of full-length murine dystrophin to the murine mdx model for Duchenne muscular dystrophy using a high-capacity adenoviral vector. We examined dystrophin expression, spread of vector, morphology and specific force production of the tibialis anterior muscle 9 weeks after intramuscular in utero injection. Recombinant dystrophin was expressed in the hindlimb muscles, with the majority of animals having expression in two muscles of the injected hindlimb. The dystrophin-glycoprotein complex was restored in those muscle fibers expressing recombinant dystrophin. Analysis of the percentage of dystrophin-expressing muscle fibers with centrally placed nuclei revealed effective protection from cycles of degeneration and regeneration normally seen in muscle fibers lacking dystrophin. However, due to low levels of muscle gene transfer, further advances in the efficiency of adenoviral vector-mediated gene delivery would be required for clinical applications of in utero gene therapy for primary myopathies such as Duchenne muscular dystrophy.

High doses of systemic corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease. A cohort study. / Dosis altas de corticoides sistémicos en pacientes ingresados por exacerbación de enfermedad pulmonar obstructiva crónica. Un estudio de cohortes.

OBJECTIVES: To assess the effect of high doses of corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: A prospective cohort study was conducted on patients hospitalized with COPD between January and March 2015, grouped according to the glucocorticoid dosage administered (cutoff, 40mg of prednisone/day). We compared the results of hospital stay, readmission and mortality at 3 months of discharge. RESULTS: We analysed 87 patients. The median daily dose was 60mg of prednisone (interquartile range, 46.67-82.33mg/day), and the administration route was intravenous in 96.6% of the cases. We established a relative risk (RR) for hospital stays longer than 8 days of 1.095 (95% CI 0.597-2.007; P=.765) when steroid dosages greater than 40mg/day were employed. In these patients, the hazard ratio (HR) for readmission in the 3 months after discharge was 0.903 (95% CI 0.392-2.082; P=.811), and the mortality was 1.832 (95% CI 0.229-16.645; P=.568). Neither the RR nor the HR varied in a statistically significant manner after adjusting for confounding factors. CONCLUSIONS: A daily dose greater than 40mg of prednisone in patients hospitalised for COPD exacerbation was not associated with a shorter hospital stay or a reduction in readmissions or mortality at 3 months.

Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma.

In rats with diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC), we studied in vivo gene transfer efficiency using intraportal injections of recombinant adenovirus carrying the lacZ reporter gene (AdCMVlacZ) and the therapeutic efficacy of adenovirus-mediated transfer of the thymidine kinase gene of the herpes simplex virus (HSV-tk) followed by ganciclovir (GCV) administration. DENA was very effective in inducing HCC but also stimulated nontumor cell replication, as shown by proliferating cell nuclear antigen (PCNA) staining. The study of in vivo gene transfer efficiency in tumor-bearing rats showed that nontumor tissue and small tumor nodules were transduced effectively whereas a poor transduction rate was noted in large tumor nodules. Concerning therapeutic efficacy, three groups of rats with established HCC were studied: group A and B received intraportally recombinant adenovirus carrying HSV-tk (AdCMVtk) or AdCMVlacZ, respectively, and 2 days after GCV was given intraperitoneally for 9 days; group C received only saline. Of the rats from groups B and C, 100% and 93% respectively, exhibited multiple HCC tumor nodules at end of the study. In contrast, a complete regression of tumor was observed in 63% of animals from group A. This group showed significant elevation of serum transaminases and a diffuse hepatotoxic lesion in liver tissue; histological signs of regeneration were observed in surviving animals. Nine out of 19 rats from group A died during the treatment period. We conclude that (i) in the DENA model of HCC, tumoral cells can be destroyed in vivo by the HSV-tk/GCV system despite poor transduction of large tumor nodules, suggesting that toxic metabolites generated by nontumor cells may exert a bystander effect on tumor tissue; (ii) significant hepatoxicity and a high mortality rate occurred in HSV-tk/GCV-treated rats; these side effects appear to be due to the fact that in DENA-treated livers enhanced cell proliferation was present not only in tumor nodules but also in nontumor parenchyma, leading to GCV sensitization of both tissues; (iii) our results have implications concerning the efficacy and potential risks of the HSV-tk/GCV system in the treatment of human HCC.

Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model.

Gene therapy for hepatocellular carcinoma (HCC) has shown some promise, but its evaluation requires relevant experimental models. With this aim, we present an evaluation of the interest of using the woodchuck model of HCC to assess in vivo gene transfer efficiency. We tested the transduction efficacy of the adenoviral vectors directing lacZ gene product expression under the control of the cytomegalovirus and alpha-fetoprotein (AFP) regulatory sequences. We have also investigated whether an adenoviral cytomegalovirus-thymidine kinase (Tk) vector might induce an antitumoral effect in this model. Our results demonstrate that with direct intratumoral and intrahepatic arterial injections, transduction of a significant proportion of tumor cells occurred even in large HCC nodules. Furthermore, due to intra-arterial anastomoses, direct intratumoral injection led to transduction of some noninjected HCC nodules. Moreover, direct intratumoral injection of a herpes simplex virus-1 Tk-encoding vector induced, on ganciclovir administration, a significant antitumoral effect in the two animals evaluated. However, in one animal, massive hepatic failure occurred due to Tk expression in nontumor cells. These results emphasize the need to target the expression of the Tk gene to tumor cells using a hepatoma-specific promoter such as AFP promoter. However, we showed that, in vivo, lacZ expression as driven by the AFP promoter was extremely low, thus emphasizing some potential pitfalls when using this approach. Altogether, our data stress the need to test gene therapy-based strategies in such in vivo animal models of HCC and evaluate gene transduction, expression, and biological activity, as well as its potential toxicity.

Horner syndrome as an isolated manifestation of an intrapetrous internal carotid artery dissection.

PURPOSE: To describe the atypical localization and unusual clinical manifestation of an internal carotid artery dissection. METHODS: We examined a 43-year-old woman who had sudden onset of left ptosis and miosis with vague dysesthesia around her eye. RESULTS: Her examination showed an intrapetrous carotid artery dissection. CONCLUSIONS: The intrapetrous segment is an extremely rare localization for an internal carotid artery dissection. The differential diagnosis of acute Horner syndrome should include carotid dissection, which is usually accompanied by other neurologic manifestations.

Acetylene soot reaction with NO in the presence of CO.

The heterogeneous reaction of soot with NO can be considered as a means of reduction of the emissions of both pollutants from combustion systems. In this paper, the influence of the presence of CO in the soot-NO reaction is studied. Soot was obtained by pyrolysis at 1373 K of 5000 ppmv acetylene in nitrogen. The study of the influence of CO on the soot-NO reaction was performed in experiments fixing NO concentration at 900 ppmv and introducing different CO concentrations among 0 and 9900 ppmv. An increase in both the carbon consumption rate and NO reduction by acetylene soot was observed as the concentration of CO increases. These results can be explained by the oxide-stripping reaction, CO+C(f)(O)-->CO(2)+C(f). The direct reaction of CO with NO catalyzed by the carbon surface, CO+NO-->CO(2)+1/2N(2) may not be considered in this case the dominant process due to the absence of mineral impurities in the acetylene soot. The influence of CO in the acetylene soot-NO reaction was also tested in the presence of oxygen (250-5000 ppmv). In these conditions and for relatively high CO/O(2) ratios, CO seems to also contribute to NO reduction by the previous oxide-stripping reaction.

Signo de Hutchinson como predictor de afectación ocular en herpes zoster oftálmico / Hutchinson's sign as a predictor of ocular impairment in herpes zoster ophthalmicus

No disponible

Dosis altas de corticoides sistémicos en pacientes ingresados por exacerbación de enfermedad pulmonar obstructiva crónica. Un estudio de cohortes / High doses of systemic corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease. A cohort study

Objetivos. Evaluar el efecto de las dosis altas de corticoides en pacientes ingresados por exacerbación de una enfermedad pulmonar obstructiva crónica (EPOC). Pacientes y métodos. Estudio de cohortes prospectivo de enfermos hospitalizados con EPOC entre enero y marzo de 2015, agrupados en función de la dosis de glucocorticoides recibida (punto de corte: 40mg de prednisona/día). Se compararon los resultados de estancia hospitalaria, y de reingreso y mortalidad a los 3 meses del alta. Resultados. Se analizaron 87 pacientes. La mediana de la dosis diaria recibida fue de 60mg de prednisona/día (rango intercuartílico: 46,67-82,33mg/día); la vía de administración fue endovenosa en el 96,6% de los casos. Se estableció un riesgo relativo (RR) de estancia superior a 8 días de 1,095 [intervalo de confianza (IC) 95%: 0,597-2,007; p=0,765] cuando se usaban dosis de esteroides superiores a 40mg/día. Además, en estos pacientes la hazard ratio (HR) para el reingreso durante los 3 meses siguientes al alta fue de 0,903 [IC 95%: 0,392-2,082; p=0,811] y la mortalidad de 1,832 (IC 95%: 0,229-16,645; p=0,568]. Ni el RR ni las HR observadas variaron de forma estadísticamente significativa tras el ajuste por factores de confusión. Conclusiones. Una dosis superior a 40mg diarios de prednisona en pacientes ingresados por exacerbación de EPOC no se asocia a una menor estancia hospitalaria ni a una disminución del reingreso y de la mortalidad a los 3 meses (AU)

Objectives. To assess the effect of high doses of corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease (COPD). Patients and methods. A prospective cohort study was conducted on patients hospitalized with COPD between January and March 2015, grouped according to the glucocorticoid dosage administered (cutoff, 40mg of prednisone/day). We compared the results of hospital stay, readmission and mortality at 3 months of discharge. Results. We analysed 87 patients. The median daily dose was 60mg of prednisone (interquartile range, 46.67-82.33mg/day), and the administration route was intravenous in 96.6% of the cases. We established a relative risk (RR) for hospital stays longer than 8 days of 1.095 (95% CI 0.597-2.007; P=.765) when steroid dosages greater than 40mg/day were employed. In these patients, the hazard ratio (HR) for readmission in the 3 months after discharge was 0.903 (95% CI 0.392-2.082; P=.811), and the mortality was 1.832 (95% CI 0.229-16.645; P=.568). Neither the RR nor the HR varied in a statistically significant manner after adjusting for confounding factors. Conclusions. A daily dose greater than 40mg of prednisone in patients hospitalised for COPD exacerbation was not associated with a shorter hospital stay or a reduction in readmissions or mortality at 3 months (AU)

Comparison of high-capacity and first-generation adenoviral vector gene delivery to murine muscle in utero.

In utero gene delivery could offer the advantage of treatment at an early stage for genetic disorders such as Duchenne muscular dystrophy (DMD) in which the inevitable process of muscle degeneration is already initiated at birth. Furthermore, treatment of fetal muscle with adenoviral (Ad) vectors is attractive because of a high density of Ad receptors, easy vector accessibility due to immaturity of the basal lamina and the possibility of treating stem cells. Previously, we demonstrated the efficient transduction of fetal muscle by high-capacity Ad (HC-Ad) vectors. In this study, we compared HC-Ad and first-generation Ad (FG-Ad) vectors for longevity of lacZ transgene expression, toxicity and induction of immunity after direct vector-mediated in utero gene delivery to fetal C57BL/6 mice muscle 16 days after conception (E-16). The total amount of beta-galactosidase (betagal) expressed from the HC-Ad vector remained stable for the 5 months of the study, although the concentration of betagal decreased due to muscle growth. Higher survival rates that reflect lower levels of toxicity were observed in those mice transduced with an HC-Ad vector as compared to an FG-Ad vector. The toxicity induced by FG-Ad vector gene delivery was dependent on mouse strain and vector dose. Animals treated with either HC-Ad and FG-Ad vectors developed non-neutralizing antibodies against Ad capsid and antibodies against betagal, but these antibodies did not cause loss of vector genomes from transduced muscle. In a mouse model of DMD, dystrophin gene transfer to muscle in utero using an HC-Ad vector restored the dystrophin-associated glycoproteins. Our results demonstrate that long-term transgene expression can be achieved by HC-Ad vector-mediated gene delivery to fetal muscle, although strategies of vector integration may need to be considered to accommodate muscle growth.

Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase.

We have analyzed the ability of a recombinant replication-defective adenovirus to transfer the thymidine kinase gene of herpes simplex virus (HSV-tk) into hepatocellular carcinoma (HCC) cells to confer sensitivity to ganciclovir. Three HCC cell lines (Hep3B, PLC/PRF/5, and HepG2) were efficiently infected in vitro by a recombinant adenovirus carrying lacZ reporter gene (AdCMVlacZ). Expression of HSV-tk in HCC cells infected with a recombinant adenovirus carrying HSV-tk gene (AdCMVtk) induced sensitivity to ganciclovir in a dose-dependent manner. A bystander killing effect was observed when 90% of uninfected tumor cells were mixed with only 10% of AdCMVtk-infected cells. These data show that recombinant adenoviruses are efficient vectors for transduction of drug-sensitizing genes to HCC cells in vitro. We suggest that a gene therapy approach to hepatocellular carcinoma can be established using adenoviral transfer of HSV-tk to tumor cells and subsequent administration of ganciclovir.

Antitumor effect of allogenic fibroblasts engineered to express Fas ligand (FasL).

Fas ligand is a type II transmembrane protein which can induce apoptosis in Fas-expressing cells. Recent reports indicate that expression of FasL in transplanted cells may cause graft rejection and, on the other hand, tumor cells may lose their tumorigenicity when they are engineered to express FasL. These effects could be related to recruitment of neutrophils by FasL with activation of their cytotoxic machinery. In this study we investigated the antitumor effect of allogenic fibroblasts engineered to express FasL. Fibroblasts engineered to express FasL (PA317/FasL) did not exert toxic effects on transformed liver cell line (BNL) or colon cancer cell line (CT26) in vitro, but they could abrogate their tumorigenicity in vivo. Histological examination of the site of implantation of BNL cells mixed with PA317/FasL revealed massive infiltration of polymorphonuclear neutrophils and mononuclear cells. A specific immune protective effect was observed in animals primed with a mixture of BNL or CT26 and PA317/FasL cells. Rechallenge with tumor cells 14 or 100 days after priming resulted in protection of 100 or 50% of animals, respectively. This protective effect was due to CD8+ cells since depletion of CD8+ led to tumor formation. In addition, treatment of pre-established BNL tumors with a subcutaneous injection of BNL and PA317/FasL cell mixture at a distant site caused significant inhibition of tumor growth. These data demonstrate that allogenic cells engineered with FasL are able to abolish tumor growth and induce specific protective immunity when they are mixed with neoplastic cells.

The use of dietary manipulation by parents of children with atopic dermatitis.

BACKGROUND: In 1989 we demonstrated that 71% of children referred to our paediatric dermatology clinic with atopic dermatitis (AD) had been subject to dietary manipulation by their parents in order to manage their disease. We have re-examined our clinic population to determine whether the documented rise in the use of complementary therapy in children with skin disease has been accompanied by a rise in dietary manipulation. OBJECTIVES: To qualify and quantify the usage of dietary manipulation in children with AD in secondary care. METHODS: A face-to-face structured questionnaire study of 100 children with AD. RESULTS: The mean age of the children interviewed was 7.3 years (median 5.9, range 0.6-17.1) and ethnic origin was 59% white, 35% Indo-Asian, 3% Afro-Caribbean and 3% mixed race. Seventy-five per cent of patients (75 of 100) had tried some form of dietary exclusion; the most common foods omitted were dairy products in 48% (36 of 75), eggs in 27% (20 of 75) and cow's milk in 25% (19 of 75). Forty-one per cent of patients (41 of 100) had tried some form of dietary supplementation. The most common dietary supplement was evening primrose oil in 59% (24 of 41), of whom 13% (three of 24) felt this had helped their skin. Only 51% (38 of 75) had consulted a doctor or dietician before commencing any dietary change, but 39% (29 of 75) felt that their skin had improved as a result of this dietary manipulation. CONCLUSIONS: In comparison with our previous study, the proportion of patients excluding foods from their diet had increased from 71% to 75%. The proportion of these dietary changes that are unsupervised has remained the same, as have the food types avoided. The proportion of patients who report that unsupervised dietary manipulation is beneficial has increased from 10% to 39%.

The use of complementary medicine in children with atopic dermatitis in secondary care in Leicester.

BACKGROUND: The use of 'complementary' or 'alternative' medicine continues to rise in patients with skin disease, especially in those with chronic, inflammatory dermatoses. OBJECTIVES: To qualify and quantify the usage of complementary medicine (CM) in children with atopic dermatitis (AD) in secondary care. METHODS: A face-to-face structured questionnaire study of 100 consecutive children with AD and their parent or guardian. RESULTS: The mean age of the children interviewed was 7.3 years (median age 6.0 years, range 0.6-17.1) and ethnic origin was 59% white, 35% Indian, 3% Afro-Caribbean and 3% mixed race. Forty-six of 100 patients (46%) had used, or were currently using, CM. Of the 54 patients who had not yet used CM, 17 of 54 (31%) said they intended to try this in the future. The most commonly used CM was Chinese herbal medicine by 20 of 46 patients (43% of those who had used CM), followed by herbal medicine (41%) and homeopathy (35%). Of 74 patients using CM, 26 (35%) felt their AD had improved while 39 of 74 (53%) reported that it had remained unchanged. Twenty-six of 46 (56%) CM users in this study would not recommend CM to other patients with AD. There was a strong association between the use of CM and ethnicity (P = 0.01). Half of the patients who had used CM (23 of 46) had used it on the recommendation of family or friends with skin disease, 17 of 46 (37%) from family or friends without skin disease and three of 46 (6%) each from health professionals or from the media or internet. Twenty-five of 46 (54%) of CM users did so because conventional treatment was not working, and eight of 46 (17%) because they were worried about the side-effects of conventional treatment. While 39 of 100 (39%) of all patients felt that CM was safer than conventional medicine, only 14 of 100 felt it was more efficacious. Fifty-one of 100 were happy to combine both types of treatment and 66 of 100 felt that CM should be available from the National Health Service. CONCLUSIONS: In a population of children with AD attending a teaching hospital clinic in Leicester, U.K., 63% use or intend to use CM. This use is associated with ethnicity.

[Identification of yeast and sensitivity in vitro against different antifungal agents]. / Identificación de levaduras y sensibilidad in vitro a diversos antifúngicos.

INTRODUCTION: The increasing incidence of Candida yeasts infections and its hospital and community repercussion (vaginal thrush), as well as the will to acquire the knowledge of the new antifungal that were launched to the therapeutic store, have motivated us to identify that type of yeasts from different sources, as well as to study their behaviour against the antifungal, using commercial procedures with easy clinical application. MATERIALS AND METHODS: An amount of 317 Candida yeasts were identified through commercial procedures (CHROMagar Candida and Auxacolor): 108 vaginals, 138 from ICU newborn children and 71 from ICU adults, while the antifungal drug susceptibilities was done to 199 of the isolated ones using another commercial procedure (Fungitest). RESULTS AND CONCLUSIONS: Candida albicans is identified as the most frequent in both hospital and community samples (78.7 and 45.93%, respectively), followed by Candida glabrata (19.44 and 28.23%, respectively). The sensitivity to amphotericin B and to 5-flucytosine was very high in every studied group, while sensitivity to imidazole derivatives depends on the samples source (lower sensitivity in the ICU newborn isolated ones) and the species (C. glabrata is less sensitive than C. albicans).

Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma.

BACKGROUND/AIMS: Gene therapy has emerged as a new form of treatment for unresectable hepatocellular carcinoma (HCC). We evaluate here the effect of IL-12 and the suicide gene thymidine kinase as single agents and in combination to treat experimental liver cancer. METHODS: Recombinant adenoviruses expressing mouse interleukin-12 (AdCMVIL-12) or thymidine kinase of herpes simplex virus (AdCMVtk) or lacZ reporter gene (AdCMVlacZ) were constructed. The efficacy of the treatment was evaluated in a murine HCC model based on subcutaneous implantation of liver tumor cells (BNL). RESULTS: Transduction of BNL cells after in vitro infection with AdCMVlacZ was very low at multiplicity of infection (moi) of 100, whereas 10-15% of cells were transduced when using moi 1,000. Similarly, production of IL-12 was detectable only in BNL cells infected with AdCMVIL-12 at moi 1,000. In vitro infection of BNL cells with AdCMVIL-12 at moi 100 did not abrogate tumorigenicity, whereas moi 1,000 resulted in inhibition of tumor growth in all mice as well as in abrogation of tumor formation in 3 out of 8 animals. In vivo studies showed that intratumor injection of AdCMVIL-12 induced a dose-dependent effect on tumor regression. However, none of the animals exhibited complete tumor elimination with this treatment. We observed that suppression of tumor growth was more intense in animals treated with the combination of AdCMVIL-12 plus AdCMVtk than in animals which received AdCMVtk or AdCMVIL-12 alone. The combined treatment resulted in a significant increase in animal survival, and 25% of treated animals were free of tumor for over 100 days without recurrence of the disease. CONCLUSIONS: Combination of AdCMVIL-12 and AdCMVtk is more efficient than either of the two vectors alone for the treatment of the murine model of HCC used in this study.

A blood-tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds.

We have evaluated gene transfer efficiency to tumor nodules in diethylnitrosoamine (DENA)-induced hepatocellular carcinoma (HCC) in rats using adenoviral vectors administered by three different routes: intraportal, intra-arterial and intratumoral injection. Our results showed that intraportal infusion could not transduce tumor nodules greater than 1 mm in diameter while the intra-arterial route allowed transduction of nodules up to 2-5 mm in diameter. Tumors greater than this size were resistant to transduction by intravascular route, but could be transduced by direct intratumoral injection, indicating that the obstacle preventing gene transfer to tumor cells was mainly at the level of tumor vasculature and not at the level of neoplastic cells. We have studied the extracellular matrix in tumoral lesions to assess whether nodules with different size and histological pattern have different profiles in relation to transduction efficacy. Immunohistochemical detection showed a high expression of fibronectin (FN), laminin (LN) and alpha-smooth muscle actin (alpha-SMA) in those large HCC, which were resistant to adenoviral infection. Intra-arterial infusion of vasoactive compounds (histamine, angiotensin II or nitric oxide donor nitroglycerin) before vector administration enhanced gene transfer to tumor nodules that were poorly transduced without pre-treatment. Nitroglycerin was active to enhance transduction of large tumors with trabecular or pseudoglandular histological pattern, which were impermeable to adenoviral vectors even after histamine or angiotensin treatments. Our data indicate the presence of a physical barrier between blood and neoplastic cells, which prevents transduction of the tumor by vectors given by the intravascular route. The thickness and impermeability of the barrier increases as the tumor nodule grows. Vasoactive compounds may be of value in gene therapy of liver cancer by increasing transduction efficiency by intravascularly administered vectors.

Alpha(v)beta(3) integrin-mediated adenoviral transfer of interleukin-12 at the periphery of hepatic colon cancer metastases induces VCAM-1 expression and T-cell recruitment.

We previously reported that systemic injection of recombinant adenovirus resulted in a rim of gene transduction around experimental liver tumor nodules. This zone of higher infection is dependent on the alpha(v)beta(3) integrin, acting as an adenovirus internalization receptor, which is overexpressed in tissues surrounding liver metastases. When a recombinant adenovirus encoding interleukin-12 (AdCMVIL-12) is given into a subcutaneous tumor nodule in mice also bearing concomitant liver tumors, a fraction of AdCMVIL-12 reaches the systemic circulation and infects liver tissue, especially at the malignant/healthy tissue interface. As a result of the expression at this location of the interleukin-12 transgenes, VCAM-1 is induced on vessel cells and mediates the recruitment of adoptively transferred anti-tumor cytolytic T-lymphocytes. These studies provide mechanistic explanations for the potent therapeutic synergy observed between interleukin-12 gene transfer and adoptive T-cell therapy.