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Biomedical subjects

G Forni

Publications and source records attributed to G Forni.

At least 19 recordsLinked to original sources
PubMed2007

WIP null mice display a progressive immunological disorder that resembles Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency syndrome caused by mutations in the WAS protein (WASP). This participates in signalling and cytoskeletal homoeostasis, and some of its activities are regulated by its binding to the WASP interacting protein (WIP). WIP deficiency, however, has not yet been shown to be of pathological significance in humans. Here we show that, in WIP null (WIP(-/-)) mice, it produces haematological alterations and anatomical abnormalities in several organs, most probably as a consequence of autoimmune attacks. Granulocytosis and severe lymphopenia are associated with a proportional increase in segmented cells and fewer bone marrow erythrocytes and lymphocytes. Splenomegaly is accompanied by an increase of haematopoietic tissue and red pulp, reduction of the white pulp, and fewer B (B220(+)) lymphocytes (also apparent in the lymph nodes and Peyer's patches). Ulcerative colitis, interstitial pneumonitis, glomerular nephropathy with IgA deposits, autoantibodies, and joint inflammation are also evident. These progressive immunological disorders closely mimic those seen in WAS. WIP deficiency may thus be implicated in some cases in which mutations in the gene encoding WASP are not detected.

Animals↗
PubMed2006

A completely automated CAD system for mass detection in a large mammographic database.

Mass localization plays a crucial role in computer-aided detection (CAD) systems for the classification of suspicious regions in mammograms. In this article we present a completely automated classification system for the detection of masses in digitized mammographic images. The tool system we discuss consists in three processing levels: (a) Image segmentation for the localization of regions of interest (ROIs). This step relies on an iterative dynamical threshold algorithm able to select iso-intensity closed contours around gray level maxima of the mammogram. (b) ROI characterization by means of textural features computed from the gray tone spatial dependence matrix (GTSDM), containing second-order spatial statistics information on the pixel gray level intensity. As the images under study were recorded in different centers and with different machine settings, eight GTSDM features were selected so as to be invariant under monotonic transformation. In this way, the images do not need to be normalized, as the adopted features depend on the texture only, rather than on the gray tone levels, too. (c) ROI classification by means of a neural network, with supervision provided by the radiologist's diagnosis. The CAD system was evaluated on a large database of 3369 mammographic images [2307 negative, 1062 pathological (or positive), containing at least one confirmed mass, as diagnosed by an expert radiologist]. To assess the performance of the system, receiver operating characteristic (ROC) and free-response ROC analysis were employed. The area under the ROC curve was found to be Az = 0.783 +/- 0.008 for the ROI-based classification. When evaluating the accuracy of the CAD against the radiologist-drawn boundaries, 4.23 false positives per image are found at 80% of mass sensitivity.

Algorithms↗
PubMed2005

Anti-HER-2 DNA vaccine protects Syrian hamsters against squamous cell carcinomas.

This paper illustrates the efficacy of DNA vaccination through electroporation in the prevention of oral transplantable carcinoma in Syrian hamsters. At 21 and 7 days before tumour challenge, 19 hamsters were vaccinated with plasmids coding for the extracellular and transmembrane domains of rat HER-2 receptor (EC-TM plasmids), whereas 19 control hamsters were injected intramuscularly with the empty plasmid. Immediately following plasmid injection, hamsters of both groups received two square-wave 25 ms, 375 V cm(-1) electric pulses via two electrodes placed on the skin of the injection area. At day 0, all hamsters were challenged in the submucosa of the right cheek pouch with HER-2-positive HCPC I cells established in vitro from an 7,12-dimethylbenz[a]anthracene-induced oral carcinoma. This challenge gave rise to HER-2-positive buccal neoplastic lesions in 14 controls (73.37%), compared with only seven (36.8%, P<0.0027) vaccinated hamsters. In addition, the vaccinated hamsters displayed both a stronger proliferative and cytotoxic response than the controls and a significant anti-HER-2 antibody response. Most of the hamsters that rejected the challenge displayed the highest antibody titres. These findings suggest that DNA vaccination may have a future in the prevention of HER-2-positive human oral cancer.

Animals↗
PubMed2005

GPCALMA: a Grid-based tool for mammographic screening.

OBJECTIVES: The next generation of high energy physics (HEP) experiments requires a GRID approach to a distributed computing system: the key concept is the Virtual ORGANISATION (VO), a group of distributed users with a common goal and the will to share their resources. METHODS: A similar approach, applied to a group of hospitals that joined the GPCALMA project (Grid Platform for Computer Assisted Library for MAmmography), will allow common screening programs for early diagnosis of breast and, in the future, lung cancer. The application code makes use of neural networks for the image analysis and is useful in improving the radiologists' diagnostic performance. GRID services allow remote image analysis and interactive online diagnosis, with a potential for a relevant reduction of the delays presently associated with screening programs. RESULTS AND CONCLUSIONS: A prototype of the system, based on AliEn GRID Services [1], is already available, with a central server running common services [2] and several clients connecting to it. Mammograms can be acquired in any location; the related information required to select and access them at any time is stored in a common service called Data Catalogue, which can be queried by any client. Thanks to the PROOF facility [3], the result of a query can be used as input for analysis algorithms, which are executed on the nodes where the input images are stored,. The selected approach avoids data transfers for all the images with a negative diagnosis and allows an almost real time diagnosis for the set of images with high cancer probability.

Algorithms↗
PubMed2004

A study on two different CAD systems for mammography as an aid to radiological diagnosis in the search of microcalcification clusters.

OBJECTIVE: The aim of the present study was to evaluate the efficacy of two different computer aided detection (CAD) systems for mammography in improving radiological diagnosis in the search of microcalcification clusters. The CAD systems used are: the SecondLooktrade mark (CADx Medical Systems, Canada) commercial system and the CALMA (computer assisted library in MAmmography) research CAD system. Three radiologists were asked to read mammographic images with and without the support of the CAD systems. MATERIAL AND METHODS: Three radiologists with respectively 3, 5 and 7 years of practice in mammogram reading in an Italian public hospital analysed a dataset composed of 120 digitized mammograms of healthy subjects with no lesion (proven by a radiological follow up of at least 3 years) and 70 images of patients with malignant cluster of microcalcification (proven by histopathological examination) both with no CAD support as well as with the help of the SecondLooktrade mark system. After 3 months they were asked to observe the same digitized mammograms with the assistance of the CALMA system. The radiologists worked independently and were unaware of the final diagnosis. The values of the area A(z) under the ROC curve, diagnostic sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were evaluated with and without the support of the CAD systems. The reading time and qualitative evaluations of each radiologist were also reported. RESULTS: With the support of the two CAD systems an improvement in A(z) area was obtained ranging from 0.01 to 0.04. Sensitivity increased from +8.6 to +15.7% and specificity decreased from 0.8 to 4.2%. CONCLUSION: In our study, not conditioned by the dataset, the CAD systems as second reader produced an increase in overall sensitivity of up to 15.7%, with a little decrease in specificity of up to 4.2%. Based on these results both CAD systems might be used in the current practise to improve the sensitivity values of conventional reading (radiologist alone). The results of this study show that no significant differences exist in term of A(z), sensitivity and specificity between CALMA and CADx.

Breast Diseases↗
PubMed2001

Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

Adjuvants, Immunologic↗
PubMed2001

Interleukin 12-activated lymphocytes influence tumor genetic programs.

T-lymphocytes (LYs) from normal and IFN-gamma knockout mice were activated by anti-CD3 and anti-CD28 antibodies and cultured in inserts in the presence of interleukin (IL)-12 (IL-12-activated LYs) or not (activated LYs). Their ability to modulate the genetic programs of two tumor lines growing at the bottom of transwells was evaluated. cDNA gene expression array, reverse transcription-PCR, and protein expression showed that LPS, transcription termination factor 1, transforming growth factor, and fibroblast growth factor genes were up-modulated by factors other than IFN-gamma released by activated LYS: The high levels of IFN-gamma released by normal IL-12-activated LYs up-modulated the expression of STAT1, IRF-1, LMP2, LMP7, monokine induced by IFN-gamma, monocyte chemoattractant protein 1, and angiopoietin 2 genes but down-modulated the expression of vascular endothelial growth factor. PA28, IFN-inducible protein 10, inducible NO synthetase, and macrophage-inhibitory protein 2 genes were up-modulated by factors released only by IL-12-activated LYs apart from IFN-gamma. The opposite modulations of vascular endothelial growth factor expression and of angiopoietin 2, monokine induced by IFN-gamma, IFN-inducible protein 10, and inducible NO synthetase by IL-12-activated LYs fit in well with the inhibition of angiogenesis that characterizes the antitumor activity of IL-12. T-LYs thus modify a tumor's behavior so that it becomes a party to its own inhibition.

Adenocarcinoma↗
PubMed2001

A light, nontoxic interleukin 12 protocol inhibits HER-2/neu mammary carcinogenesis in BALB/c transgenic mice with established hyperplasia.

With a slight asynchronous but consistent progression, all of the mammary glands of female BALB/c mice transgenic for the transforming rat HER-2/neu oncogene progress to atypical hyperplasia and to invasive carcinoma. Previous studies have shown that chronic administration of interleukin (IL) 12 started at the 2nd week of age hampers this progression because of its ability to inhibit tumor angiogenesis and activate a nonspecific immune response. Here we show that a similar inhibition is achieved when 7-week-old mice with fully blown atypical hyperplasia receive a weekly injection of 100 ng IL-12 for 16 times. This lower-dose and later IL-12 administration induces high and sustained levels of serum IFN-gamma equivalent to those elicited by more frequent administrations. A lower-dose and less toxic treatment may thus be envisaged as a possible option in the management of preneoplastic mammary lesions.

Animals↗
PubMed2001

IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk.

In vivo IL-12-dependent tumor inhibition rests on the ability of IL-12 to activate a CD8-mediated cytotoxicity, inhibit angiogenesis, and cause vascular injury. Although in vivo studies have shown that such inhibition stems from complex interactions of immune cells and the production of IFN-gamma and other downstream angiostatic chemokines, the mechanisms involved are still poorly defined. Here we show that IL-12 activates an anti-angiogenic program in Con A-activated mouse spleen cells (activated spc) or human PBMC (activated PBMC). The soluble factors they release in its presence arrest the cycle of endothelial cells (EC), inhibit in vitro angiogenesis, negatively modulate the production of matrix metalloproteinase-9, and the ability of EC to adhere to vitronectin and up-regulate ICAM-1 and VCAM-1 expression. These effects do not require direct cell-cell contact, yet result from continuous interaction between activated lymphoid cells and EC. We used neutralizing Abs to show that the IFN-inducible protein-10 and monokine-induced by IFN-gamma chemokines are pivotal in inducing these effects. Experiments with nu/nu mice, nonobese diabetic-SCID mice, or activated spc enriched in specific cell subpopulations demonstrated that CD4(+), CD8(+), and NK cells are all needed to mediate the full anti-angiogenetic effect of IL-12.

Angiogenesis Inhibitors↗
PubMed2001

Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation.

As T cell response to tumor-associated antigens may be impaired by the acidic microenvironment typical of solid tumors, we assessed the effect of extracellular pH (pH(e)) on the activation and proliferation of human T lymphocytes and generation of the cytotoxic response. T lymphocytes stimulated with anti-CD3 mAb or PHA at low pH(e) were unable to secrete IL-2 and IFN-gamma and their ability to progress through the cell cycle was impaired. T lymphocytes also displayed up-regulation of IFN-gammaR2 chain and CTLA-4 expression, rendering them sensitive to negative regulatory signals. Agonistic mAb against CD28, but not against CD2, completely restored cytokine production and cell cycle progression, but down-regulated IFN-gammaR2 and CTLA-4 expression. The anti-CD28mAb rescued the CTL response of allogeneic anti-tumor cultures generated at low pH(e). Following anti-CD28 mAb treatment, T cells synthesized cyclooxygenase-2 (Cox-2) protein, which is involved in the early phases of T cell activation. This rescue of T cell activation was independent of the inducible 6-phosphofructo-2-kinase (iPFK-2) pathway, which stimulates proliferation in hypoxic and acidic conditions. The restoration of proliferative and cytotoxic T cell responses by CD28-triggering provides insight into the mechanisms by which B7 enhances the T cell anti-tumor response in vivo.

Abatacept↗
PubMed2001

Insertion of the DNA for the 163-171 peptide of IL1beta enables a DNA vaccine encoding p185(neu) to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice.

An assessment was made of the effectiveness of DNA vaccination in prevention of the mammary adenocarcinomas of BALB/c female mice transgenic for the activated rat Her-2/neu oncogene. Atypical hyperplasia is evident in their mammary glands when they are 6 weeks old and in situ carcinoma by the 13th week. Palpable invasive carcinomas appear around the 17th week and are always evident in all 10 glands by the 33rd week. Intramuscular vaccinations with 100 microg plasmid DNA encoding the extracellular domain of the Her-2/neu p185 (ECD) performed at the 6th, 12th, 18th and 24th week provided no significant protection, whereas those ECD plasmids in which the DNA coding for the immunomodulatory 163-171 (VQGEESNDK) nonapeptide of human IL1beta (ECD-IL1betap) had been inserted both delayed carcinogenesis and reduced tumor multiplicity. This reduction was associated with a marked immune-inflammatory reaction and a conspicuous leukocyte infiltrate located in the stroma surrounding the hyperplastic mammary ductul-alveolar structures. It was also directly correlated with a high anti-p185(neu) antibody production and an immunoglobulin switch to IgG2a and IgA. No anti-p185(neu) cytotoxic response was found. No significant protection was obtained when the DNA coding for the non-active peptide 189-197 of IL1beta was inserted.

Animals↗
PubMed2001

Therapy of lung metastases through combined vaccination with carcinoma cells engineered to release IL-13 and IFN-gamma.

TS/A spontaneous mouse mammary adenocarcinoma cells were engineered to release interferon-gamma (IFN-gamma), a Th1 cytokine (TS/A-IFNgamma) and interleukin-13 (IL-13), a Th2 cytokine (TS/A-IL13). Mice bearing lung micrometastases induced by parental TS/A cells received repeated subcutaneous vaccinations with TS/A-IFN-gamma admixed with TS/A-IL13 engineered cells. This combined treatment cured up to 75% of mice, whereas vaccinations with either TS/A-IFNgamma or TS/A-IL13 alone cured only 20-40% of mice. Combined TS/A-IL13 and TS/A-IFNgamma therapeutic vaccinations elicited a reactive infiltrate of CD4+ and CD8+ lymphocytes in lung metastases and an increased production of IFN-gamma in the spleen and lung, suggesting a shift of the immune response toward the Th1 type. The type of infiltrating cells along with the lack of efficacy in T cell-deficient mice point to a major role of T cells. In conclusion, no antagonism but a synergistic and effective definitive cure stems from the combined vaccination with tumor cells engineered to release a Th1 and a Th2 cytokine.

Adenocarcinoma↗
PubMed2001

Six-minute walking performance in patients with moderate-to-severe heart failure; is it a useful indicator in clinical practice?

AIMS: The 6-min walk test has been incorporated into studies on the efficacy of new therapies and into prognostic stratification for chronic heart failure patients. Firm conclusions on the usefulness of the test in clinical practice are still lacking. The aim of this study was to investigate (1) the correlation between walk test performance and standard indices of cardiac function and exercise capacity, and (2) the prognostic value of the walk test with respect to peak VO2 and NYHA class. METHODS AND RESULTS: Three hundred and fifteen chronic heart failure patients (age: 53+/-9 years, NYHA class: II (182), III (133)) underwent a functional evaluation and a 6-min walk test. Of these, 270 were followed-up for a minimum of 6 months (mean 387+/-177 days). Walked distance was 396+/-92 m. There was no significant correlation between distance walked and central haemodynamic data. Functional capacity, as measured by ergometry, correlated moderately with distance walked (duration: r=0.48, peak VO2: r=0.59, anaerobic threshold: r=0.54; all P<0.001). During follow-up, 46 patients died from cardiovascular causes and 12 were urgently transplanted. Either of these events were considered end points of the study. Survival analysis was performed from a continuous walk test and peak VO2 measurements or after categorization of (a) quartile segmentation, (b) cut-off points from the literature and (c) thresholds from receiver operating characteristic curves. At univariate survival analysis (Cox regression), the association of the walk test with survival was of significance (P=0.03, continuous variable), or borderline significance (0.05< or =P< or =0.1, after categorization). Peak VO2 was always significant, independent of the scale used (0.005< or =P< or =0.03). The strongest association was found for NYHA class (P<0.001), which showed the highest sensitivity and specificity for the prediction of the event (0.64 and 0.65, respectively). When walk test performance, continuous or categorized, was entered into a multivariate model with NYHA class or peak VO2, it lost any significant association with survival (P>0.76 in all models with NYHA class and P>0.27 in all models with peak VO2). CONCLUSION: In moderate-to-severe chronic heart failure patients, the 6-min walk test is not related to cardiac function and only moderately related to exercise capacity. Walking performance does not provide prognostic information which can complement or substitute for that provided by peak VO2 or NYHA class. Hence the test is of limited usefulness as a decisional indicator in clinical practice.

Adult↗
PubMed2001

Neutrophils in anti-cancer immunological strategies: old players in new games.

This review highlights the new "immunological identity" of neutrophils within the cytokine network and their role in biology of diseases, particularly in tumor biology. The latest preclinical evidence of their involvement in anti-cancer immunotherapeutic and prophylactic strategies will be discussed with particular reference to the real possibilities of transferring experimental results to a clinical setting.

Cytokines↗
PubMed2001

Regulation of interferon-gamma receptor (INF-gammaR) chains: a peculiar way to rule the life and death of human lymphocytes.

Interferon-gamma (IFN-gamma) is a lymphokine produced by activated T lymphocytes and NK cells, that plays an important role in host defense mechanisms by exerting pleiotropic activities on a wide range of cell types. Cellular responses to IFN-gamma are mediated by its heterodimeric cell surface receptor (IFN-gammaR), which activates downstream signal transduction cascades, ultimately leading to the regulation of gene expression. Several observations suggest that the signals resulting from the binding of IFN-gamma to its receptor depend on the number of surface receptors transducing the IFN-gamma signal. This review summarizes recent advances in the understanding of the fine regulation of the response of human lymphocytes to IFN-gamma through an interplay between surface expression of IFN-gammaR and a variety of environmental factors that combine to control their fate.

Apoptosis↗
PubMed2001

Inhibition of mammary carcinogenesis by systemic interleukin 12 or p185neu DNA vaccination in Her-2/neu transgenic BALB/c mice.

Because BALB/c mice transgenic for the rat Her-2/neu oncogene develop multifocal carcinomas in all mammary glands by week 33, they constitute an aggressive model for investigation of treatments designed to oppose mammary carcinogenesis. Nonspecific immune reaction elicited by systemic interleukin (IL)-12 both delayed the appearance of the first tumor and reduced the number of glands affected. However, only 5% of mice were tumor free at week 33. On the other hand, specific vaccination with plasmids encoding for the rat p185neu resulted in a further delay, so much so that 58% of mice were tumor free at week 33. No CTL response was evoked in either IL-12-treated or DNA-vaccinated mice, whereas an anti-rat p185neu antibody response was evident in the latter. Pathological examinations showed that in both IL-12-treated and DNA-vaccinated mice, the tumor growth area was infiltrated by reactive cells associated with expression of endothelial adhesion molecules and antiangiogenic proinflammatory cytokines. In the vaccinated mice, reduction of the number of cells expressing rat p185neu was combined with down-regulation of its membrane expression and even a marked inhibition in development of the terminal ductal lobular units. The reactive infiltrate in vaccinated mice contained numerous granulocytes that likely played an antiangiogenic and angiodestructive role and also joined other cells in the antibody-mediated killing of the r-p185neu+ cells. These results suggest that the elicitation of nonspecific and specific immunity could be beneficially used in individuals with a high risk of developing tumors.

Animals↗