STEFANIA ZANUSSI - Academia.edu (original) (raw)

Papers by STEFANIA ZANUSSI

Proceedings of the National Academy of Sciences of the United States of America, Jun 28, 2022

AIDS-defining cancers declined after combined antiretroviral therapy (cART) introduction, but lym... more AIDS-defining cancers declined after combined antiretroviral therapy (cART) introduction, but lymphomas are still elevated in HIV type 1 (HIV-1)–infected patients. In particular, non-Hodgkin’s lymphomas (NHLs) represent the majority of all AIDS-defining cancers and are the most frequent cause of death in these patients. We have recently demonstrated that amino acid (aa) insertions at the HIV-1 matrix protein p17 COOH-terminal region cause protein destabilization, leading to conformational changes. Misfolded p17 variants (vp17s) strongly impact clonogenic B cell growth properties that may contribute to B cell lymphomagenesis as suggested by the significantly higher frequency of detection of vp17s with COOH-terminal aa insertions in plasma of HIV-1–infected patients with NHL. Here, we expand our previous observations by assessing the prevalence of vp17s in large retrospective cohorts of patients with and without lymphoma. We confirm the significantly higher prevalence of vp17s in lymphoma patients than in HIV-1–infected individuals without lymphoma. Analysis of 3,990 sequences deposited between 1985 and 2017 allowed us to highlight a worldwide increasing prevalence of HIV-1 mutants expressing vp17s over time. Since genomic surveillance uncovered a cluster of HIV-1 expressing a B cell clonogenic vp17 dated from 2011 to 2019, we conclude that aa insertions can be fixed in HIV-1 and that mutant viruses displaying B cell clonogenic vp17s are actively spreading.

List of peak masses enabling the identification of the neutrophil activating protein by mass spec... more List of peak masses enabling the identification of the neutrophil activating protein by mass spectrometry. The trypsin-digested peptides of the gel portion at ~ 15 kDa were also separated by MALDI-TOF to search for masses of the ‘neutrophil activating protein, NapA’. The list of peak masses, which were generated by an in silico tripsin-digestion of the protein P43313 corresponding to the NapA, are listed together with both those found in the spot 204 digestion, and those detected in the digested 15 kDa bands. (PPT 167 kb)

Current clinical pathology, 2019

It is estimated that chronic inflammation contributes to nearly 25% of human cancers. Inflammatio... more It is estimated that chronic inflammation contributes to nearly 25% of human cancers. Inflammation of the gastric mucosa is dependent on various modulatory components such as microbes, environment, and host predisposition. Helicobacter pylori (H. pylori) can initiate and sustain gastric inflammation by its virulence factors as well as by altered cellular pathways that are involved in the restoration of the tissue homeostasis after infection. Indeed, in an attempt to repair injured mucosa, immune system may contribute to gastric cancer development through its physiological pro-inflammatory and anti-inflammatory activities which, particularly in a setting of chronic antigenic stimulation, can turn in pro-tumorigenic effects. In this chapter some of the mechanisms connected to H. pylori-related inflammation will be depicted, also focusing on microenvironmental cellular and soluble driving factors recently highlighted in gastric cancer promotion.

Clinical and Experimental Immunology, Aug 1, 1996

In most HIV-1-infected patients, clinical and immunological progression develops within a few yea... more In most HIV-1-infected patients, clinical and immunological progression develops within a few years. Few infected people, termed long-term non-progressors (LTNP), remain healthy and immunologically stable for a long time. The factors governing the maintenance of this condition are not well known, but it is conceivable that CD8 lymphocytes, cells that play a central role in controlling in vitro HIV replication, may have a part in vivo in this process. The aim of this study was to characterize the phenotypic profile and the cytokine production of CD8 cells in a group of LTNP patients who had stable CD4 cell counts (>500/mm 3) for at least 7 years. Their CD8 absolute numbers were similar to a control group composed of HIV-1 patients who have a progressive decline of their CD4 cell counts. However, our multiparameter immunofluorescence studies show that a clinical and immunologically stable condition is associated with the presence of a CD28 , CD95 strongly positive CD8 population, while disease progression is marked by the CD28 ÿ CD95 CD8 subset. Purified CD8 cells from LTNP retain their ability to produce IL-2, interferon-gamma (IFN-°) and, to a lesser degree, to produce IL-10 and IL-4. In contrast, CD8 cells from progressors are unable to secrete IL-2 and IL-10. Although CD8 cytokine profile does not fit with the proposed T helper (Th)1/Th2 switch in progressive HIV infection, LTNP CD8 T cells maintain their capacity to produce IL-2 and IL-10 (Th0-like), a pattern very similar to that observed in normal HIV healthy controls. We suggest that CD8 cells expressing CD28, CD95 and having a Th0-like profile may be considered to be associated with long-term survival.

Journal of acquired immune deficiency syndromes and human retrovirology, 1999

A phase II study was performed to evaluate the feasibility and activity of subcutaneous (SC) inte... more A phase II study was performed to evaluate the feasibility and activity of subcutaneous (SC) interleukin-2 (IL-2) administration plus zidovudine (ZDV) and didanosine (ddI) in patients with early stage HIV infection. Between October 1995 and October 1996, 12 patients completed 6 cycles of the following scheduled therapy: ZDV plus ddI and SC self-administration of 6 mIU of IL-2 at days 1 to 5 and 8 to 12 of a 28-day cycle for a total of 6 cycles (24 weeks). After 6 cycles, patients received only ZDV plus ddI and they were observed up for an additional 24 weeks. Our schedule was well tolerated as an outpatient regimen and led to a significant elevation in CD4 count, which lasted for 24 weeks after the end of IL-2 therapy. Moreover, CD4/CD25, as well as CD4/CD45RO and CD4/CD45RA, cell levels were significantly increased at the end of the therapy and remained significantly elevated after 24 weeks. During the 6 cycles, HIV-associated viremia was significantly decreased and, accordingly, we observed a significant decline of proviral DNA in peripheral blood mononuclear cells (PBMCs). During follow-up, 10 of 12 treated patients continued to show levels of HIV-related viremia <500 copies/ml. Our results demonstrated that IL-2 and ZDV plus ddI is a well tolerated and effective therapy for patients with HIV in early stages of the disease.

Journal of Acquired Immune Deficiency Syndromes, Apr 1, 2000

Digestive and Liver Disease, Mar 1, 2012

Gastroenterology, May 1, 2012

Microbiologia medica, 1996

Digestive and Liver Disease, Mar 1, 2013

Microbiologia medica, Sep 30, 2010

Valutazione dei livelli di HIV-1 DNA in pazienti con linfoma riceventi trapianto autologo di cell... more Valutazione dei livelli di HIV-1 DNA in pazienti con linfoma riceventi trapianto autologo di cellule staminali (ASCT) SUMMARY Objective. Aim of our study was to evaluate the kinetics of HIV-1 DNA levels (HIV DNA) and its clinical role in HIV-related lymphoma patients undergoing autologous stem cell transplantation (ASCT). Materials and methods. HIV DNA was measured by real-time PCR in the peripheral blood mononuclear cells (PBMCs) of 22 patients, 16 with non-Hodgkin's lymphoma and 6 with Hodgkin's disease. Results: Baseline HIV DNA levels were associated with HIV-1 RNA levels (HIV RNA) (r = 0.56, p = 0.02), but not with CD4 counts (r =-0.10, p = 0.68).The viremia was undetectable for all the follow-up time post-ASCT, while HIV DNA could be evaluated in a high percentage of patients before ASCT and during the entire follow-up (median, 89.5%). At 3 months and at 1 year from transplantation, the median HIV DNA levels were 113 copies/10 6 PBMCs (baseline vs. 3 months, p > 0.05) and 66 copies/10 6 PBMCs (baseline vs. 1 year, p > 0.05), respectively. Moreover, baseline HIV DNA levels were significantly different between alive and deceased patients (p = 0.03), and the overall survival (OS) analysis showed that patients with higher HIV DNA levels at baseline had an increased and nearly significant risk of dying if compared to patients with lower levels (HR, 8.33, 95% CI, 0.99-70.06, p = 0.05). Conclusions: Our study demonstrated the association between increased HIV DNA levels at baseline and overall survival after ASCT, in one of the largest cohorts of HIV-lymphoma patients, treated with salvage therapy.

Microbiologia medica, Jun 30, 2004

M e d i c a 169 un'attività abbastanza efficace vs gli altri Enterobatteri, (vedi Ticarcillina 81... more M e d i c a 169 un'attività abbastanza efficace vs gli altri Enterobatteri, (vedi Ticarcillina 81% di S), e vs P. aeruginosa, (vedi Aztreonam 77% di S), porta alla considerazione che la valutazione degli antibiogrammi eseguiti in una ben definita area geografica, consente non solo di avere un quadro delle resistenze batteriche per quell'ambiente ma, la conoscenza di questi dati epidemiologici potrebbe rappresentare una guida locale per una condotta terapeutica razionale nelle riacutizzazioni delle BPCO, evitando ove possibile, trattamenti empirici che potrebbero aggravare il problema dell'antibiotico resistenza, favorendo la selezione di ceppi batterici multiresistenti. A questo proposito diventa fondamentale, l'identificazione dell'agente eziologico responsabile della riacutizzazione.

Cancer Immunology, Immunotherapy, May 23, 2001

The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with c... more The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with chemotherapy (CT) for the treatment of high-grade/intermediate non-Hodgkin's lymphomas (NHL) in HIVnegative populations. This therapeutic combination is currently also being explored in HIV-positive patients with NHL (HIV-NHL). The objective of our study was to determine CD4 and CD8T cell counts, HIV plasma viremia and proviral load in patients with CD20-positive HIV-NHL treated with Rituximab plus CT and highly active antiretroviral therapy (HAART). We studied eight patients with HIV-NHL treated by anti-CD20 and CT before, after three, and after six cycles of therapy; CD4, CD8 and CD19 lymphocyte subsets were measured by monoclonal antibodies and¯ow cytometry. HIV plasma viremia was determined by the b-DNA assay, and proviral load by a quantitative competitive PCR. CD4T cell counts remained stable after three cycles of therapy, while a signi®cant reduction of this subset was present at the end of therapy. HIV plasma viremia was signi®cantly reduced after the third cycle, but returned to pretreatment levels at the end of therapy; we also observed individual¯uctuations of proviral load during therapy, this marker being increased in two out of three patients at the end of therapy. These observations suggest that Rituximab plus CT accelerated the rate of CD4 depletion and of HIV replication in the peripheral blood of HIV-NHL patients and that HA-ART may be able to delay these eects.

Clinical and Experimental Immunology, Jun 1, 1999

This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained f... more This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti-retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL-2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL-2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL-2-treated, but not of the HAART-treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible effects on cytokine production by PBMC, the combined use of HAART + IL-2 was unable to increase the endogenous production of IL-2, but caused an increase of IL-4, IL-13 and interferon-gamma (IFN-γ) and a reduction of monocyte chemoattractant protein-1 (MCP-1) production. These data suggest that, although in this schedule IL-2 has minimal efficacy on CD4 recovery when compared with HAART alone, it produces an increase of ‘naive’ and CD26+CD4 cells and a partial restoration of cytokine production. These data may be used to better define clinical trials aiming to improve the IL-2-dependent immunological reconstitution of HIV-infected subjects.

Microbiologia medica, 1996

Biomedicine & Pharmacotherapy, Jul 1, 2000

Proceedings of the National Academy of Sciences of the United States of America, Jun 28, 2022

AIDS-defining cancers declined after combined antiretroviral therapy (cART) introduction, but lym... more AIDS-defining cancers declined after combined antiretroviral therapy (cART) introduction, but lymphomas are still elevated in HIV type 1 (HIV-1)–infected patients. In particular, non-Hodgkin’s lymphomas (NHLs) represent the majority of all AIDS-defining cancers and are the most frequent cause of death in these patients. We have recently demonstrated that amino acid (aa) insertions at the HIV-1 matrix protein p17 COOH-terminal region cause protein destabilization, leading to conformational changes. Misfolded p17 variants (vp17s) strongly impact clonogenic B cell growth properties that may contribute to B cell lymphomagenesis as suggested by the significantly higher frequency of detection of vp17s with COOH-terminal aa insertions in plasma of HIV-1–infected patients with NHL. Here, we expand our previous observations by assessing the prevalence of vp17s in large retrospective cohorts of patients with and without lymphoma. We confirm the significantly higher prevalence of vp17s in lymphoma patients than in HIV-1–infected individuals without lymphoma. Analysis of 3,990 sequences deposited between 1985 and 2017 allowed us to highlight a worldwide increasing prevalence of HIV-1 mutants expressing vp17s over time. Since genomic surveillance uncovered a cluster of HIV-1 expressing a B cell clonogenic vp17 dated from 2011 to 2019, we conclude that aa insertions can be fixed in HIV-1 and that mutant viruses displaying B cell clonogenic vp17s are actively spreading.

List of peak masses enabling the identification of the neutrophil activating protein by mass spec... more List of peak masses enabling the identification of the neutrophil activating protein by mass spectrometry. The trypsin-digested peptides of the gel portion at ~ 15 kDa were also separated by MALDI-TOF to search for masses of the ‘neutrophil activating protein, NapA’. The list of peak masses, which were generated by an in silico tripsin-digestion of the protein P43313 corresponding to the NapA, are listed together with both those found in the spot 204 digestion, and those detected in the digested 15 kDa bands. (PPT 167 kb)

Current clinical pathology, 2019

It is estimated that chronic inflammation contributes to nearly 25% of human cancers. Inflammatio... more It is estimated that chronic inflammation contributes to nearly 25% of human cancers. Inflammation of the gastric mucosa is dependent on various modulatory components such as microbes, environment, and host predisposition. Helicobacter pylori (H. pylori) can initiate and sustain gastric inflammation by its virulence factors as well as by altered cellular pathways that are involved in the restoration of the tissue homeostasis after infection. Indeed, in an attempt to repair injured mucosa, immune system may contribute to gastric cancer development through its physiological pro-inflammatory and anti-inflammatory activities which, particularly in a setting of chronic antigenic stimulation, can turn in pro-tumorigenic effects. In this chapter some of the mechanisms connected to H. pylori-related inflammation will be depicted, also focusing on microenvironmental cellular and soluble driving factors recently highlighted in gastric cancer promotion.

Clinical and Experimental Immunology, Aug 1, 1996

In most HIV-1-infected patients, clinical and immunological progression develops within a few yea... more In most HIV-1-infected patients, clinical and immunological progression develops within a few years. Few infected people, termed long-term non-progressors (LTNP), remain healthy and immunologically stable for a long time. The factors governing the maintenance of this condition are not well known, but it is conceivable that CD8 lymphocytes, cells that play a central role in controlling in vitro HIV replication, may have a part in vivo in this process. The aim of this study was to characterize the phenotypic profile and the cytokine production of CD8 cells in a group of LTNP patients who had stable CD4 cell counts (>500/mm 3) for at least 7 years. Their CD8 absolute numbers were similar to a control group composed of HIV-1 patients who have a progressive decline of their CD4 cell counts. However, our multiparameter immunofluorescence studies show that a clinical and immunologically stable condition is associated with the presence of a CD28 , CD95 strongly positive CD8 population, while disease progression is marked by the CD28 ÿ CD95 CD8 subset. Purified CD8 cells from LTNP retain their ability to produce IL-2, interferon-gamma (IFN-°) and, to a lesser degree, to produce IL-10 and IL-4. In contrast, CD8 cells from progressors are unable to secrete IL-2 and IL-10. Although CD8 cytokine profile does not fit with the proposed T helper (Th)1/Th2 switch in progressive HIV infection, LTNP CD8 T cells maintain their capacity to produce IL-2 and IL-10 (Th0-like), a pattern very similar to that observed in normal HIV healthy controls. We suggest that CD8 cells expressing CD28, CD95 and having a Th0-like profile may be considered to be associated with long-term survival.

Journal of acquired immune deficiency syndromes and human retrovirology, 1999

A phase II study was performed to evaluate the feasibility and activity of subcutaneous (SC) inte... more A phase II study was performed to evaluate the feasibility and activity of subcutaneous (SC) interleukin-2 (IL-2) administration plus zidovudine (ZDV) and didanosine (ddI) in patients with early stage HIV infection. Between October 1995 and October 1996, 12 patients completed 6 cycles of the following scheduled therapy: ZDV plus ddI and SC self-administration of 6 mIU of IL-2 at days 1 to 5 and 8 to 12 of a 28-day cycle for a total of 6 cycles (24 weeks). After 6 cycles, patients received only ZDV plus ddI and they were observed up for an additional 24 weeks. Our schedule was well tolerated as an outpatient regimen and led to a significant elevation in CD4 count, which lasted for 24 weeks after the end of IL-2 therapy. Moreover, CD4/CD25, as well as CD4/CD45RO and CD4/CD45RA, cell levels were significantly increased at the end of the therapy and remained significantly elevated after 24 weeks. During the 6 cycles, HIV-associated viremia was significantly decreased and, accordingly, we observed a significant decline of proviral DNA in peripheral blood mononuclear cells (PBMCs). During follow-up, 10 of 12 treated patients continued to show levels of HIV-related viremia <500 copies/ml. Our results demonstrated that IL-2 and ZDV plus ddI is a well tolerated and effective therapy for patients with HIV in early stages of the disease.

Journal of Acquired Immune Deficiency Syndromes, Apr 1, 2000

Digestive and Liver Disease, Mar 1, 2012

Gastroenterology, May 1, 2012

Microbiologia medica, 1996

Digestive and Liver Disease, Mar 1, 2013

Microbiologia medica, Sep 30, 2010

Valutazione dei livelli di HIV-1 DNA in pazienti con linfoma riceventi trapianto autologo di cell... more Valutazione dei livelli di HIV-1 DNA in pazienti con linfoma riceventi trapianto autologo di cellule staminali (ASCT) SUMMARY Objective. Aim of our study was to evaluate the kinetics of HIV-1 DNA levels (HIV DNA) and its clinical role in HIV-related lymphoma patients undergoing autologous stem cell transplantation (ASCT). Materials and methods. HIV DNA was measured by real-time PCR in the peripheral blood mononuclear cells (PBMCs) of 22 patients, 16 with non-Hodgkin's lymphoma and 6 with Hodgkin's disease. Results: Baseline HIV DNA levels were associated with HIV-1 RNA levels (HIV RNA) (r = 0.56, p = 0.02), but not with CD4 counts (r =-0.10, p = 0.68).The viremia was undetectable for all the follow-up time post-ASCT, while HIV DNA could be evaluated in a high percentage of patients before ASCT and during the entire follow-up (median, 89.5%). At 3 months and at 1 year from transplantation, the median HIV DNA levels were 113 copies/10 6 PBMCs (baseline vs. 3 months, p > 0.05) and 66 copies/10 6 PBMCs (baseline vs. 1 year, p > 0.05), respectively. Moreover, baseline HIV DNA levels were significantly different between alive and deceased patients (p = 0.03), and the overall survival (OS) analysis showed that patients with higher HIV DNA levels at baseline had an increased and nearly significant risk of dying if compared to patients with lower levels (HR, 8.33, 95% CI, 0.99-70.06, p = 0.05). Conclusions: Our study demonstrated the association between increased HIV DNA levels at baseline and overall survival after ASCT, in one of the largest cohorts of HIV-lymphoma patients, treated with salvage therapy.

Microbiologia medica, Jun 30, 2004

M e d i c a 169 un'attività abbastanza efficace vs gli altri Enterobatteri, (vedi Ticarcillina 81... more M e d i c a 169 un'attività abbastanza efficace vs gli altri Enterobatteri, (vedi Ticarcillina 81% di S), e vs P. aeruginosa, (vedi Aztreonam 77% di S), porta alla considerazione che la valutazione degli antibiogrammi eseguiti in una ben definita area geografica, consente non solo di avere un quadro delle resistenze batteriche per quell'ambiente ma, la conoscenza di questi dati epidemiologici potrebbe rappresentare una guida locale per una condotta terapeutica razionale nelle riacutizzazioni delle BPCO, evitando ove possibile, trattamenti empirici che potrebbero aggravare il problema dell'antibiotico resistenza, favorendo la selezione di ceppi batterici multiresistenti. A questo proposito diventa fondamentale, l'identificazione dell'agente eziologico responsabile della riacutizzazione.

Cancer Immunology, Immunotherapy, May 23, 2001

The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with c... more The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with chemotherapy (CT) for the treatment of high-grade/intermediate non-Hodgkin's lymphomas (NHL) in HIVnegative populations. This therapeutic combination is currently also being explored in HIV-positive patients with NHL (HIV-NHL). The objective of our study was to determine CD4 and CD8T cell counts, HIV plasma viremia and proviral load in patients with CD20-positive HIV-NHL treated with Rituximab plus CT and highly active antiretroviral therapy (HAART). We studied eight patients with HIV-NHL treated by anti-CD20 and CT before, after three, and after six cycles of therapy; CD4, CD8 and CD19 lymphocyte subsets were measured by monoclonal antibodies and¯ow cytometry. HIV plasma viremia was determined by the b-DNA assay, and proviral load by a quantitative competitive PCR. CD4T cell counts remained stable after three cycles of therapy, while a signi®cant reduction of this subset was present at the end of therapy. HIV plasma viremia was signi®cantly reduced after the third cycle, but returned to pretreatment levels at the end of therapy; we also observed individual¯uctuations of proviral load during therapy, this marker being increased in two out of three patients at the end of therapy. These observations suggest that Rituximab plus CT accelerated the rate of CD4 depletion and of HIV replication in the peripheral blood of HIV-NHL patients and that HA-ART may be able to delay these eects.

Clinical and Experimental Immunology, Jun 1, 1999

This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained f... more This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti-retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL-2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL-2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL-2-treated, but not of the HAART-treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible effects on cytokine production by PBMC, the combined use of HAART + IL-2 was unable to increase the endogenous production of IL-2, but caused an increase of IL-4, IL-13 and interferon-gamma (IFN-γ) and a reduction of monocyte chemoattractant protein-1 (MCP-1) production. These data suggest that, although in this schedule IL-2 has minimal efficacy on CD4 recovery when compared with HAART alone, it produces an increase of ‘naive’ and CD26+CD4 cells and a partial restoration of cytokine production. These data may be used to better define clinical trials aiming to improve the IL-2-dependent immunological reconstitution of HIV-infected subjects.

Microbiologia medica, 1996

Biomedicine & Pharmacotherapy, Jul 1, 2000