Publications by authors named "Cecilia Carbone"

19 Publications

  • Page 1 of 1

Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia.

Hematol Oncol 2020 Dec 29;38(5):754-762. Epub 2020 Sep 29.

Hematology Department, ASST Spedali Civili, Brescia, Italy.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.
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http://dx.doi.org/10.1002/hon.2806DOI Listing
December 2020

Prevalence of the age-related diseases in older patients with acquired thrombotic thrombocytopenic purpura.

Eur J Intern Med 2020 05 20;75:79-83. Epub 2020 Mar 20.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano,Via Pace 9, Milan, 20122, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and Fondazione Luigi Villa, Milan, Italy. Electronic address:

Background: The prevalence of older patients with acquired thrombotic thrombocytopenic purpura (TTP) is increasing. There is scarce information on the prevalence of multimorbidity, polypharmacy and age-related diseases in aging TTP patients. This study aimed to evaluate the prevalence of multimorbidity and polypharmacy in a population of acquired TTP patients aged 65 years or more compared with a group of age-matched controls.

Methods: Acquired TTP patients enrolled in the Milan TTP registry from December 1st 1999 to March 31th 2018 and aged 65 years or more at the date of last follow-up were evaluated. Controls were Italian healthy individuals recruited from 2006 to March 31th 2018 among friends and non-consanguineous relatives of patients tested for thrombophilia screening at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan.

Results: 36 TTP patients and 127 age-matched controls were included. Compared with controls, TTP patients had a higher prevalence of multimorbidity and polypharmacy. They also showed a higher prevalence of autoimmune diseases, osteoporosis and arterial hypertension and were more chronically treated with corticosteroids and antiplatelets for primary cardiovascular prevention. All these results were confirmed after adjusting for sex. Compared with the general elderly population, TTP patients showed a higher prevalence of ischemic heart disease and stroke.

Conclusions: Our findings suggest that a careful comprehensive geriatric assessment of acquired TTP patients is necessary. It is important to look for other autoimmune diseases and such age-related comorbidities as osteoporosis, arterial hypertension, ischemic heart disease and cerebrovascular disease.
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http://dx.doi.org/10.1016/j.ejim.2020.01.024DOI Listing
May 2020

Microbiological contaminations of laboratory mice and rats in conventional facilities in Argentina.

Rev Argent Microbiol 2020 Apr - Jun;52(2):96-100. Epub 2019 Sep 4.

Experimental Animal Laboratory, Faculty of Veterinary Sciences, National University of La Plata, Buenos Aires, Argentina.

Routine microbiological monitoring of rodent colonies in animal facilities is essential to evaluate the health status of the animals used in research studies. In the present study, animals were examined for the presence of selected microbial infections. In order to determine the contamination rates of mice and rats in Argentina, animals from 102 conventional facilities were monitored from 2012 to 2016. The most frequent bacteria isolated were Pseudomonas aeruginosa and Proteus spp. The common parasites identified were Syphacia spp. and Tritrichomonas spp. Serological assays demonstrated the highest prevalence for Mouse hepatitis virus in mice and Sialodacryoadenitis virus in rats. The results indicate that there is a high incidence of infections, so it is suggested that an efficient management system and effective sanitary barriers should be implemented in conventional facilities in Argentina in order to improve sanitary standards.
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http://dx.doi.org/10.1016/j.ram.2019.05.003DOI Listing
September 2019

Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome.

Leuk Lymphoma 2019 12 23;60(12):3044-3050. Epub 2019 May 23.

Hematology, ASST-Spedali Civili, Brescia, Italy.

We evaluated the impact of invasive pulmonary aspergillosis (IPA) on epidemiology and outcome in acute leukemia (AL), analyzing all acute myeloid (AML) and acute lymphoblastic leukemia (ALL) consecutively admitted to our Institution during a 5-year period of observation. Only AML patients received anti-mold prophylaxis. Among 175 AL patients (136 AML/39 ALL), possible and proven/probable IPA were diagnosed in 28 (16%). Frequency of IPA was similar in AML (16.2%) and in ALL (15.4%). Two-year overall survival (OS) was significantly affected by IPA (no IPA: 69.8% vs IPA: 31.7%  = .002). OS was similar in patients with proven/probable (28.2%) and possible IPA (36.4%) ( = .003 and .065, respectively). When censoring patients at transplant, IPA still affected 2-year survival (49.6% vs 79.2%,  = .02), but only proven/probable IPA was associated with lower survival (34.7%,  = .0003). IPA negatively impacts on long-term survival of leukemia patients; antifungal prophylaxis should be adopted also during induction in ALL and in AML beyond induction therapy.
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http://dx.doi.org/10.1080/10428194.2019.1613535DOI Listing
December 2019

Non-aversive photographic measurement method for subcutaneous tumours in nude mice.

Lab Anim 2019 Aug 21;53(4):352-361. Epub 2018 Aug 21.

1 Laboratorio de Animales de Experimentación, Facultad de Cs Veterinarias, UNLP, Argentina.

We have developed a new method for the measurement of subcutaneous tumour volume which consists in taking photographs of mice in their home cages, to refine the standard method of measurement with calipers. We consider this new method to be non-aversive, as it may be more compatible with mice behavioural preferences and, therefore, improve their welfare. Photographs are captured when mice voluntarily go into an acrylic tube containing graph paper that is later used as a scale. Tumour volumes measured with the caliper and the non-aversive photographic method were compared to those obtained by water displacement volume and weight. Behavioural and physiological changes were evaluated to assess animal welfare. Significant differences were found between measurements obtained with the caliper and the non-aversive photographic method, v. the reference volume acquired by water displacement ( < 0.001). Nevertheless, there was good consistency for these measurements when tumours were measured repeatedly, with all Intra-Class Correlation Coefficients above 0.95. Mice on which the non-aversive photographic method was employed were significantly less reluctant to establish contact with the experimenter ( < 0.001) and behaved less anxiously in a modified-Novelty Suppressed Feeding test. Particularly, statistically significant differences were found in connection with the latency to eat an almond piece ( < 0.05), the frequency of grooming ( < 0.001) and the frequency of defecation ( < 0.001). Corticosterone concentration in faeces and blood glucose were determined and no significant changes were found. Therefore, we propose the non-aversive photographic method to measure subcutaneous tumours as a way to refine methodologies in the field of experimental oncology.
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http://dx.doi.org/10.1177/0023677218793450DOI Listing
August 2019

Determination of soyasaponins in Fagioli di Sarconi beans (Phaseolus vulgaris L.) by LC-ESI-FTICR-MS and evaluation of their hypoglycemic activity.

Anal Bioanal Chem 2018 Feb 21;410(5):1561-1569. Epub 2017 Dec 21.

Dipartimento di Scienze, Università degli Studi della Basilicata, via dell'Ateneo Lucano, 10-85100, Potenza, Italy.

Soyasaponins are oleanene-type triterpenoid saponins, naturally occurring in many edible plants that have attracted a great deal of attention for their role in preventing chronic diseases. The aim of this study was to establish the distribution and the content of soyasaponins in 21 ecotypes of Fagioli di Sarconi beans (Phaseolus vulgaris, Leguminosae). High-performance reversed-phase liquid chromatography (RPLC) with positive electrospray ionization (ESI(+)) and Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) in conjunction with infrared multiphoton dissociation (IRMPD) was applied for the unambiguous identification of soyasaponins Ba (m/z 959.5213, [CHO]), Bb (m/z 943.5273, [CHO]), Bd (m/z 957.5122, [CHO]), and Be (m/z 941.5166, [CHO]), which are the only commercially available reference standards. In addition, the several diagnostic product ions generated by IRMPD in the ICR-MS cell allowed us the putative identification of soyasaponins Bb' (m/z 797.4680, [CHO]), αg (m/z 1085.5544, [CHO]), βg (m/z 1069.5600, [CHO]), and γg (m/z 923.5009, [CHO]), establishing thus their membership in the soyasaponin group. Quantitative and semiquantitative analysis of identified soyasaponins were also performed by RPLC-ESI(+) FTICR-MS; the total concentration levels were found ranging from 83.6 ± 9.3 to 767 ± 37 mg/kg. In vitro hypoglycemic outcomes of four soyasaponin standards were evaluated; significant inhibitory activities were obtained with IC values ranging from 1.5 ± 0.1 to 2.3 ± 0.2 μg/mL and 12.0 ± 1.1 to 29.4 ± 1.4 μg/mL for α-glucosidase and α-amylase, respectively. This study represents the first detailed investigation on the antidiabetic activity of bioactive constituents found in Fagioli di Sarconi beans. Graphical abstract The first detailed RPLC-ESI(+) FTICR-MS investigation of the qualitative and semiquantitative profile of soyasaponins, occurring in 21 ecotypes of Fagioli di Sarconi beans (P. vulgaris L.).
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http://dx.doi.org/10.1007/s00216-017-0806-8DOI Listing
February 2018

Indirect ELISA (iELISA) for routine detection of antibodies against Minute Virus of Mice (MVM) in mice colonies.

Rev Argent Microbiol 2017 Jul - Sep;49(3):210-215. Epub 2017 May 24.

Department of Virology, Faculty of Veterinary Sciences National University of La Plata, La Plata, Buenos Aires, Argentina; Scientific Research Commission of Buenos Aires Province (CIC-PBA), Buenos Aires, Argentina.

In this study we developed an indirect ELISA to detect antibodies against Minute Virus of Mice (MVM) using an antigen produced from BHK-21 cells infected with a prototype strain of the virus. The optimal antigen concentration and serum dilutions were established. In order to analyze variability in the laboratory, reproducibility and repeatability within and between plates were determined. Then, a panel of 460 sera from conventional facilities and previously classified as positive or negative by the indirect fluorescent antibody assay was analyzed. The cutoff value was determined by a receiver operating characteristic (ROC) curve. The results of the indirect ELISA were compared with those of the indirect fluorescent antibody assay. The ELISA assay showed 100% sensitivity and 99% specificity. ELISA is a useful tool to be developed in standard virology laboratories and can be used for screening animals faster than the traditional indirect fluorescent antibody assay.
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http://dx.doi.org/10.1016/j.ram.2017.02.005DOI Listing
February 2019

In vitro and in vivo antitumor effects of the VO-chrysin complex on a new three-dimensional osteosarcoma spheroids model and a xenograft tumor in mice.

J Biol Inorg Chem 2016 Dec 1;21(8):1009-1020. Epub 2016 Oct 1.

Cátedra de Bioquímica Patológica, Facultad Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900, La Plata, Argentina.

Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized disease. Vanadium is an ultra-trace element that after being absorbed accumulates in bone. Besides, vanadium compounds have been studied during recent years to be considered as representative of a new class of non-platinum antitumor agents. Moreover, flavonoids are a wide family of polyphenolic compounds that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, the in vitro and in vivo effects of an oxidovanadium(IV) complex with the flavonoid chrysin on the new 3D human osteosarcoma and xenograft osteosarcoma mice models. The pharmacological results show that VOchrys inhibited the cell viability affecting the shape and volume of the spheroids and VOchrys suppressed MG-63 tumor growth in the nude mice without inducing toxicity and side effects. As a whole, the results presented herein demonstrate that the antitumor action of the complex was very promissory on human osteosarcoma models, whereby suggesting that VOchrys is a potentially good candidate for future use in alternative antitumor treatments.
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http://dx.doi.org/10.1007/s00775-016-1397-0DOI Listing
December 2016

Identification of a new protective antigen of Bordetella pertussis.

Vaccine 2011 Nov 30;29(47):8731-9. Epub 2011 Aug 30.

Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina.

Antigenic proteins whose expression is induced under iron starvation, an environmental condition that bacterial pathogens have to face during colonization, might be potential candidates for improved vaccine. By mean of immune proteomics we identified novel antigens of Bordetella pertussis maximally expressed under iron limitation. Among them, Bp1152 (named as IRP1-3) showed a particularly strong reaction with human IgG purified from pooled sera of pertussis-infected individuals. Computer analysis showed IRP1-3 as a dimeric membrane protein potentially involved in iron uptake. Experimental data revealed the surface-exposure of this protein and showed its increase under iron starvation to be independent of bacterial virulence phase. Immunization of mice with the recombinant IRP1-3 resulted in a strong antibody response. These antibodies not only recognized the native protein on bacterial surface but also promote effective bacterial phagocytosis by human PMN, a key protecting activity against this pathogen. Accordingly, IRP1-3 proved protective against B. pertussis infection in mouse model. Expression of IRP1-3 was found conserved among clinical isolates of B. pertussis and positively regulated by iron starvation in these strains. Taken together these results suggest that this protein might be an interesting novel vaccine candidate.
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http://dx.doi.org/10.1016/j.vaccine.2011.07.143DOI Listing
November 2011

Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.

Acta Haematol 2010 6;124(1):19-22. Epub 2010 Jul 6.

Pediatric Hematology Oncology, Department of Pediatrics, University of Padua, Padua, Italy.

Background: Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID).

Aims: To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome.

Methods: 1,251 AA patients from 18 EBMT centers were assessed.

Results: Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA.

Conclusions: Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID.
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http://dx.doi.org/10.1159/000313783DOI Listing
August 2010

Tumor associated stromal cells play a critical role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.

PLoS One 2009 8;4(4):e5119. Epub 2008 Apr 8.

Laboratory of Molecular and Cellular Therapy, Instituto Leloir, IIBBA-CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.

The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd) is still limited by the inefficient infection of the tumor mass. Since tumor growth is essentially the result of a continuous cross-talk between malignant and tumor-associated stromal cells, targeting both cell compartments may profoundly influence viral efficacy. Therefore, we developed SPARC promoter-based CRAds since the SPARC gene is expressed both in malignant cells and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes Simplex thymidine kinase gene (Ad-F512 and Ad(I)-F512-TK, respectively) exerted a lytic effect on a panel of human melanoma cells expressing SPARC; but they were completely attenuated in normal cells of different origins, including fresh melanocytes, regardless of whether cells expressed or not SPARC. Interestingly, both CRAds displayed cytotoxic activity on SPARC positive-transformed human microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were therapeutically effective on SPARC positive-human melanoma tumors growing in nude mice but exhibited restricted efficacy in the presence of co-administered HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced the oncolytic efficacy of Ad(I)-F512-TK on SPARC-negative MIA PaCa-2 pancreatic cancer cells in vivo. Moreover, conditioned media produced by stromal cells pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on pancreatic cancer cells, but not on melanoma cells. The whole data indicate that stromal cells might play an important role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663040PMC
June 2009

A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models.

Clin Cancer Res 2009 May 31;15(9):3037-49. Epub 2009 Mar 31.

Laboratorio de Terapia Molecular y Celular, Instituto Leloir and Instituto de Investigaciones Bioquimicas de Buenos Aires, Argentina.

Purpose: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC).

Experimental Design: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo.

Results: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs.

Conclusions: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1161DOI Listing
May 2009

Evaluation of an indirect enzyme-linked immunosorbent assay for routine screening of Theiler's murine encephalomyelitis virus antibodies in mice colonies.

J Vet Diagn Invest 2008 Nov;20(6):789-91

Department of Virology, Faculty of Veterinary Sciences, National University of La Plata, 1900 La Plata, Buenos Aires, Argentina.

The current study demonstrates the ability of an indirect enzyme-linked immunosorbent assay (iELISA) to detect antibodies against Theiler's murine encephalomyelitis virus in mice colonies. The antigen was produced from infected baby hamster kidney (BHK)-21 cells and treated with 1% Nonidet P40 in saline buffer. Control antigen was prepared following the same procedure using uninfected BHK-21 cells. The optimal antigen and serum dilutions were established. The reaction was revealed using an anti-mouse-horseradish peroxidase conjugate and 2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid). Optimized iELISA was validated by detection of antibodies in known positive and negative serum samples before testing the samples of unknown status. Performance of the iELISA was compared with the indirect fluorescent antibody test, and the cutoff value was determined by receiver operating curve. Indirect ELISA showed 100% sensitivity, 99.38% specificity, and 97.78% predictive positive value. The antigen used is easy to produce, and no special equipment is required. The iELISA developed is simple and provides a rapid and less costly tool for diagnosis and research.
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http://dx.doi.org/10.1177/104063870802000612DOI Listing
November 2008

SPARC endogenous level, rather than fibroblast-produced SPARC or stroma reorganization induced by SPARC, is responsible for melanoma cell growth.

J Invest Dermatol 2007 Nov 12;127(11):2618-28. Epub 2007 Jul 12.

Laboratory of Molecular and Cellular Therapy, Leloir Institute-CONICET-University of Buenos Aires, Patricias Argentinas 435, (C1405BWE), Buenos Aires, Argentina.

SPARC (secreted protein acidic and rich in cysteine) is a matricellular protein whose overexpression in malignant or tumor-stromal cells is often associated with increased aggressiveness and bad prognosis in a wide range of human cancer types, particularly melanoma. We established the impact that changes in the level of SPARC produced by malignant cells and neighboring stromal cells have on melanoma growth. Melanoma cell growth in monolayer was only slightly affected by changes in SPARC levels. However, melanoma growth in spheroids was strongly inhibited upon SPARC hyperexpression and conversely enhanced when SPARC expression was downregulated. Interestingly, SPARC overexpression in neighboring fibroblasts had no effect on spheroid growth irrespective of SPARC levels expressed by the melanoma cells, themselves. Downregulation of SPARC expression in melanoma cells induced their rejection in vivo through a mechanism mediated exclusively by host polymorphonuclear cells. On the other hand, SPARC hyperexpression enhanced vascular density, collagen deposition, and fibroblast recruitment in the surrounding stroma without affecting melanoma growth. In agreement with the in vitro data, overexpression of SPARC in co-injected fibroblasts did not affect melanoma growth in vivo. All the data indicate that melanoma growth is not subject to regulation by exogenous SPARC, nor by stromal organization, but only by SPARC levels produced by the malignant cells themselves.
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http://dx.doi.org/10.1038/sj.jid.5700962DOI Listing
November 2007

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.

Blood 2007 Feb 31;109(4):1401-7. Epub 2006 Oct 31.

Dipartimento di Biotecnologia Cellulari ed Ematologia, Università degli Studi di Roma La Sapienza, and Divisione di Ematologia, Ospedale pediatrico Bambino Gesù, Rome, Italy.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.
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http://dx.doi.org/10.1182/blood-2005-12-015222DOI Listing
February 2007

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.

Blood 2007 Feb 31;109(4):1401-7. Epub 2006 Oct 31.

Dipartimento di Biotecnologia Cellulari ed Ematologia, Università degli Studi di Roma La Sapienza, and Divisione di Ematologia, Ospedale pediatrico Bambino Gesù, Rome, Italy.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.
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http://dx.doi.org/10.1182/blood-2005-12-015222DOI Listing
February 2007

[Pasteurella pneumotropica produces regression of human tumors transplanted in immunodeficiency mice].

Medicina (B Aires) 2006 ;66(3):242-4

Cátedra de Animales de Laboratorio y Bioterio, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, Argentina.

The technique of human tumor cell line transplantation in immunodeficient mice is used worldwide as a model for cancer research. In accordance with international recommendations, animals used in biomedical research should be free of microorganisms which can interfere in experimental results; including Pasteurella pneumotropica. The object of this study was to evaluate the interference produced by P. pneumotropica in the human adenocarcinoma cell line A549 transplanted in N:NIH(S)-nu mice. A total of 40 mice divided into 4 groups of 10 animals each was used to perform this study. Group 1: inoculated with the cell line; group 2, with the bacteria; group 3, with the cell line and the bacteria; group 4, as control with no inoculations. Significant differences were observed in tumor growth in groups 1 and 3, infected and not infected with P. pneumotropica. Although this microorganism is non lethal and only opportunistic, the infected animals are to be considered not suitable to be transplanted with the tumor cell line A549 for experimental studies since these bacteria interfere with tumor growth. However, the fact that a growing tumor regresses in the presence of the bacteria is an interesting observation which deserves further exploration in order to elucidate the mechanism involved.
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March 2007

Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity.

Cancer Res 2005 Jun;65(12):5123-32

Leloir Institute, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.

The expression of secreted protein acidic and rich in cysteine (SPARC) has been associated with the malignant progression of different types of human cancer. SPARC was associated with tumor cell capacity to migrate and invade, although its precise role in tumor progression is still elusive. In the present study, we show that SPARC produced by melanoma cells modulates the antitumor activity of polymorphonuclear leukocytes (PMN). Administration to nude mice of human melanoma cells in which SPARC expression was transiently or stably knocked down by antisense RNA (SPARC-sup cells) promoted PMN recruitment and obliterated tumor growth even when SPARC-sup cells accounted for only 10% of injected malignant cells. In addition, SPARC-sup cells stimulated the in vitro migration and triggered the antimelanoma cytotoxic capacity of human PMN, an effect that was reverted in the presence of SPARC purified from melanoma cells or by reexpressing SPARC in SPARC-sup cells. Leukotrienes, interleukin 8, and growth-related oncogene, in combination with Fas ligand and interleukin 1, mediated SPARC effects. These data indicate that SPARC plays an essential role in tumor evasion from immune surveillance through the inhibition of the antitumor PMN activity.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-1102DOI Listing
June 2005

Role of lipids in the early developmental stages of experimental immune diabetes induced by multiple low-dose streptozotocin.

J Appl Physiol (1985) 2005 Mar;98(3):1064-9

School of Biochemistry, University of Litoral, Ciudad Universitaria Paraje El Pozo, CC 242, 3000 Santa Fe, Argentina.

The present work examines the role of lipids in the development of the Type 1 diabetes induced by the administration of multiple low doses of streptozotocin (STZ) in C57BL/6J mice. The study was performed before and after the onset of clear hyperglycemia, and the results were as follows. First, 6 days after the first dose of STZ, while plasma glucose and insulin levels remained similar to those observed in the control mice, plasma free fatty acid (FFA) levels were significantly increased (P < 0.05). At that time, a marked increase of triglyceride content in gastronemius muscle was accompanied by a diminished activity of pyruvate dehydrogenase complex, suggesting an impaired glucose oxidation. Furthermore, a decrease of both triglyceride content and lipoprotein lipase activity was observed in the epididymal fat tissue. Second, 12 days after the first injection of STZ, hyperglycemia was accompanied by hypertriglyceridemia, a more pronounced increase of plasma FFA, and a significant (P < 0.05) reduction of insulinemia. At this time, both the adipose tissue and the gastrocnemius muscle showed a further deterioration of all parameters mentioned after 6 days. Moreover, in the gastrocnemius muscle, an impaired nonoxidative pathway of glucose metabolism was observed [significant reduction (P < 0.05) of glycogen mass, glucose-6-phosphate content, and glycogen synthase activities] at this time point. Finally, the data suggest for the first time that, in mice, Type 1 diabetes induced by multiple low doses of STZ and enhanced lipolysis of fat pads leads to an increase in the availability of plasma FFA, which seems to play a role in the early steps of diabetes evolution.
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http://dx.doi.org/10.1152/japplphysiol.00559.2004DOI Listing
March 2005