Publications by authors named "Leandra Naira Zambelli Ramalho"

53 Publications

Cigarette smoke exposure causes systemic and autonomic cardiocirculatory changes in rats depending on the daily exposure dose.

Life Sci 2021 Apr 20;277:119498. Epub 2021 Apr 20.

Medical School, University of Ribeirão Preto, Ribeirão Preto, SP, Brazil. Electronic address:

Aims: To evaluate the systemic changes and autonomic cardiocirculatory control of awaken rats chronically exposed to the cigarette smoke (CS) of 1 or 2 cigarettes/day.

Main Methods: Rats were exposed to clean air (control) or cigarette smoke of 1 (CS1) or 2 (CS2) cigarettes/animal/day for 30 days. Then, arterial pressure (AP) and heart rate (HR) were recorded in conscious rats to assess spontaneous baroreflex sensitivity and HR and AP variabilities. Evoked baroreflex and cardiac autonomic tone were evaluated by vasoactive drugs and autonomic blockers, respectively. In another group, ventilatory and cardiovascular parameters were recorded under hypoxia and hypercapnia stimulus. At the end of protocols, heart, lung, kidneys and liver were collected for histological analysis.

Key Findings: Rats exposed to CS showed morphological changes, being more evident in the CS2 group. Also, less weight gain and cardiac hypertrophy were prominent in CS2 rats. Basal AP and HR, spontaneous baroreflex sensitivity and cardiovascular variabilities were similar among groups. CS exposure progressively blunted the bradycardia response to phenylephrine (-2.2 ± 0.1 vs. -1.7 ± 0.2 vs. -1.5 ± 0.2) while the tachycardia response to sodium nitroprusside was slightly increased compared to control. Vagal tone was not affected by CS, but CS2 rats exhibited higher sympathetic tone (-25 ± 4 vs. -28 ± 4 vs. -56 ± 9) and lower intrinsic HR (411 ± 4 vs. 420 ± 8 vs. 390 ± 6). Exposure to CS of 2 cigarettes also exacerbated the reflex cardiovascular and ventilatory responses to hypoxia and hypercapnia.

Significance: CS exposure for 30 days promoted systemic changes and autonomic cardiocirculatory dysfunction in rats depending on the daily exposure dose.
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http://dx.doi.org/10.1016/j.lfs.2021.119498DOI Listing
April 2021

Ex vivo model of human skin (hOSEC) for assessing the dermatokinetics of the anti-melanoma drug Dacarbazine.

Eur J Pharm Sci 2021 May 19;160:105769. Epub 2021 Feb 19.

Division of Dermatology - Wound Healing & Hansen's Disease Lab, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address:

Alternative models to replace animals in experimental studies remain a challenge in testing the effectiveness of dermatologic and cosmetic drugs. We proposed a model of human organotypic skin explant culture (hOSEC) to assess the profile of cutaneous drug skin distribution, adopting dacarbazine as a model, and respective new methodologies for dermatokinetic analysis. The viability tests were evaluated in primary keratinocytes and fibroblasts, and skin by MTT and TTC assays, respectively. Then, dacarbazine was applied to the culture medium, and the hOSEC method was applied to verify the dynamics of skin distribution of dacarbazine and determine its dermatokinetic profile. The results of cell and tissue viability showed that both were considered viable. The dermatokinetic results indicated that dacarbazine can be absorbed through the skin, reaching a concentration of 36.36 µg/mL (18,18%) of the initial dose (200 µg/mL) after 12 h in culture. Histological data showed that the skin maintained its structure throughout the tested time that the hOSEC method was applied. No apoptotic cells were observed in the epidermal and dermal layers. No visible changes in the dermo-epidermal junction and no inflammatory processes with the recruitment of defense cells were observed. Hence, these findings suggest that the hOSEC concept as an alternative ex vivo model for assessing the dynamics of skin distribution of drugs, such as dacarbazine, and determining their respective dermatokinetic profiles.
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http://dx.doi.org/10.1016/j.ejps.2021.105769DOI Listing
May 2021

HLA-E gene polymorphisms in chronic hepatitis C: Impact on HLA-E liver expression and disease severity.

Hum Immunol 2021 Mar 15;82(3):177-185. Epub 2021 Feb 15.

Immunology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil.

Hepatitis C virus usually produces chronic infection and liver damage. Considering that: i) the human leukocyte antigen-E (HLA-E) molecule may modulate the immune response, and ii) little is known about the role of HLA-E gene variability on chronic hepatitis C, we studied the impact of HLA-E polymorphisms on the magnitude of HLA-E liver expression and severity of hepatitis C. HLA-E variability was evaluated in terms of: i) single nucleotide polymorphism (SNP) alleles and genotypes along the gene (beginning of the promoter region, coding region and 3'UTR), and ii) ensemble of SNPs that defines the coding region alleles, considered individually or as genotypes. The comparisons of the HLA-E variation sites between patients and controls revealed no significant results. The HLA-E + 424 T > C (rs1059510), +756 G > A (rs1264457) and + 3777 G > A (rs1059655) variation sites and the HLA-E*01:01:01:01 and HLA-E*01:03:02:01 alleles, considered at single or double doses, were associated with the magnitude of HLA-E liver expression in Kupfer cell, steatosis, inflammatory activity and liver fibrosis. Although these associations were lost after corrections for multiple comparisons, these variable sites may propitiate biological clues for the understanding of the mechanisms associated with hepatitis C severity.
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http://dx.doi.org/10.1016/j.humimm.2021.01.018DOI Listing
March 2021

Durometry as an alternative tool to the modified Rodnan's skin score in the assessment of diffuse systemic sclerosis patients: a cross-sectional study.

Adv Rheumatol 2020 09 21;60(1):48. Epub 2020 Sep 21.

Ribeirão Preto Nursing School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, 14049-900, Brazil.

Background: The reproducibility and reliability of the modified Rodnan's Skin Score (mRSS) are debated due to investigator-related subjectivity. Here, we evaluate if durometry correlates with mRSS in patients with diffuse systemic sclerosis (SSc).

Methods: This cross-sectional study was conducted from December 2018 to June 2019, including 58 diffuse SSc patients. Two certified researchers, blind to each other's scores, performed the mRSS, followed by durometry at 17 predefined skin sites. For durometry and mRSS, individual scores per skin site were registered. Durometry and mRSS results measured by each researcher, as well as scores from different researchers, were compared. Skin thickness measurements from forearm skin biopsies were available in a subset of the patients, for comparisons. Statistical analyses included Cohen's Kappa Coefficient, Intraclass Correlation Coefficient, Kendall's Coefficient and Spearman's test.

Results: Mean (standard deviation, SD) patient age was 44.8 (12.9) years, and 88% were female. Inter-rater agreement varied from 0.88 to 0.99 (Intraclass correlation coefficient) for durometry, and 0.54 to 0.79 (Cohen's Kappa coefficient) for mRSS, according to the specific evaluated sites. When data were compared with skin thickness assessed in forearm biopsies, durometry correlated better with skin thickness than mRSS.

Conclusion: Durometry may be considered as an alternative method to quantify skin involvement in patients with diffuse SSc. The strong inter-rater agreement suggests that the method may be useful for the assessment of patients by multiple researchers, as in clinical trials.
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http://dx.doi.org/10.1186/s42358-020-00152-6DOI Listing
September 2020

Increased HLA-G Expression in Tissue-Infiltrating Cells in Inflammatory Bowel Diseases.

Dig Dis Sci 2020 Aug 24. Epub 2020 Aug 24.

Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.

Background: Since HLA-G is an immune checkpoint molecule and since Crohn's disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension.

Methods: HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA.

Results: HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P < 0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P = 0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P = 0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P < 0.0001) than in controls, but no difference was observed between diseases.

Conclusions: Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.
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http://dx.doi.org/10.1007/s10620-020-06561-3DOI Listing
August 2020

HLA-G liver expression and HLA-G extended haplotypes are associated with chronic hepatitis C in HIV-negative and HIV-coinfected patients.

Clin Immunol 2020 08 27;217:108482. Epub 2020 May 27.

Commissariat à l'Energie Atomique et aux Energies Alternatives, Direction de la Recherche Fondamentale, Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris, France; Université Paris-Diderot, UMR 976 HIPI, Institut de Recherche Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris, France. Electronic address:

Chronic hepatitis C virus (HCV) infection induces liver damage and the HCV/Human Immunodeficiency Virus (HIV)-coinfection may further contribute to its progression. The HLA-G molecule inhibits innate and adaptive immunity and may be deleterious for chronically virus-infected cells. Thus we studied 204 HCV-mono-infected patients, 142 HCV/HIV-coinfected patients, 104 HIV-mono-infected patients and 163 healthy subjects. HLA-G liver expression was similarly induced in HCV and HCV/HIV specimens, increasing with advanced fibrosis and necroinflammatory activity, and with increased levels of liver function-related enzymes. Plasma soluble HLA-G (sHLA-G) levels were higher in HCV/HIV patients compared to HCV, HIV and to healthy individuals. sHLA-G continued to be higher in coinfected patients even after stratification of samples according to degree of liver fibrosis and necroinflammatory activity when compared to mono-infected patients. Some HLA-G gene haplotypes differentiated patient groups and presented few associations with liver and plasma HLA-G expression. HLA-G thus may help to distinguish patient groups.
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http://dx.doi.org/10.1016/j.clim.2020.108482DOI Listing
August 2020

Human Antigen Leucocyte (HLA)-G and HLA-E are differentially expressed in pancreatic disorders.

Hum Immunol 2019 Nov 25;80(11):948-954. Epub 2019 Sep 25.

Postgraduate Program of Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil; Department of Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil. Electronic address:

Background: Little information is available regarding the expression of the immunomodulatory Human Leukocyte Antigen (HLA)-G and -E molecules in pancreatic disorders.

Aim: To analyze HLA-G and -E expression in specimens of alcoholic chronic pancreatitis (ACP), idiopathic chronic pancreatitis (ICP), type 1 (T1D) and type 2 diabetes (T2D) and in histologically normal pancreas (HNP).

Methods: HLA-G and -E expression (ACP = 30, ICP = 10, T1D = 10, T2D = 30 and HNP = 20) was evaluated by immunohistochemistry in three different areas (acini, islets and inflammatory infiltrate).

Results: Acini and islets from HNP specimens exhibited higher HLA-G and -E expression compared to corresponding areas from all other patient groups. In inflammatory infiltrate, HLA-G and -E expression was observed only among the pancreatic disorders. We observed higher HLA-G and -E expression in acini from T2D compared to ACP, as well as higher HLA-G expression compared to ICP.

Conclusion: The decreased expression of HLA-G and -E in islets and acini together with the expression of these molecules in the inflammatory infiltrating cells were shared features among chronic inflammatory and autoimmune pancreatic disorders evaluated in this study, possibly reflecting tissue damage.
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http://dx.doi.org/10.1016/j.humimm.2019.09.002DOI Listing
November 2019

Looking beyond the skin: Cutaneous and systemic oxidative stress in UVB-induced squamous cell carcinoma in hairless mice.

J Photochem Photobiol B 2019 Jun 16;195:17-26. Epub 2019 Apr 16.

Laboratory of Molecular Pathology, Londrina State University (UEL), Londrina, Paraná, Brazil, UEL, Rod. Celso Garcia Cid, PR-445, km 380, 86051-990 Londrina, Paraná, Brazil. Electronic address:

Cumulative ultraviolet (UV) exposure is associated with squamous skin cell carcinoma. UV radiation induces oxidative modifications in biomolecules of the skin leading to photocarcinogenesis. Indeed, the cyclobutene pyrimidine dimers and other dimers formed by photoaddition between carbon-carbon bonds also have an important role in the initiation process. However, information on the systemic redox status during these processes is scarce. Thus, we investigated the systemic redox profile in UVB-induced squamous cell carcinoma in mice. Female hairless mice were exposed to UVB radiation (cumulative dose = 17.1 J/cm). The dorsal skin of these mice developed actinic keratosis (AK) and squamous cell carcinoma (SCC) and presented increased levels of oxidative and nitrosative stress biomarkers (4-hydroxy-2-nonenal and 3-nitrotyrosine), and decreased antioxidant defenses. Systemically, we observed the consumption of plasmatic antioxidant defenses and increased levels of advanced oxidized protein products (AOPP), an oxidative stress product derived from systemic inflammatory response. Taken together, our results indicate that UVB chronic irradiation leads not only to adjacent and tumoral oxidative stress in the skin, but it systemically is reflected through the blood. These new findings clarify some aspects of the pathogenesis of SCC and should assist in formulating better chemoprevention strategies, while avoiding additional primary SCC development and metastasis.
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http://dx.doi.org/10.1016/j.jphotobiol.2019.04.007DOI Listing
June 2019

Exposure to acetaminophen impairs vasodilation, increases oxidative stress and changes arterial morphology of rats.

Arch Toxicol 2019 07 24;93(7):1955-1964. Epub 2019 Apr 24.

Laboratory of Pharmacology, Faculty of Pharmacy, Federal University of Goias, Av. Universitária com 1a Avenida s/n, Setor Universitário, Goiânia, GO, CEP 74605-220, Brazil.

Acetaminophen (APAP) is one of the most widely consumed drugs in the world. Studies have shown renal and hepatic damage as the direct result of high oxidative stress induced by APAP. Since the cardiovascular system is sensitive to oxidative stress and literature describes increased cardiovascular dysfunction in APAP consumers, this work aimed to evaluate harmful effects of APAP on the vascular system. Rats were exposed to APAP (400 mg/kg/day in drinking water) for 14 days. Plasma and aortas were collected and stored in - 80 °C and a selection of arteries was prepared for isometric tension recordings, morphological, immunohistochemical and protein expression analysis. The APAP-treated group presented increased transaminases (ALT/AST) and malondialdehyde levels in the plasma compared to controls. Lipid peroxidation, glutathione reductase and superoxide dismutase levels were increased in the plasma and arteries of the APAP group. Nevertheless, glutathione level was reduced as compared to control group. The vasodilation response to acetylcholine and sodium nitroprusside (0.1 nM to 10 µM) was also impaired after APAP treatment; however, the vascular relaxation was restored after treatment with vitamin C (100 µM). Arteries from the APAP group presented reduced wall thickness, collagen deposition, elastic fibers and increased immunoreactivity to nitrotyrosine. eNOS and sGC protein expression remained unchanged and were at similar levels as controls. These findings showed higher oxidative stress and impaired vasodilation in rats exposed to APAP. Furthermore, arteries presented reduced cell layers, collagen, elastin deposition and significantly increased immunoreactivity to nitrotyrosine after APAP treatment.
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http://dx.doi.org/10.1007/s00204-019-02463-0DOI Listing
July 2019

A novel type of C11orf95-LOC-RELA fusion in a grade II supratentorial ependymoma: report of a case with literature review.

Childs Nerv Syst 2019 04 10;35(4):689-694. Epub 2019 Jan 10.

Departments of Pediatrics, Ribeirão Preto Medical of School, University of São Paulo, Ribeirão Preto, SP, Brazil.

Background: Ependymoma (EPN) is the third most common central nervous system tumor in childhood. Recent advances in the molecular classification of EPN revealed a supratentorial (ST) ependymoma subgroup characterized by C11orf95-RELA fusion.

Case Report: We describe a novel RELA-fusion composed by a chimeric transcript C11orf95-LOC-RELA in a supratentorial WHO grade II EPN occurring in a 4-year-old child. Metastatic loci at the brain, leptomeningeal involvement, and pulmonary nodules were identified at tumor recurrence. The child eventually died before 1 year after recurrence.

Conclusion: This index case showed aggressive behavior and nuclear accumulation of p65/RELA.
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http://dx.doi.org/10.1007/s00381-018-04028-5DOI Listing
April 2019

Curcuma supplementation in high-fat-fed C57BL/6 mice: no beneficial effect on lipid and glucose profile or prevention of weight gain.

Eur J Nutr 2020 Feb 2;59(1):93-102. Epub 2019 Jan 2.

Division of Nutrology, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil.

Purpose: This experimental study investigated the effects of curcuma supplementation on weight gain, Body Adiposity Index, glucose and lipid profile, and liver and pancreas histology in C57BL/6 mice fed with a high-fat diet.

Methods: 40 animals were separated into four groups: standard diet (SD), standard diet plus curcuma (SD + C), high-fat diet (HFD), and high-fat diet plus curcuma (HFD + C). Curcuma dose was 8 mg/animal/day. Histological and biochemical analyses were performed at the end of the experimental period.

Results: Curcuma prevented weight gain, despite a higher food intake, and increased brown adipose tissue weight only in mice receiving standard diet. However, these changes were not observed in HFD + C group. The groups that received curcuma (SD + C and HFD + C) showed a pancreas with diffuse macro- and microgoticular steatosis.

Conclusions: Curcuma supplementation did not prevent weight gain or improved glucose and lipid profile in mice receiving high-fat diet. Furthermore, there was evidence of possible curcuma toxicity in the pancreas of C57BL/6 mice. The implications of these findings on humans still need to be investigated.
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http://dx.doi.org/10.1007/s00394-018-1887-7DOI Listing
February 2020

P16INK4a expression in patients with penile cancer.

PLoS One 2018 12;13(10):e0205350. Epub 2018 Oct 12.

Department of Pathology, Ribeirão Preto Medical of School, University of São Paulo (USP), Ribeirao Preto, Brazil.

Background: Infection with human papillomavirus (HPV) is reported to be present in 30-50% of penile cancer cases. The immunohistochemical test for p16INK4a is used as an indicator of the presence of HPV and as a prognostic marker for squamous cell carcinomas in various sites. However, the role of this marker in penile carcinoma has not yet been completely elucidated. The aim of this study was to analyze whether the expression of p16INK4a is associated with the presence of HPV, histological parameters, and survival in penile cancer.

Methods: A study was conducted from 2014 to 2016 that included 55 patients with penile carcinoma. HPV DNA was detected through PCR using fresh tumor tissue, and immunohistochemistry was performed for analysis of p16INK4a protein using paraffin-embedded tissue. Evaluation of histological parameters was performed following complete embedding of the tumor tissue in paraffin.

Results: HPV DNA (low-risk and high-risk genotypes) was found in 49 (89.1%) cases, and 46/49 (93.9%) showed high-oncogenic risk HPV (HR-HPV). Of the 22 cases positive for p16INK4a, HR-HPV DNA was present in 21 (95.5%) (p = 0.032). Regarding histological parameters, p16INK4a and HR-HPV were significantly associated only with tumor subtype (p = 0.036 and p = 0.032, respectively); all carcinomas with basaloid characteristics were positive for p16INK4a. Although HPV+ patients had a higher disease-free survival (p <0.001), p16INK4a expression was not associated with patient survival.

Conclusions: Our study, using fresh tissue samples, showed the highest incidence of HPV compared to that observed in the literature. Expression of the p16INK4a protein was significantly associated with the presence of HR-HPV and this expression may serve as a marker for the presence of the virus. The p16INK4a protein was not associated with the histological prognostic parameters, with the exception of tumor subtype, nor with patient survival. In the results, we showed that the objective of the present study was reached.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205350PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185731PMC
March 2019

The comparative efficacy of renin-angiotensin system blockers in schistosomal hepatic fibrosis.

Exp Parasitol 2018 Aug 8;191:9-18. Epub 2018 Jun 8.

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Brazil. Electronic address:

Schistosomiasis mansoni is involved in hepatic fibrogenesis and portal hypertension. Previous studies proved that blockade of some components of the renin-angiotensin system (RAS) reduce liver fibrogenesis. However, the effects of inhibition of early stages of RAS pathway in schistosomal fibrosis have not been studied yet. Thus, the aim of this study was to compare the role of different antihypertensive drugs on hepatic fibrosis in murine schistosomiasis. BALB/c mice (n = 50) weighing 20g were subjected to inoculation of 50 cercariae and submitted to different treatments: aliskiren, 50 mg/kg (n = 10); bradykinin, 2 μg/kg (n = 5); losartan, 10 mg/kg (n = 10); lisinopril 10 mg/kg (n = 5) and control, proportional volume vehicle (n = 5); daily for 14 weeks. Six animals were not subjected to cercariae inoculation or any type of treatment. Ultrasound, histological, immunohistochemical and proteomic analyzes were performed to evaluate markers associated with hepatic fibrogenesis. The hepatic areas stained with Sirius red and thenumber of cells marked by α-SMA in animals treated with aliskiren, bradykinin, lisinopril and losartan were diminished when compared to control group, demonstrating reduced hepatic fibrosis after RAS blockade. These results were reinforced by ultrasonography analysis and protein expression of TGFβ. These findings demonstrated the effect of RAS inhibition on hepatic fibrosis in murine schistosomiasis, with the most evident results being observed in the losartan and aliskiren treated groups. The main mechanisms underlying this process appear to involve anti-fibrogenic activity through the inhibition of collagen and TGFβ synthesis.
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http://dx.doi.org/10.1016/j.exppara.2018.05.004DOI Listing
August 2018

Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally?

BMC Urol 2018 May 29;18(1):50. Epub 2018 May 29.

University Hospital of Federal University of Maranhão, Barão de Itapari Street, Centro, São Luís, Brazil.

Background: The objectives of this study were to determine the minimum incidence of penile cancer in the poorest Brazilian state, and to describe the epidemiologic and clinical characteristics of patients diagnosed with the disease.

Methods: A retrospective study of 392 patients diagnosed with penile cancer in the three most important referral center in the state was conducted during 2004-2014.

Results: The age-standardized incidence was 6.15 per 100,000 and the crude annual incidence was 1.18 per 100,000. More than half (61.1%) of the tumors were histological grades 2 and 3, and 66.4% of tumors were classified as at least stage T2. The average age of patients was 58.6 ± 15.7 years (range, 18 to 103 years), with 20.8% of patients ≤40 years of age at diagnosis. The vast majority underwent penectomy (93%). Only 41.8% underwent lymphadenectomy, 58 patients (14.8%) received chemotherapy, and 54 patients (13.8%) received radiotherapy. Stage 3/4 and vascular invasion were statically significant at disease-free survival analysis.

Conclusion: The state of Maranhão has the highest incidence of penile cancer in Brazil and globally. Tumors are locally advanced and at the time of diagnosis, and there is a high frequency among young individuals. Patients have a low socioeconomic status, making it difficult to complete treatment and receive appropriate follow-up.
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http://dx.doi.org/10.1186/s12894-018-0365-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975591PMC
May 2018

The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection.

Hum Immunol 2017 Feb 29;78(2):166-171. Epub 2016 Dec 29.

Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil.

Background And Aims: HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection.

Methods: We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers.

Results: The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients.

Conclusions: Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses.
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http://dx.doi.org/10.1016/j.humimm.2016.12.011DOI Listing
February 2017

Mitogen activated protein kinases SakA(HOG1) and MpkC collaborate for Aspergillus fumigatus virulence.

Mol Microbiol 2016 06 23;100(5):841-59. Epub 2016 Mar 23.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.

Here, we investigated which stress responses were influenced by the MpkC and SakA mitogen-activated protein kinases of the high-osmolarity glycerol (HOG) pathway in the fungal pathogen Aspergillus fumigatus. The ΔsakA and the double ΔmpkC ΔsakA mutants were more sensitive to osmotic and oxidative stresses, and to cell wall damaging agents. Both MpkC::GFP and SakA::GFP translocated to the nucleus upon osmotic stress and cell wall damage, with SakA::GFP showing a quicker response. The phosphorylation state of MpkA was determined post exposure to high concentrations of congo red and Sorbitol. In the wild-type strain, MpkA phosphorylation levels progressively increased in both treatments. In contrast, the ΔsakA mutant had reduced MpkA phosphorylation, and surprisingly, the double ΔmpkC ΔsakA had no detectable MpkA phosphorylation. A. fumigatus ΔsakA and ΔmpkC were virulent in mouse survival experiments, but they had a 40% reduction in fungal burden. In contrast, the ΔmpkC ΔsakA double mutant showed highly attenuated virulence, with approximately 50% mice surviving and a 75% reduction in fungal burden. We propose that both cell wall integrity (CWI) and HOG pathways collaborate, and that MpkC could act by modulating SakA activity upon exposure to several types of stresses and during CW biosynthesis.
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http://dx.doi.org/10.1111/mmi.13354DOI Listing
June 2016

Genetic background affects the expansion of macrophage subsets in the lungs of Mycobacterium tuberculosis-infected hosts.

Immunology 2016 May;148(1):102-13

Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

M1 macrophages are more effective in the induction of the inflammatory response and clearance of Mycobacterium tuberculosis than M2 macrophages. Infected C57BL/6 mice generate a stronger cellular immune response compared with BALB/c mice. We hypothesized that infected C57BL/6 mice would exhibit a higher frequency and function of M1 macrophages than infected BALB/c mice. Our findings show a higher ratio of macrophages to M2 macrophages in the lungs of chronically infected C57BL/6 mice compared with BALB/c mice. However, there was no difference in the functional ability of M1 and M2 macrophages for the two strains in vitro. In vivo, a deleterious role for M2 macrophages was confirmed by M2 cell transfer, which rendered the infected C57BL/6, but not the BALB/c mice, more susceptible and resulted in mild lung inflammation compared with C57BL/6 mice that did not undergo cell transfer. M1 cell transfer induced a higher inflammatory response, although not protective, in infected BALB/c mice compared with their counterparts that did not undergo cell transfer. These findings demonstrate that an inflammation mediated by M1 macrophages may not induce bacterial tolerance because protection depends on the host genetic background, which drives the magnitude of the inflammatory response against M. tuberculosis in the pulmonary microenvironment. The contribution of our findings is that although M1 macrophage is an effector leucocyte with microbicidal machinery, its dominant role depends on the balance of M1 and M2 subsets, which is driven by the host genetic background.
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http://dx.doi.org/10.1111/imm.12591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819146PMC
May 2016

Infliximab-associated fulminant hepatic failure in ulcerative colitis: a case report.

J Med Case Rep 2015 Oct 30;9:249. Epub 2015 Oct 30.

Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.

Introduction: Infliximab, an antibody against tumor necrosis factor alpha, is used to treat inflammatory bowel disease and has well-established efficacy and proven safety. Complications of this treatment are related to immunosuppression and include higher risk of serious infections and malignant neoplasia. Although extremely rare, fulminant liver damage related to infliximab therapy has been reported.

Case Presentation: We present the case of a 38-year-old Afro-Brazilian woman with refractory ulcerative colitis who was started on infliximab. She had no previous history of liver disease, alcohol abuse, or infection. After the fifth dose of the medication, drug-induced liver injury was diagnosed. Treatment was discontinued but our patient's condition was aggravated by severe cholestasis and grade III/IV encephalopathy, requiring liver transplantation.

Conclusion: Drug-induced liver injury is an uncommon complication of infliximab. Current consensus recommends screening for liver dysfunction prior to and during therapy. This case emphasizes the need for vigilance and highlights a rare and potentially lethal complication.
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http://dx.doi.org/10.1186/s13256-015-0730-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627392PMC
October 2015

Increased nitric oxide levels in cerebellum of cachectic rats with Walker 256 solid tumor.

Folia Neuropathol 2015 ;53(2):139-46

Alessandra L. Cecchini, Departamento de Patologia Geral - Centro de Ciencias Biologicas, Universidade Estadual de Londrina, Laboratorio de Patologia Molecular CEP 86051-990 Londrina, Brazil, phone: (+55-43) 3371-4529, fax: (+55-43) 3371-4267, e-mail:

In cancer cachexia, the role of nitric oxide (NO) in the central nervous system remains unclear. Cerebellar degeneration has been reported in cancer patients, but the participation of NO has not been studied. Thus, this study investigated the mechanism of oxidative cerebellar injury in a time-course cancer cachexia experimental model. The cachexia index is progressive and evident during the evolution of the tumor. Nitric oxide and lipid hydroperoxidation quantification was performed using a very sensitive and precise chemiluminescence method, which showed that both analyzed parameters were increased after tumor implantation. In the day 5 group, NO was significantly increased, and this experimental time was chosen to treat the rats with the NO inhibitors N-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). When treated with NO inhibitors, a significant decrease in both NO and lipid hydroperoxide levels occurred in the cerebellum. 3-nitrotyrosine was also analyzed in cerebellar tissue by immunohistochemistry; it was increased at the three experimental time points studied, and decreased when treated with L-NAME and AG. Besides demonstrating that lipid hydroperoxidation in the cerebellum of rats with cachexia increases in a time-dependent manner, this study is the first to describe the participation of NO and its oxidized product 3-NT in the cerebellum of cachectic rats bearing the Walker 256 solid tumor.
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http://dx.doi.org/10.5114/fn.2015.52410DOI Listing
December 2016

Xenogeneic Mesenchymal Stromal Cells Improve Wound Healing and Modulate the Immune Response in an Extensive Burn Model.

Cell Transplant 2016 7;25(2):201-15. Epub 2015 May 7.

Department of Biochemistry and Immunology, Basic and Applied Immunology Program, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Major skin burns are difficult to treat. Patients often require special care and long-term hospitalization. Besides specific complications associated with the wounds themselves, there may be impairment of the immune system and of other organs. Mesenchymal stromal cells (MSCs) are a recent therapeutic alternative to treat burns, mainly aiming to accelerate the healing process. Several MSC properties favor their use as therapeutic approach, as they promote angiogenesis, stimulate regeneration, and enhance the immunoregulatory function. Moreover, since patients with extensive burns require urgent treatment and because the expansion of autologous MSCs is a time-consuming process, in this present study we chose to evaluate the therapeutic potential of xenogeneic MSCs in the treatment of severe burns in rats. MSCs were isolated from mouse bone marrow, expanded in vitro, and intradermally injected in the periphery of burn wounds. MSC-treated rats presented higher survival rates (76.19%) than control animals treated with PBS (60.86%, p < 0.05). In addition, 60 days after the thermal injury, the MSC-treated group showed larger proportion of healed areas within the burn wounds (90.81 ± 5.05%) than the PBS-treated group (76.11 ± 3.46%, p = 0.03). We also observed that CD4(+) and CD8(+) T cells in spleens and in damaged skin, as well as the percentage of neutrophils in the burned area, were modulated by MSC treatment. Plasma cytokine (TGF-β, IL-10, IL-6, and CINC-1) levels were also altered in the MSC-treated rats, when compared to controls. Number of injected GFP(+) MSCs progressively decreased over time, and 60 days after injection, few MSCs were still detected in the skin of treated animals. This study demonstrates the therapeutic effectiveness of intradermal application of MSCs in a rat model of deep burns, providing basis for future regenerative therapies in patients suffering from deep burn injuries.
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http://dx.doi.org/10.3727/096368915X688128DOI Listing
December 2016

The Aspergillus fumigatus sitA Phosphatase Homologue Is Important for Adhesion, Cell Wall Integrity, Biofilm Formation, and Virulence.

Eukaryot Cell 2015 Aug 24;14(8):728-44. Epub 2015 Apr 24.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil National Laboratory of Science and Technology of Bioethanol (CTBE), Campinas, Brazil

Aspergillus fumigatus is an opportunistic pathogenic fungus able to infect immunocompromised patients, eventually causing disseminated infections that are difficult to control and lead to high mortality rates. It is important to understand how the signaling pathways that regulate these factors involved in virulence are orchestrated. Protein phosphatases are central to numerous signal transduction pathways. Here, we characterize the A. fumigatus protein phosphatase 2A SitA, the Saccharomyces cerevisiae Sit4p homologue. The sitA gene is not an essential gene, and we were able to construct an A. fumigatus null mutant. The ΔsitA strain had decreased MpkA phosphorylation levels, was more sensitive to cell wall-damaging agents, had increased β-(1,3)-glucan and chitin, was impaired in biofilm formation, and had decreased protein kinase C activity. The ΔsitA strain is more sensitive to several metals and ions, such as MnCl2, CaCl2, and LiCl, but it is more resistant to ZnSO4. The ΔsitA strain was avirulent in a murine model of invasive pulmonary aspergillosis and induces an augmented tumor necrosis factor alpha (TNF-α) response in mouse macrophages. These results stress the importance of A. fumigatus SitA as a possible modulator of PkcA/MpkA activity and its involvement in the cell wall integrity pathway.
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http://dx.doi.org/10.1128/EC.00008-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519751PMC
August 2015

Systemic oxidative profile after tumor removal and the tumor microenvironment in melanoma patients.

Cancer Lett 2015 Jun 12;361(2):226-32. Epub 2015 Mar 12.

Laboratory of Molecular Pathology, Department of General Pathology, State University of Londrina, PR445, Km 380, Londrina, PR 86057-970, Brazil. Electronic address:

This study highlights the systemic oxidative changes in patients submitted to primary cutaneous melanoma removal. Cutaneous melanoma is highly aggressive and its incidence is increasing worldwide. We evaluated systemic oxidative stress (OS) and 3-nitrotyrosine (3-NT) expression in melanoma tissue in relation to the Breslow thickness in patients under surveillance. Forty-three patients with cutaneous melanoma and 50 healthy volunteers were recruited. Patients were divided into two groups according to the tumor's Breslow thickness: T1/T2 (<2 mm) and T3/T4 (≥2 mm). Systemic OS and inflammatory mediators were evaluated in plasma, and the 3-NT expression was analyzed via immunohistochemistry. Compared with the controls, the patients had lower blood levels of reduced glutathione, higher malondialdehyde and thiol levels, and a higher total radical-trapping antioxidant parameter to uric acid ratio. The C-reactive protein and γ-glutamyl transpeptidase were increased only in the T3/T4 group. High levels of 3-NT were present only in T3/T4 patients. Our data suggested that a correlation exists between the Breslow thickness and a systemic pro-oxidant status, and that oxidative changes induced by the melanoma remain in the microenvironment post-surgery, demonstrating a role for oxygen species in melanoma.
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http://dx.doi.org/10.1016/j.canlet.2015.03.007DOI Listing
June 2015

High osmolarity glycerol response PtcB phosphatase is important for Aspergillus fumigatus virulence.

Mol Microbiol 2015 Apr 11;96(1):42-54. Epub 2015 Feb 11.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.

Aspergillus fumigatus is a fungal pathogen that is capable of adapting to different host niches and to avoid host defenses. An enhanced understanding of how, and which, A. fumigatus signal transduction pathways are engaged in the regulation of these processes is essential for the development of improved disease control strategies. Protein phosphatases are central to numerous signal transduction pathways. To comprehend the functions of protein phosphatases in A. fumigatus, 32 phosphatase catalytic subunit encoding genes were identified. We have recognized PtcB as one of the phosphatases involved in the high osmolarity glycerol response (HOG) pathway. The ΔptcB mutant has both increased phosphorylation of the p38 MAPK (SakA) and expression of osmo-dependent genes. The ΔptcB strain was more sensitive to cell wall damaging agents, had increased chitin and β-1,3-glucan, and impaired biofilm formation. The ΔptcB strain was avirulent in a murine model of invasive pulmonary aspergillosis. These results stress the importance of the HOG pathway in the regulation of pathogenicity determinants and virulence in A. fumigatus.
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http://dx.doi.org/10.1111/mmi.12919DOI Listing
April 2015

ChIP-seq reveals a role for CrzA in the Aspergillus fumigatus high-osmolarity glycerol response (HOG) signalling pathway.

Mol Microbiol 2014 Nov 30;94(3):655-74. Epub 2014 Sep 30.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.

Aspergillus fumigatus is an opportunistic pathogen and allergen of mammals. Calcium signalling is essential for A. fumigatus pathogenicity and is regulated by the CrzA transcription factor. We used ChIP-seq (Chromatin Immunoprecipitation DNA sequencing) to explore CrzA gene targets in A. fumigatus. In total, 165 potential binding peaks including 102 directly regulated genes were identified, resulting in the prediction of the A[GT][CG]CA[AC][AG] CrzA-binding motif. The 102 CrzA putatively regulated genes exhibited a diverse array of functions. The phkB (Afu3g12530) histidine kinase and the sskB (Afu1g10940) MAP kinase kinase kinase of the HOG (high-osmolarity glycerol response) pathway were regulated by CrzA. Several members of the two-component system (TCS) and the HOG pathway were more sensitive to calcium. CrzA::GFP was translocated to the nucleus upon osmotic stress. CrzA is important for the phosphorylation of the SakA MAPK in response to osmotic shock. The ΔsskB was more sensitive to CaCl2 , NaCl, and paraquat stress, while being avirulent in a murine model of invasive pulmonary aspergillosis. The presence of CaCl2 and osmotic stresses resulted in synergistic inhibition of ΔcrzA and ΔsskB growth. These results suggest there is a genetic interaction between the A. fumigatus calcineurin-CrzA and HOG pathway that is essential for full virulence.
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http://dx.doi.org/10.1111/mmi.12785DOI Listing
November 2014

The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

PLoS One 2014 1;9(8):e103957. Epub 2014 Aug 1.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil; National Laboratory of Science and Technology of Bioethanol (CTBE), Campinas, Brazil.

Aspergillus fumigatus is a major opportunistic pathogen and allergen of mammals. Calcium homeostasis and signaling is essential for numerous biological processes and also influences A. fumigatus pathogenicity. The presented study characterized the function of the A. fumigatus homologues of three Saccharomyces cerevisiae calcium channels, voltage-gated Cch1, stretch-activated Mid1 and vacuolar Yvc1. The A. fumigatus calcium channels cchA, midA and yvcA were regulated at transcriptional level by increased calcium levels. The YvcA::GFP fusion protein localized to the vacuoles. Both ΔcchA and ΔmidA mutant strains showed reduced radial growth rate in nutrient-poor minimal media. Interestingly, this growth defect in the ΔcchA strain was rescued by the exogenous addition of CaCl2. The ΔcchA, ΔmidA, and ΔcchA ΔmidA strains were also sensitive to the oxidative stress inducer, paraquat. Restriction of external Ca(2+) through the addition of the Ca(2+)-chelator EGTA impacted upon the growth of the ΔcchA and ΔmidA strains. All the A. fumigatus ΔcchA, ΔmidA, and ΔyvcA strains demonstrated attenuated virulence in a neutropenic murine model of invasive pulmonary aspergillosis. Infection with the parental strain resulted in a 100% mortality rate at 15 days post-infection, while the mortality rate of the ΔcchA, ΔmidA, and ΔyvcA strains after 15 days post-infection was only 25%. Collectively, this investigation strongly indicates that CchA, MidA, and YvcA play a role in A. fumigatus calcium homeostasis and virulence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118995PMC
November 2015

Evaluation of Mucoadhesive Gels with Propolis (EPP-AF) in Preclinical Treatment of Candidiasis Vulvovaginal Infection.

Evid Based Complement Alternat Med 2013 7;2013:641480. Epub 2013 Aug 7.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil ; Laboratório de Pesquisa, Desenvolvimento e Inovação, Apis Flora Indl. Coml. Ltda., 14020-670 Ribeirão Preto, SP, Brazil.

Vulvovaginal candidiasis is the second cause of vaginal infection in the USA. Clinical treatment of C. albicans infections is routinely performed with polyenes and azole derivatives. However, these drugs are responsible for undesirable side effects and toxicity. In addition, C. albicans azole and echinocandin resistance has been described. Propolis is a bee product traditionally used due to its antimicrobial, anti-inflammatory, and other properties. Therefore, the present work aimed to evaluate different propolis presentations in order to evaluate their in vitro and in vivo efficacy. The methodologies involved antifungal evaluation, chemical analysis, and the effects of the rheological and mucoadhesive properties of propolis based gels. The obtained results demonstrated the fungicide action of propolis extracts against all three morphotypes (yeast, pseudohyphae, and hyphae) studied. The highest level of fungal cytotoxicity was reached at 6-8 hours of propolis cell incubation. Among the based gel formulations developed, the rheological and mucoadhesive results suggest that propolis based carbopol (CP1%) and chitosan gels were the most pseudoplastic ones. CP1% was the most mucoadhesive preparation, and all of them presented low thixotropy. Results of in vivo efficacy demonstrated that propolis based gels present antifungal action similar to clotrimazole cream, suggesting that future clinical studies should be performed.
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http://dx.doi.org/10.1155/2013/641480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749595PMC
September 2013

Identification of the cell targets important for propolis-induced cell death in Candida albicans.

Fungal Genet Biol 2013 Nov 13;60:74-86. Epub 2013 Jul 13.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.

Candida albicans is the most common fungal pathogen of humans, forming both commensal and opportunistic pathogenic interactions, causing a variety of skin and soft tissue infections in healthy people. In immunocompromised patients C. albicans can result in invasive, systemic infections that are associated with a high incidence of mortality. Propolis is a complex mixture of several resinous substances which are collected from plants by bees. Here, we demonstrated the fungicidal activity of propolis against all three morphogenetic types of C. albicans and that propolis-induced cell death was mediated via metacaspase and Ras signaling. To identify genes that were involved in propolis tolerance, we screened ~800 C. albicans homozygous deletion mutants for decreased tolerance to propolis. Fifty-one mutant strains were identified as being hypersensitive to propolis including seventeen genes involved in cell adhesion, biofilm formation, filamentous growth, phenotypic switching and pathogenesis (HST7, GIN4, VPS34, HOG1, ISW2, SUV3, MDS3, HDA2, KAR3, YHB1, NUP85, CDC10, MNN9, ACE2, FKH2, and SNF5). We validated these results by showing that propolis inhibited the transition from yeast-like to hyphal growth. Propolis was shown to contain compounds that conferred fluorescent properties to C. albicans cells. Moreover, we have shown that a topical pharmaceutical preparation, based upon propolis, was able to control C. albicans infections in a mouse model for vulvovaginal candidiasis. Our results strongly indicate that propolis could be used as a strategy for controlling candidiasis.
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http://dx.doi.org/10.1016/j.fgb.2013.07.001DOI Listing
November 2013

Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis.

Pediatr Blood Cancer 2013 Nov 20;60(11):1809-16. Epub 2013 Jun 20.

Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Background: Pediatric adrenocortical tumors (ACT) are rare malignancies and treatment has a small impact on survival in advanced disease and the discovery of potential target genes could be important in new therapeutic approaches.

Methods: The mRNA expression levels of spindle checkpoint genes AURKA, AURKB, BUB, and BUBR1 were analyzed in 60 children with ACT by quantitative real time PCR. The anticancer effect of ZM447439, an experimental AURK inhibitor, was analyzed in a primary childhood ACT culture carrying the TP53 p.R337H mutation.

Results: A significant association was observed between malignancy as defined by Weiss score ≥3 and higher AURKA (2.0-fold, P = 0.01), AURKB (7.0-fold, P = 0.007), and BUBR1 (5.8-fold, P = 0.007) gene expression, and between unfavorable event (death or relapse) and higher expression of AURKA (6.0-fold, P = 0.034) and AURKB (17-fold, P = 0.013). Overexpression of AURKA and AURKB was associated with lower event-free survival in uni- (P < 0.001 and P = 0.006, respectively) and multivariate (P = 0.002 and P = 0.03, respectively) analysis. Significant lower Event free survival (EFS) was also observed in patients with moderate/strong immunostaining to AURKA (P = 0.012) and AURKB (P = 0.045). ZM447439 was able to induce inhibition of proliferation and colony formation in a primary childhood ACT culture carrying the TP53 p.R337H mutation.

Conclusion: Our results suggest that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease and the inhibition of these proteins could be an interesting approach for the treatment of these tumors.
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http://dx.doi.org/10.1002/pbc.24653DOI Listing
November 2013

Renal macrophage infiltration is associated with a poor outcome in IgA nephropathy.

Clinics (Sao Paulo) 2012 Jul;67(7):697-703

University of São Paulo, Faculty of Medicine of Ribeirão Preto, Department of Pathology, Ribeirão Preto/SP, Brazil.

Objectives: The objectives of our study were as follows: 1) to analyze the prognostic value of macrophage infiltration in primary IgA nephropathy (IgAN) and 2) to study the relationship between macrophages and other factors associated with the development of renal fibrosis, including mast cells, TGF-β1, α-SMA and NF-kB.

Methods: We analyzed 62 patients who had been diagnosed with IgAN between 1987 and 2003. Immunohistochemical staining was performed with monoclonal antibodies against CD68 and mast cell tryptase and polyclonal antibodies against TGF-β1, α-SMA and NF-kB p65. We also used Southwestern histochemistry for the in situ detection of activated NF-kB.

Results: The infiltration of macrophages into the tubulointerstitial compartment correlated with unfavorable clinical and histological parameters, and a worse clinical course of IgAN was significantly associated with the number of tubulointerstitial macrophages. Kaplan-Meier curves demonstrated that increased macrophage infiltration was associated with decreased renal survival. Moreover, the presence of macrophages was associated with mast cells, tubulointerstitial α-SMA expression and NF-kB activation (IH and Southwestern histochemistry). In the multivariate analysis, the two parameters that correlated with macrophage infiltration, proteinuria and tubulointerstitial injury, were independently associated with an unfavorable clinical course.

Conclusion: An increased number of macrophages in the tubulointerstitial area may serve as a predictive factor for poor prognosis in patients with IgAN, and these cells were also associated with the expression of pro-fibrotic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400157PMC
http://dx.doi.org/10.6061/clinics/2012(07)01DOI Listing
July 2012