Interleukin-10 levels and the risk of thromboembolism according to COMPASS-Cancer associated thrombosis score in breast cancer patients prior to undergoing doxorubicin-based chemotherapy.

Venous thromboembolism (VTE) is an important cause of morbidity/mortality in cancer patients, and COMPASS-CAT score must be used to VTE-risk prediction. There is a relationship between cytokines and thrombus formation and/or resolution. This study aimed to investigate the VTE risk and cytokines level in breast cancer patients prior to chemotherapy with doxorubicin (DOXO). Eighty women with breast cancer and indication for DOXO treatment were selected. TNF, IL-1ß, IL-6, and IL-10 were measured after the diagnosis and immediately before DOXO treatment. All 80 patients presented a high risk for VTE when evaluated by COMPASS-CAT model (score ≥7). A positive correlation was observed between IL-10 plasma levels and VTE risk score. Our data showed that higher IL-10 levels before chemotherapy are associated to increased risk of VTE in breast cancer patients. This finding suggests that IL-10 levels and the combination with COMPASS-CAT score could be good markers to predict increased risk of VTE in these patients.

Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression.

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.

High soluble OX40 levels correlate with metastatic gastric cancer.

BACKGROUND AND OBJECTIVES: Previous studies demonstrated an association between OX40+T cell expression with poor prognosis in gastric cancer (GC). The soluble form of OX40 (sOX40) could block the interactions between OX40 on the effector T cell, and it is a ligand (OX40L) in dendritic cells. However, the role of sOX40 as a pretreating biomarker and prognostic predictor remains unclear. This study aimed to evaluate the association of levels of sOX40 and sOX40L with disease progression in GC. METHODS: Between 2017 and 2018, a cross-sectional study was performed on 83 GC patients and 20 healthy controls. RESULTS: Among 83 GC patients (median of 63 years), 32.4% of patients with I/II stages, 42.3% III, and 25.3% in IV stages. Metastatic GC patients had significantly higher levels of soluble OX40 compared with stage III (p = 0.0003) and early stages I and II patients (p = 0.005). There was no significant differences in the sOX40 and sOX40L levels between Lauren's histological subtype (intestinal, diffuse, and mixed). CONCLUSIONS: This study showed that soluble OX40 levels have an essential role in GC progression. OX40 molecules may constitute a predictor for poor prognosis and a potential target for immunotherapy in GC.

Cancer risk-reducing surgery: Brazilian Society of Surgical Oncology Guideline Part 2 (Gastrointestinal and thyroid).

BACKGROUND: Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population. OBJECTIVES: The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations. METHODS: The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Eleven questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations. RESULTS: For all questions including risk-reducing colectomy, gastrectomy, and thyroidectomy, a major agreement was achieved by the participants, always using accessible alternatives. CONCLUSION: This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO and it should serve as an important reference for the management of families with cancer predisposition.

Unbalanced expression of sICOS and sPD-1 correlates with tumor progression in gastric cancer.

BACKGROUND AND OBJECTIVES: T cells are central in antitumor immunity in gastric cancer (GC). The inducible costimulatory molecule (ICOS) is a T cell receptor that primarily transmits positive signals for T cell activation and is associated with poor prognosis in GC. In contrast, the costimulatory molecule programmed death 1 (PD-1) is an inhibitory receptor related to tumor immune escape. This study aimed to analyze soluble sites and sPD-1 levels in GC. METHODS: This study enrolled 83 GC patients and 20 healthy controls. RESULTS: The median survival time was 23.22 months in the GC patients. Low levels of sPD-1 and sICOS in GC patients compared to the control group (p = 0.003; p < 0.0001, respectively). High sPD-1 levels in stage IV patients compared to I/II and III stages groups (p = 0.008 and p = 0.0004, respectively). GC patients with stages I and II had higher levels of sICOS compared to III and IV stages (p = 0.0005 and p = 0.02, respectively). There were no significant differences in sPD-1 and sICOS levels between Lauren subtypes. CONCLUSION: These results suggest a predominance of inhibitory costimulatory signals in advanced stages of GC, facilitating tumor immune escape, as the opposite occurs in early stages, resulting in an effective antitumor T-cell-mediated immune response.

Evaluation of platelet activation marker expression and its correlation with tumorigenesis and tumor progression in patients with gastric cancer.

BACKGROUND AND OBJECTIVES: Gastric cancer (GC) remains responsible for over one million new cases in 2020. Activated platelets express the CD40 ligand (CD40L) and CD62P in the cytoplasmic membrane, and interaction with the vascular endothelium can induce the production of tumor growth factors and metastases. We aimed to characterize the soluble levels of sCD40L and sCD62P in GC patients. METHODS: A cross-sectional study was performed on 83 GC patients and 20 healthy controls. RESULTS: High levels of sCD40L were obtained in GC patients compared to healthy controls (p = 0.003) and in the I/II compared with III and IV stages (p < 0.0001 and p = 0.007, respectively). Low levels of sCD62P in the GC patients compared to healthy controls (p = 0.009). High soluble levels of sCD62P in I/II compared with III and IV stages (p = 0.002 and p = 0.01, respectively). There are no significant differences in the levels of sCD40L and sCD62P were observed between intestinal, diffuse, and mixed types. CONCLUSIONS: We concluded that sCD40L and sCD62P molecules may be predictive biomarkers since the increase in plasma levels was associated with disease progression and metastasis in GC. In addition, the serum sCD40L and sCD62P can potentially be used as an indicator of response to anticancer therapy.

Carboxymethylcellulose biofunctionalized ternary quantum dots for subcellular-targeted brain cancer nanotheranostics.

Among the most lethal forms of cancer, malignant brain tumors persist as one of the greatest challenges faced by oncologists, where nanotechnology-driven theranostics can play a critical role in developing novel polymer-based supramolecular nanoarchitectures with multifunctional and multi-modal characteristics to fight cancer. However, it is virtually a consensus that, besides the complexity of active delivering anticancer drugs by the nanocarriers to the tumor site, the current evaluation methods primarily relying on in vitro assays and in vivo animal models have been accounted for the low translational effectiveness to clinical applications. In this view, the chick chorioallantoic membrane (CAM) assay has been increasingly recognized as one of the best preclinical models to study the effects of anticancer drugs on the tumor microenvironment (TME). Thus, in this study, we designed, characterized, and developed novel hybrid nanostructures encompassing chemically functionalized carboxymethylcellulose (CMC) with mitochondria-targeting pro-apoptotic peptide (KLA) and cell-penetrating moiety (cysteine, CYS) with fluorescent inorganic semiconductor (Ag-In-S, AIS) for simultaneously bioimaging and inducing glioblastoma cancer cell (U-87 MG, GBM) death. The results demonstrated that the CMC-peptide macromolecules produced supramolecular vesicle-like nanostructures with aqueous colloidal stability suitable as nanocarriers for passive and active targeting of cancer tumors. The optical properties and physicochemical features of the nanoconjugates confirmed their suitability as photoluminescent nanoprobes for cell bioimaging and intracellular tracking. Moreover, the results in vitro demonstrated a notable killing activity towards GBM cells of cysteine-bearing CMC conjugates coupled with pro-apoptotic KLA peptides. More importantly, compared to doxorubicin (DOX), a model anticancer drug in chemotherapy that is highly toxic, these innovative nanohybrids nanoconjugates displayed higher lethality against U-87 MG cancer cells. In vivo CAM assays validated these findings where the nanohybrids demonstrated a significant reduction of GBM tumor progression (41% area) and evidenced an antiangiogenic activity. These results pave the way for developing polymer-based hybrid nanoarchitectonics applied as targeted multifunctional theranostics for simultaneous imaging and therapy against glioblastoma while possibly reducing the systemic toxicity and side-effects of conventional anticancer chemotherapeutic agents.

Successful growth of fresh retinoblastoma cells in chorioallantoic membrane.

The authors developed a retinoblastoma model using fresh harvested cells from an enucleated eye that were transplanted in chick embryos (chorioallantoic membrane model). The transplanted embryos were treated with escalating doses of Melphalan. This exploratory model was developed with the goal of testing drug sensitivity. Our findings suggest this tumor model could be employed to personalize treatment for patients with retinoblastoma, especially those with bilateral and more refractory disease.

Soluble levels of sCD40L and s4-1BB are associated with a poor prognosis in elderly patients with colorectal cancer.

BACKGROUND AND OBJECTIVES: The prognosis of colorectal cancer (CRC) has improved in the last decades, however, a lower overall survival persists in the elderly. The understanding of immunity changes in the elderly with CRC will allow the emergence of new treatments with higher response rates. 4-1BB and CD40L, an immune checkpoint stimulator, play an important role in T-cell responses and platelets. Our aim was to characterize the soluble levels of CD40L and 4-1BB in CRC elderly patients. METHODS: A cross-sectional study was performed in 41 patients with CRC and 35 healthy elderly controls. Patients with CRC were divided into three groups according to staging: 13 patients with advanced tumor restricted to the organ (stages II); 16 patients with lymph node metastasis (stage III); and 12 patients with distant metastasis (stage IV). RESULTS: There were higher levels of soluble s4-1BB and sCD40L in CRC elderly stage II patients when compared with healthy controls (P = .0009 and P < .0001, respectively), stage III patients (P = .008 and P < .0001, respectively) and stage IV patients (P = .007 and P < .0001, respectively). CONCLUSIONS: We concluded that sCD40L and s4-1BB molecules may be prognostic biomarkers, since the reduction in plasma levels of these molecules was associated with disease progression.

Novel Symmetrical 1,4-Disubstituted-bis-1,2,3-Triazoles: Synthesis by Double CuAAC and Cytotoxicity Evaluation.

BACKGROUND: A series of symmetrical 1,4-disubstituted bis-1,2,3-triazoles was prepared by double copper catalyzed Azide-alkyne Cycloaddition (CuAAC) from aliphatic bis-azides and a tetraethylene glycol bis-azide derivative. The eighteen novel compounds were evaluated in vitro for their cytotoxic activity against two human tumor cell lines: Human breast adenocarcinoma (MDA-MB 231) and ovarian adenocarcinoma (TOV-21G). RESULTS AND CONCLUSION: The results of colorimetric MTT assays showed that compounds 4j and 4q exhibited a better selectivity index and cell viability comparable with the standard drug doxorubicin. These compounds induced apoptosis in both tested cell lines, as assessed by BrdU assay. The results suggest that these structurally simple compounds may be promising prototypes for antitumoral agents.

Digoxin reduces the mutagenic effects of Mitomycin C in human and rodent cell lines.

Digoxin is a drug widely used to treat heart failure and studies have demonstrated its potential as anticancer agent. In addition, digoxin presents the potential to interact with a series of other compounds used in medicine. The aim of the present study was to evaluate in vitro the cytotoxicity, genotoxicity and mutagenicity of digoxin and its potential to interact with the mutagen Mitomycin C (MMC). The cytotoxicity of digoxin was assessed by employing the MTT method and the comet assay was performed to assess the genotoxicity of this medicine in CHO-K1 and HeLa cell lines. Besides, the cytokinesis-block micronucleus assay was performed to assess the mutagenicity and the antimutagenicity of this drug. The Ames assay was also performed with TA98 and TA100 strains of S. typhimurium. Results showed that digoxin was cytotoxic, genotoxic and mutagenic for HeLa and CHO-K1 cell lines at concentrations many times higher than those observed in human therapeutic conditions. Nevertheless, an antimutagenic effect against the mutagen MMC was observed on both cell lines in concentrations near those used therapeutically in humans. This chemoprotective effect observed is an interesting finding that should be better explored regarding its impact in anticancer chemotherapy.

γ-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect.

Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.

21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions.

Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.

Production and characterization of monoclonal antibodies against Campylobacter fetus subsp. venerealis / Produção e caracterização de anticorpos monoespecíficos contra Campylobacter fetus subsp. venerealis

Myeloma cells Sp2/0-Ag14 and spleen cells from BALB/c mouse immunized with sonicated Campylobacter fetus subsp. venerealis NCTC 10354 were fused with polyethylene glycol (PEG) for the selection of clones producing antibodies. Clones were obtained by limiting dilution and screened for the production of specific antibodies to C. fetus subsp. venerealis NCTC 10354 by indirect ELISA and western blot against a panel of bacteria: C. fetus subsp. venerealis NCTC 10354, C. fetus subsp fetus ADRI 1812, C. sputorum biovar sputorum LMG 6647, C. lari NCTC 11352, and Arcobacter skirrowii LMG 6621 for the ELISA and C. fetus subsp. venerealis NCTC 10354 and C. sputorum biovar sputorum LMG 6647 for the western blotting. Fifteen clones producing monoclonal antibodies (MAbs) anti-C. fetus subsp. venerealis of the IgM (1) and IgG (14) classes were further screened for species-specificity. Four clones of the 15 obtained were producers of species-specific monoclonal antibodies (MAbs): two were specific for C. fetus subsp. venerealis and two were specific for C. fetus subsp. fetus. None of the clones were reactive against C. sputorum biovar sputorum LMG 6647. All clones recognized a protein with molecular mass of approximately 148 kDa from lysed C. fetus subsp. venerealis NCTC 10354.

Para a produção de anticorpos monoclonais contra Campylobacter fetus subsp. venerealis foram utilizadas as linhagens de células de mieloma Sp2/0-Ag14 e células de baço de camundongos BALB/c imunizados com sonicado de C. fetus subsp. venerealis NCTC 10354. A detecção dos anticorpos monoclonais foi realizada por ELISA indireto utilizando antígeno sonicado de C. fetus subsp. venerealis NCTC 10354. A clonagem foi realizada por diluição limitante e os clones foram caracterizados por ELISA indireto utilizando um painel de bactérias escolhidas em função da prevalência e habitats: C. fetus subsp. venerealis NCTC 10354, C. fetus subsp. fetus ADRI 1812, C. sputorum biovar sputorum LMG 6647, C. lari NCTC 11352 e Arcobacter skirrowii LMG 6621; e no "western blotting" utilizando antígenos sonicados de C. fetus subsp. venerealis NCTC 10354 e C. sputorum biovar sputorum LMG 6647. Foram obtidos 15 clones produtores de anticorpos anti- C. fetus subsp. venerealis das classes IgM (1) e IgG (14). Quatro clones dentre os 15 clones obtidos foram produtores de anticorpos monoclonais espécie-específicos: dois clones reagiram com maior especificidade contra C. fetus subsp. venerealis NCTC 10354 e dois clones reagiram com maior especificidade contra C. fetus subsp. fetus ADRI 1812. Nenhum dos clones reagiu contra C. sputorum biovar sputorum LMG 6647, comprovando a especificidade dos anticorpos monoclonais testados. Todos os clones reconheceram uma proteína de massa molecular de aproximadamente 148 kDa no sonicado de C. fetus subsp. venerealis NCTC 10354.

Correlação entre a Visual Gait Assessment Scale, Edinburgh Visual Gait Scale e Escala Observacional da Marcha em crianças com paralisia cerebral diparética espástica / Correlation among the Visual Gait Assessment Scale, Edinburgh Visual Gait Scale and Observational Gait Scale in children with spastic diplegic cerebral palsy

CONTEXTUALIZAÇÃO: Desordens da marcha são comuns em crianças com paralisia cerebral (PC) diparética espástica. Com o intuito de aprimorar a marcha dessas crianças e quantificar os desfechos de tal intervenção, torna-se necessário que se faça uma análise instrumentada pré e pós-intervenção. OBJETIVOS: Correlacionar a Edinburgh Visual Gait Scale (EVGS), a Visual Gait Assessment Scale (VGAS) e a Escala Observacional de Marcha (EOM). MÉTODOS: Estudo transversal de análise da marcha por meio das escalas EVGS, VGAS e EOM, envolvendo oito crianças com PC diparética espástica, nível I ou II do Gross Motor Function Classification System (GMFCS), avaliadas por três examinadores. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Estadual de Campinas - UNICAMP. Os dados foram analisados pelo índice Kappa ponderado, considerando um nível de significância de 5%. RESULTADOS: O estudo intra-avaliadores mostrou que a concordância entre os métodos na classificação dos sujeitos foi de moderada a excelente (k=0,41, 1,00), sendo a comparação entre a VGAS e a EVGS a de maior índice de concordância, enquanto a EOM obteve grande discordância em comparação com as outras escalas. A concordância interavaliadores se mostrou predominantemente alta. CONCLUSÃO: Os resultados fornecem evidências de que a VGAS e a EVGS são mais adequados para avaliação da marcha de crianças com PC diparética quando comparadas à EOM.

BACKGROUND: Gait disorders are very common in children with spastic diplegia cerebral palsy (CP). In order to improve the CP children's gait and to quantify the outcomes of this intervention it becomes essential to perform an instrumented analysis before and after the intervention. OBJECTIVES: To analyze the correlation among the Edinburgh Visual Gait Scale (EVGS), the Visual Gait Assessment Scale (VGAS) and the Observational Gait Scale (OGS). METHODS: Cross sectional study aiming to analyze the gait of 8 children with spastic diplegia CP with level I or II in the Gross Motor Function Classification System (GMFCS) through the EVGS, VGAS and OGS scales performed by 3 examiners. This study was approved by the Research Ethics Committee of the Universidade Estadual de Campinas (UNICAMP). Weighted Kappa scores were used to analyze the data considering a significance level of 5%. RESULTS: The intra-rater analyses showed a moderate to excellent agreement (k=0.41, 1.00) among the methods of the children's classification, being the comparison between VGAS and the EVGS scales presented the highest level of agreement, while the OGS scale presented a considerable disagreement in comparison with other scales. The inter-rater agreement showed to be predominantly high. CONCLUSIONS: The results provide evidence that the VGAS and the EVGS scales are more suitable for children's spastic diplegia CP gait assessment when compared to OGS.

Primary culture of Rhodnius prolixus (Hemiptera: Reduviidae) salivary gland cells

In the present paper, we developed a primary culture of Rhodnius prolixus salivary gland and main salivary canal cells. Cells remained viable in culture for 30 days. Three types of cells were indentified in the salivary gland cultures, with binuclear cells being the most abundant. The supernatants of salivary cultures contained mainly 16-24 kDa proteins and presented anticoagulant and apyrase activities. Secretion vesicles were observed budding from the cellular monolayer of the main salivary canal cells. These results indicate that R. prolixus salivary proteins may be produced in vitro and suggest that the main salivary canal may have a possible secretory role.

Characterization of the vascular changes in schistosomal portal (pipestem) fibrosis of mice.

Mice chronically infected with Schistosoma mansoni develop one of two anatomical forms of hepatic lesions: severe, periportal (pipestem) fibrosis or milder, isolated granulomas. The pathogenesis of periportal fibrosis is poorly understood. In this work we compared mice with either periportal fibrosis or isolated granulomas to identify specific markers of severe pathology. BALB/c or Swiss Webster mice were infected with 30 cercarie, once or six times, and liver biopsies were performed to classify the animals into two pathological groups 16 weeks later. Sixty percent of the animals sacrificed at 20 or 24 weeks had periportal fibrosis, 15-20% had isolated granulomas and the remainder had indeterminate pathology. There was no correlation between frequency of infections or egg burden (eggs/gliver) at 20 and 24 weeks post-infection and the development of periportal fibrosis. Livers with periportal fibrosis at 20 or 24 weeks of infection were characterized by larger areas of fibrotic tissue and greater vascularization compared to livers of mice with isolated granulomas. Plastic casts of the portal vein system showed marked changes in vascular structure in mice with periportal fibrosis, including collateral vessels sprouting from the main portal branches, amputation of the more delicate peripheral ramifications, and distortions of the medium and small branches. Vascular changes were not observed in mice with isolated granulomas. These results suggest that the interaction between schistosome eggs and portal vascular changes is of paramount importance in the development of pipestem fibrosis.

Comparison of immune responses of Schistosoma mansoni-infected mice with distinct chronic forms of the disease.

BACKGROUND: Schistosoma mansoni-infected mice tend to present with either one of two different hepatic pathological patterns during chronic infection: periportal fibrosis (PF) with portal concentration of periovular granulomas and fibrosis or isolated granulomas (IG), with scattered periovular granulomas within the liver. These are models for the two clinical presentations of schistosomiasis, the severe hepatosplenic and the mild intestinal forms. In the present work, we examined the relationship between the development of these histopathological aspects and immunological markers in S. mansoni-infected mice. Although BALB/c mice with PF and IG had similar egg numbers in the liver, PF mice had higher liver collagen contents than mice with IG. Cultured spleen cells from mice with PF and IG had similar proliferation 20 and 40 weeks after S. mansoni infection upon stimulation with parasite egg antigen (SEA) or mitogen (Con A). Production of IL-4 upon SEA stimulation was higher in cell cultures from mice with PF, whereas IL-5 and IFN-gamma levels were not statistically different between PF and IG groups. Mice with IG had similar serum concentrations of total IgE and anti-SEA IgG1, IgG2a, IgG2b and IgG3 compared to sera from PF mice. Levels of IgG1 and IgG2a antibodies were the highest and the lowest detected, respectively. In conclusion, isogenic BALB/c mice infected with S. mansoni that develop periportal fibrosis or isolated granulomas have similar immunological patterns despite the two pathologic forms of schistosomal liver fibrosis.

Host nutritional status as a contributory factor to the remodeling of schistosomal hepatic fibrosis

Weaning Swiss mice were percutaneously infected with 30 cercariae of Schistosoma mansoni and submitted to a shifting either from a deficient to a balanced diet or vice-versa, for 24 weeks. The nutritional status was weekly evaluated by measurements of growth curves and food intake. Hepatic fibrosis and periovular granulomas were studied by histological, morphometric and biochemical methods. All mice fed on a deficient diet failed to develop periportal "pipestem" fibrosis after chronic infection. An unexpected finding was the absence of pipestem fibrosis in mice on normal diet, probably related to the sample size. The lower values for nutritional parameters were mainly due to the deficient diet, rather than to infection. Liver/body weight ratio was higher in "early undernutrition" group, after shifting to the balanced diet. Volume density and numerical density of egg granulomas reached lowest values in undernourished animals. The amount of collagen was reduced in undernourished mice, attaining higher concentrations in well-fed controls and in "late undernutrition" (balanced diet shifted to a deficient one), where collagen deposition appeared increased in granulomas. That finding suggested interference with collagen degradation and resorption in "late" undernourished animals. Thus, host nutritional status plays a role in connective tissue changes of hepatic schistosomiasis in mice.