A Novel Murine Model of a High Dose Brachytherapy-Induced Actinic Proctitis.

Background: Radiation proctitis affects 1-20% of cancer patients undergoing radiation exposure due to pelvic malignancies, including prostate, gynecological and rectum cancers. The patients manifest rectal discomfort, pain, discharge, and bleeding. Notably, the efficacy of prophylactic measures remains controversial due to the lack of adequate animal models that mimic this condition. Objective: The present study then aimed to develop a murine model of high-dose-rate (HDR) brachytherapy-induced proctitis. Material/Methods: C57BL/6 male mice were subjected to HDR (radiation source: iridium-192 [Ir-192]) through a cylindrical propylene tube inserted 2 cm far from the anal verge into the rectum. The animals received radiation doses once a day for three consecutive days (fractions of 9.5 Grays [Gy]), 3.0 mm far from the applicator surface. The sham group received only the applicator with no radiation source. The survival rate was recorded, and a colonoscopy was performed to confirm the tissue lesion development. Following euthanasia, samples of the rectum were collected for histopathology, cytokines dosage (IL-6 and KC), and immunohistochemical analysis (TNF-α and COX-2). Results: HDR significantly reduced animals' survival ten days post first radiation exposure (14% survival vs. 100% in the non-irradiated group). Day seven was then used for further investigation. Mice exposed to radiation presented with rectum injury confirmed by colonoscopy and histopathology (P < 0.05 vs. the control group). The tissue damage was accompanied by an inflammatory response, marked by increased KC and IL-6 tissue levels, and immunostaining for TNF-α and COX-2 (P < 0.05 vs. control group). Conclusions: We established a novel animal model of actinic proctitis induced by HDR brachytherapy, marked by inflammatory damage and low animal mortality.

Cancerous and non-neoplastic stem cells in the stomach similarly express CD44 and CD133.

CD44 and CD133 have been considered as cancer stem cell (CSC) markers. Stem cell markers are rarely described in healthy stomach tissues. However, the clinicopathological and prognostic value of CD44 and CD133 in gastric cancer remains controversial. This study investigated the expression of CD44 and CD133 in gastric cancer and non-neoplastic gastric mucosa. We used samples of primary gastric adenocarcinomas (n = 69), metastatic lymph nodes (n = 30), intestinal metaplasia (n = 17), and histologically normal gastric tissues of surgical margins (n = 54). The expression of CD44 and CD133 were studied in samples by immunohistochemistry. Fisher's exact test and a logistic regression model were used in this study. CD44 expression was observed in 12% of samples with intestinal metaplasia, 20% with lymph node metastases, 22% with normal mucosa, to 30% of samples with primary tumors. Most of these positive tumors showed immunostaining in less than 4% of cancerous cells, mainly in the diffuse type. CD133 expression was observed in 7% (intestinal metaplasia) to 46% (normal mucosa). In the positive cases of cancer (24%), in most of them, less than 3% of cells were marked. CD44 and CD133 expression in the histologically normal gastric mucosa was restricted to the deeper regions of the gastric crypts at the level where stem cells and progenitor cells are usually found. CD44 and CD133 expression occurs in few gastric cancer cells, mainly in diffuse carcinomas, and are expressed in histologically normal gastric mucosae. None of the markers are specific for cancer and are also present in intestinal metaplasia and the normal mucosa.

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan-related intestinal mucositis and late-onset diarrhoea.

BACKGROUND AND PURPOSE: Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll-like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4-/-) mice were given irinotecan to investigate the severity of the induced diarrhoea. EXPERIMENTAL APPROACH: Forty-six patients treated with irinotecan-based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild-type (WT) or Tlr4-/- mice were given irinotecan (45 or 75 mg·kg-1 , i.p.) or saline (3 ml·kg-1 ). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. KEY RESULTS: All patients with TLR4 SNPs chemotherapy-treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan-related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il-18 expression along with IL-10 decreased production in Tlr4-/- mice also indicated an intensified intestinal damage and inflammatory response. CONCLUSION AND IMPLICATIONS: TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late-onset diarrhoea during irinotecan-based treatment. Identifying patients genetically predisposed to chemotherapy-associated diarrhoea is a strategy toward precision medicine.

Cytoplasmic CCR7 (CCR7c) immunoexpression is associated with local tumor recurrence in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of cancer, which tests negative for estrogen receptors, progesterone receptors, and lacks overexpression of the human epidermal growth factor 2 (C-erbB2, HER2/neu) gene. The expression of chemokines and their receptors, including CCR7, has been described in several types of cancer, contributing to tumor progression. AIM OF THE STUDY: This study investigated the association between the membrane and cytoplasmic CCR7 expression and the prognosis of TNBC. MATERIALS AND METHODS: Surgical paraffin histopathology blocks and clinico-pathological data were assessed from 133 patients. Samples were analyzed by immunohistochemistry and immunofluorescence using the Tissue Microarray technique for scoring the intensity of CCR7 expression. RESULTS: TNBC patients in which the CCR7 labeling was predominantly in the cytoplasm of tumor cells presented increased local tumor recurrence (P = 0.033). Conversely, there was no statistical difference in five-year overall survival between the patients with low (77%) versus high (80%) cytoplasmic CCR7 expression (P = 0.7104). Additionally, the risk of death between these groups was 1.19 (95% CI = 0.48-2.91). CONCLUSION: The cytoplasmic CCR7 expression associates with an increased incidence of tumor relapse in TNBC, not affecting patients survival. Consequently, the cell compartment in which the CCR7 localizes could serve as a prognostic marker in this cancer subtype.

Immunoexpression of LGR4 and Β-Catenin in Gastric Cancer and Normal Gastric Mucosa

Background: We evaluated the immunoexpression of LGR4 and ß-catenin in primary gastric carcinomas, lymph node metastases and histologically normal gastric mucosa in the surgical margins of gastric primary tumours. Methods: We performed a cross-sectional, observational study, based on 75 gastric carcinoma specimens from gastrectomies conducted at the hospital of the Federal University of Ceará, Brazil. The samples were analysed by tissue microarray and immunohistochemistry. Chi-square, Fisher's exact test and Pearson's linear regression were used in this study. Results: LGR4 expression was greater in the histologically normal gastric mucosa (basal third of the epithelial thickness) of the tumour surgical resection margin than in the cases of primary carcinomas (P<0.001, mainly diffuse-histotype cancer margins), and also in the number of cells stained in the normal mucosa (P<0.0001). Primary intestinal-type carcinomas showed greater positivity for LGR4 than diffuse tumours (59% vs 13%, P<0.0001) and in these the positivity was higher in the metastases (P=0.0242). The membranous immunoexpression of ß-catenin was ubiquitous in the normal mucosa and present in 2/3 of the positive carcinomas. In only one case, nuclear ß-catenin expression was observed. Most LGR4-positive cases were stained for membranous ß-catenin but not the opposite (P<0.01). Conclusion: LGR4 is a likely biomarker of stem cells in the normal gastric mucosa and carcinomas of the stomach, not specific to cancer cells and positively associated with cell proliferation. LGR4 immunoexpression is more frequent and found in a larger number of cells in normal tissues than in tumour samples. Expression of ß-catenin in the junctional membrane-complex occurred predominantly, in positive cases of gastric carcinomas and very rarely in the nucleus. LGR4 apparently influenced the membranous expression of ß-catenin. These findings suggest a controversial role for LGR4, related to proliferative status and inversely related to tumour progression, in contrast to most previous reports.

Association of breast cancer with human papillomavirus (HPV) infection in Northeast Brazil: molecular evidence.

OBJECTIVE: The aim of this study is to investigate the presence of human papillomavirus DNA and genotypes in breast cancer and normal breast tissue samples obtained from women from the northeast region of Brazil. METHOD: One hundred three breast cancer samples and 95 normal breast samples, as the non-malignant controls, were studied. DNA extraction was verified by human beta-globin gene amplification, and polymerase chain reaction was conducted based on HPV L1-specific consensus primers MY09/MY11 and GP5+/GP6+, followed by nested multiplex polymerase chain reaction with type-specific primers for the E6/E7 consensus region. RESULTS: Human papillomavirus DNA was detected in 51 (49.5%) breast carcinoma samples and 15 (15.8%) normal breast samples (p<0.0001). Human papillomavirus genotypes 6 and 11 were identified in 15.2% of all samples. CONCLUSIONS: The high frequency of human papillomavirus infection in breast cancer samples indicates a potential role of this virus in breast carcinogenesis in the studied participants.

Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide.

Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 µg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 µg/kg), IFO (200 mg/kg), G-CSF (25-400 µg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1ß and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC.

Atypical Squamous Cells: Cytopathological Findings and Correlation with HPV Genotype and Histopathology.

OBJECTIVE: We aimed to assess potential associations between atypical squamous cell (ASC) subgroups: ASC-US (undetermined significance) and ASC-H (cannot exclude high-grade squamous intraepithelial lesion), regarding cytomorphological features, high-risk (HR) human papillomavirus (HPV) testing, and histological outcomes in a sample of Brazilian women. STUDY DESIGN: Cross-sectional study which evaluated 1,346 liquid-based cytologies between January 2010 and July 2016 with ASC results. ASC-US and ASC-H were analyzed for frequency, diagnostic criteria, and cytological findings and compared with HR-HPV tests and histological outcomes. RESULTS: Enlarged nucleus was the most frequent ASC-US criterion, but alternative criteria were present in 20% of the total cases. No ASC-US criteria were associated with histological outcomes or HR-HPV positivity. Parakeratosis, corneal pearl, giant cells, and binucleation were strongly associated with ASC-US while hyperkeratosis was associated with high-grade squamous intraepithelial lesions (HSIL) or a superior outcome. HR-HPV was positive in 64.39% of ASC-US and 65.38% of ASC-H. HSIL or superior outcomes also occurred in 13.33% of ASC-US and 64.71% of ASC-H cases. CONCLUSION: Alternative criteria for ASC-US were relatively frequent. Reactive cellular changes suggestive of atypias were more abundant in ASC-US. Although ASC-H is associated with worse histological outcomes, no differences in HPV positivity were found in comparison to ASC-US.

Role of regulatory T cells in irinotecan-induced intestinal mucositis.

Intestinal mucositis (IM) is a common side effect of irinotecan-based chemotherapy. The involvement of inflammatory mediators, such as TNF-α, IL1-ß, IL-18 and IL-33, has been demonstrated. However, the role of adaptive immune system cells, whose activation is partially regulated by these cytokines, is yet unknown. Thus, we investigated the role of regulatory T cells (Tregs) in irinotecan-induced IM. C57BL/6 mice were injected with saline or irinotecan (75mgkg-1, i.p.), once a day for 4days, and euthanized at day 1, 3, 5 or 7 following the first dose of irinotecan. For Treg depletion, the mice were pretreated with a low single dose of cyclophosphamide (100mgkg-1, i.p). Intestinal lamina propria lymphocytes were harvested and purified by Percoll gradient. Treg and Th17 cells were identified by flow cytometry. Blood leukocyte count was obtained and ileum samples were collected for histopathological analysis and myeloperoxidase assay. IM caused an accumulation of Tregs and Th17 cells over time. Treg depletion exacerbated intestinal damage, diarrhea, neutrophil infiltration and animal mortality, despite a reduction in Th17 cell number. The frequency of other Th cells increased and was positively correlated with neutrophil infiltration. Tregs showed a negative correlation with neutrophils and the frequency of non-regulatory Th cells. In conclusion, Tregs are important in the control of intestinal damage induced by irinotecan, and their depletion showed a deleterious effect on IM. Activation of these cells appears to be a compensatory mechanism for intestinal inflammation.

Interleukin-18 (IL-18) is equally expressed in inflammatory breast cancer and noninflammatory locally advanced breast cancer: A possible association with chemotherapy response.

AIM: Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer. The signs of inflammation such as hyperemia and hyperthermia might suggest the possible participation of inflammatory mediators. This study investigates stromal and tumor expression of nuclear factor-kappa B (NF-κB) and interleukin-18 (IL-18) in samples obtained from IBC and noninflammatory locally advanced breast cancer (LABC) and the influence of these markers on patients' prognosis. METHODS: Demographic data, tumor molecular characteristics and overall survival in both groups were also assessed. Furthermore, in this study, we evaluated the expression of IL-18 and p50 nuclear fraction of NF-κB by immunohistochemistry in specimens from IBC and LABC (T4b). RESULTS: We observed that 24.6% of women were diagnosed with IBC up to age 40. In addition, the patients with IBC showed a lower overall survival when compared to LABC. In regard to molecular markers, ER+ , C-erbB2- or triple negative IBC patients showed a significantly reduced overall survival. In addition, a higher IL-18 immunostaining in stroma of IBC and LABC was observed in comparison with tumor cells, but stromal immunoexpression was similar between IBC and LABC. Besides, IL-18 positivity seemed be related with a better clinical response to neoadjuvant chemotherapy. However, NF-κB expression was identical in both groups. CONCLUSION: The IL-18 is present in tumor stroma of IBC and LABC and seems to be associated with the complete response to neoadjuvant chemotherapy.

Association of breast cancer with human papillomavirus (HPV) infection in Northeast Brazil: molecular evidence

OBJECTIVE: The aim of this study is to investigate the presence of human papillomavirus DNA and genotypes in breast cancer and normal breast tissue samples obtained from women from the northeast region of Brazil. METHOD: One hundred three breast cancer samples and 95 normal breast samples, as the non-malignant controls, were studied. DNA extraction was verified by human beta-globin gene amplification, and polymerase chain reaction was conducted based on HPV L1-specific consensus primers MY09/MY11 and GP5+/GP6+, followed by nested multiplex polymerase chain reaction with type-specific primers for the E6/E7 consensus region. RESULTS: Human papillomavirus DNA was detected in 51 (49.5%) breast carcinoma samples and 15 (15.8%) normal breast samples (p<0.0001). Human papillomavirus genotypes 6 and 11 were identified in 15.2% of all samples. CONCLUSIONS: The high frequency of human papillomavirus infection in breast cancer samples indicates a potential role of this virus in breast carcinogenesis in the studied participants.

Dual effect of silymarin on experimental non-alcoholic steatohepatitis induced by irinotecan.

Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5ml/kg i.p.), IRI (50mg/kg i.p.), SIL (150mg/kg p.o.) or IRI (50mg/kg i.p.)+(SIL 1.5, 15 or 150mg/kg p.o.) thrice/week/7weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1ß, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1ß and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p<0.05). Additionally, SIL (1.5mg/kg) improved these parameters (p<0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p<0.05). The higher dose of SIL (150mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms.

Pattern, clinical features and response to corticoids of glomerular diseases in a Brazilian population. An analytical cross-sectional study / Perfil, características clínicas e resposta a corticoides das doenças glomerulares em uma população brasileira. Um estudo transversal analítico

CONTEXT AND OBJECTIVE: Glomerular disease registries are increasing all around the world. The aim of this study was to evaluate the clinical characteristics and treatment response among patients with glomerular diseases followed up in a tertiary hospital in Brazil. DESIGN AND SETTING: Analytical cross-sectional study; tertiary-level public hospital. METHODS: This study included patients with glomerular diseases followed up at a tertiary hospital in Fortaleza, northeastern Brazil. Clinical and laboratory data on each patient were registered. The response to specific treatment was evaluated after 3, 6 and 12 months. RESULTS: The study included 168 patients of mean age 37 ± 14 years. The most prevalent glomerular diseases were focal segmental glomerulosclerosis FSGS] (19.6%), minimal change disease MCD] (17.9%), membranous nephropathy MN] (16.7%) and lupus nephritis LN] (11.9%). The main clinical presentations were nephrotic proteinuria (67.3%) and renal insufficiency (17.9%). The mean proteinuria value decreased after the treatment began. Regarding 24-hour proteinuria on admission, there was no significant difference between patients with a good response and those with no response (7,448 ± 5,056 versus 6,448 ± 4,251 mg/24 h, P = 0.29). The glomerular disease with the highest remission rate was MCD (92%). Absence ...

CONTEXTO E OBJETIVO: Registros de glomerulopatias estão aumentando em todo o mundo. O objetivo deste estudo é avaliar as características clínicas e a resposta do tratamento de pacientes com glomerulopatias acompanhados em um hospital terciário no Brasil. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico. Hospital público terciário. MÉTODOS: O estudo incluiu pacientes com glomerulopatias acompanhados em um hospital terciário de Fortaleza, Ceará, Brasil. Foi realizado registro dos dados clínicos e laboratoriais para cada paciente. A resposta ao tratamento específico foi avaliada após 3, 6 e 12 meses. RESULTADOS: Foram incluídos 168 pacientes, com média de idade de 37 ± 14 anos. A glomerulopatia mais prevalente foi a glomerulosclerose segmentar e focal GESF] (19,6%), seguida pela doença de lesão mínima DLM] (17,9%), nefropatia membranosa NM] (16,7%) e nefrite lúpica NL] (11,9%). As principais manifestações clínicas foram proteinúria nefrótica (67,3%) e insuficiência renal (17,9%). A média dos valores de proteinúria diminuiu após o início do tratamento. Com relação à proteinúria de 24 horas na admissão, não houve diferença significativa entre os pacientes com boa resposta ao tratamento ...

Development of a subcutaneous endometriosis rat model.

PURPOSE: To present a rat model of subcutaneous endometriosis for the study of pathophysiology and the effects of drugs. METHODS: Fifty three-month-old female Wistar rats (Rattus norvergicus) were distributed into one control group and four treatment groups: estradiol (2.5; 5; 10 mg/kg s.c.), medroxyprogesterone acetate (0.5; 2; 5 mg/kg s.c.), triptorelin pamoate (0.18; 0.56 mg/kg s.c.) and acetylsalicylic acid (3 mg/kg per os). The animals were autoimplanted subcutaneously with 4x4-mm uterine fragments to induce endometriosis. The endometriomas were measured on days 1, 7, 14 and 21. The relative dry and wet weights of the endometrioma were used to evaluate response to the drug. Endometrial-like tissue was confirmed by histology. The greatest weight gain was observed on day 14 (relative wet weight: 29.1 ± 6.7 mg%, relative dry weight: 5.3 ± 0.9 mg %). Treatments were administered between day 5 and day 14. RESULTS: The relative wet weight of the hemiuterus in the 10 mg/kg estradiol group differed significantly from control and the other two estradiol groups (p=0.0001). In the medroxyprogesterone acetate group the weight decreased significantly but this decrease was not dose-dependent. Weight reduction was also significant in the triptorelin pamoate and the acetylsalicylic acid groups. CONCLUSION: The model of subcutaneous endometriosis is reproducible, low-cost and easy to perform, and suitable for the study of pathophysiology and the effects of drugs.

Development of a subcutaneous endometriosis rat model

PURPOSE: To present a rat model of subcutaneous endometriosis for the study of pathophysiology and the effects of drugs. METHODS: Fifty three-month-old female Wistar rats (Rattus norvergicus) were distributed into one control group and four treatment groups: estradiol (2.5; 5; 10mg/kg sc), medroxyprogesterone acetate (0.5; 2; 5mg/kg sc), triptorelin pamoate (0.18; 0.56mg/kg sc) and acetylsalicylic acid (3mg/kg per os). The animals were autoimplanted subcutaneously with 4x4-mm uterine fragments to induce endometriosis. The endometriomas were measured on days 1, 7, 14 and 21. The relative dry and wet weights of the endometrioma were used to evaluate response to the drug. Endometrial -like tissue was confirmed by histology. The greatest weight gain was observed on day 14 (relative wet weight: 29.1 ± 6.7mg%, relative dry weight: 5.3 ± 0.9mg %). Treatments were administered between day 5 and day 14. RESULTS: The relative wet weight of the hemiuterus in the 10mg/kg estradiol group differed significantly from control and the other two estradiol groups (p=0.0001). In the medroxyprogesterone acetate group the weight decreased significantly but this decrease was not dose-dependent. Weight reduction was also significant in the triptorelin pamoate and the acetylsalicylic acid groups. CONCLUSION: The model of subcutaneous endometriosis is reproducible, low-cost and easy to perform, and suitable for the study of pathophysiology and the effects of drugs. .

Pattern, clinical features and response to corticoids of glomerular diseases in a Brazilian population. An analytical cross-sectional study.

CONTEXT AND OBJECTIVE: Glomerular disease registries are increasing all around the world. The aim of this study was to evaluate the clinical characteristics and treatment response among patients with glomerular diseases followed up in a tertiary hospital in Brazil. DESIGN AND SETTING: Analytical cross-sectional study; tertiary-level public hospital. METHODS: This study included patients with glomerular diseases followed up at a tertiary hospital in Fortaleza, northeastern Brazil. Clinical and laboratory data on each patient were registered. The response to specific treatment was evaluated after 3, 6 and 12 months. RESULTS: The study included 168 patients of mean age 37 ± 14 years. The most prevalent glomerular diseases were focal segmental glomerulosclerosis FSGS] (19.6%), minimal change disease MCD] (17.9%), membranous nephropathy MN] (16.7%) and lupus nephritis LN] (11.9%). The main clinical presentations were nephrotic proteinuria (67.3%) and renal insufficiency (17.9%). The mean proteinuria value decreased after the treatment began. Regarding 24-hour proteinuria on admission, there was no significant difference between patients with a good response and those with no response (7,448 ± 5,056 versus 6,448 ± 4,251 mg/24 h, P = 0.29). The glomerular disease with the highest remission rate was MCD (92%). Absence of interstitial fibrosis presented a strong correlation with remission (remission in patients without fibrosis = 83.4% versus 16.3% in those with fibrosis, P = 0.001). CONCLUSIONS: The present study found that the most frequent glomerular disease was FSGS, followed by MCD, MN and LN. The presence of interstitial fibrosis was a predictor of poor therapeutic response.

Immunoexpression of metalloproteinases 2 and 14 and TIMP-2 inhibitor in main types of primary gastric carcinomas and lymph node metastasis.

Metalloproteinase-2 (MMP-2) and -14 (MMP-14) and the tissue inhibitor of metalloproteinases type 2 (TIMP-2) participate in epithelial-mesenchymal transition and tumor progression in many cancers. However, the correlation between these enzymes in gastric cancer and the metastatic potential to their respective lymph node needs to be determined. Here, we evaluated the expression of these enzymes in gastric carcinoma and lymph node metastases and their possible involvement in tumor progression. Histological samples from 83 patients with gastric cancer and their respective lymph nodes were used. MMP-2, MMP-14 and TIMP-2 immunoexpression was scored. TIMP-2 expression in tumor-associated macrophages occurred more frequently than in normal mucosa (P = 0.0128). Female tumor samples presented higher MMP-2 expression (P = 0.0248), while TIMP-2 occurred mainly in patients over 50 years old (P = 0.0034). MMP-2 was higher expressed in primary tumor macrophages than in neoplastic cells (P = 0.0118), and was also seen in macrophages from metastatic-affected lymph nodes of intestinal and diffuse histotypes (P = 0.0006). MMP-2, MMP-14 and TIMP-2 expression in mononuclear cells might be correlated with progression of gastric cancer. MMP-14 production by macrophages appears to be more involved in diffuse gastric cancer progression.

Progressive loss of E-cadherin immunoexpression during cervical carcinogenesis.

PURPOSE: To investigate E-cadherin immunoexpression during cervical carcinogenesis. METHODS: We assessed the immunohistochemical expression of E-cadherin in squamous intraepithelial lesions (SIL - 52 cases), squamous cell carcinoma (SCC) of the uterine cervix (23 cases) and also in eight cases of cervicitis. RESULTS: The results show very different E-cadherin membrane expression levels when cervicitis (88%), SILs (73%) and SCC (17%) were compared. In SILs, higher E-cadherin loss was seen in less differentiated cells in the basal third of the epithelium. This study suggests that the absence of E-cadherin expression in the membrane is a molecular event that is observed more often in SCC of the uterine cervix than in SILs or cervicitis. CONCLUSIONS: E-cadherin is an essential molecule during the process of cervical carcinogenesis and in this context exhibits a different expression pattern according to the epithelial thickness layer.

Progressive loss of E-cadherin immunoexpression during cervical carcinogenesis

PURPOSE: To investigate E-cadherin immunoexpression during cervical carcinogenesis. METHODS: We assessed the immunohistochemical expression of E-cadherin in squamous intraepithelial lesions (SIL - 52 cases), squamous cell carcinoma (SCC) of the uterine cervix (23 cases) and also in eight cases of cervicitis. RESULTS: The results show very different E-cadherin membrane expression levels when cervicitis (88%), SILs (73%) and SCC (17%) were compared. In SILs, higher E-cadherin loss was seen in less differentiated cells in the basal third of the epithelium. This study suggests that the absence of E-cadherin expression in the membrane is a molecular event that is observed more often in SCC of the uterine cervix than in SILs or cervicitis. CONCLUSIONS: E-cadherin is an essential molecule during the process of cervical carcinogenesis and in this context exhibits a different expression pattern according to the epithelial thickness layer. .

Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model.

PURPOSE: Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature. METHODS: Swiss male mice were distributed in groups (n = 8) and injected with saline (5 mL/kg, i.p.; control) or IRI (25, 50, 75 or 100 mg/kg, i.p.) thrice a week for 7 weeks. Blood samples were collected to measure the serum concentrations of proteins, alanine and aspartate aminotransferases (ALT and AST). Each week animals were euthanized, and the livers were submitted to myeloperoxidase (MPO) assay, lipid dosage, immunohistochemistry for inducible nitric oxide synthase (iNOS), TNF-α and interleukin-1ß (IL-1ß), and histopathological analysis. Survival rates were also determined. RESULTS: Mice treated with IRI had a significantly (p < 0.05) lower survival rate than controls and time- and dose-dependent body weight loss. ALT and AST plasma levels increased in relation to controls only in mice receiving IRI 50 mg/kg (p < 0.05). The histopathological features characteristic of NASH was observed, including steatosis, lobular neutrophil infiltration and ballooning hepatocytic degeneration. Additional findings included increased MPO, lipid accumulation, portal neutrophil infiltration, IL-1ß and iNOS expression and fibrosis in liver tissues and low serum protein levels compared to controls. CONCLUSION: This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.