A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling.

This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-ß1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-ß1, and TIMP-1.

Atypical Central Neurocytoma: An Investigation of Prognostic Factors.

OBJECTIVE: Central neurocytoma is a rare nervous tissue benign neoplasm. A subset of central neurocytoma has unfamiliar aggressive tendency: so-called atypical central neurocytoma (ACN). This retrospective study aims to analyze the prognostic factors and the impact of various therapy tools on atypical central neurocytoma. METHODS: Twenty-two patients diagnosed with ACN between January 2009 and March 2018 were included. Data collected included the patient's age, gender, tumor location, presenting symptoms, and treatment received. Patients were followed up to detect recurrence and to assess survival. RESULTS: Median overall survival was 57 months, with a 5-year survival of 35%. Better survival was observed for patients <35 years old (66 vs. 47 months; P = 0.061) and patients with gross total resection over subtotal resection or biopsy (76, 45, and 22 months, respectively; P < 0.0001). Patients with a tumor located in the posterior half of the lateral ventricle had better survival, with no statistical significance (P = 0.053). Multivariate analysis showed prognostic significance with the extent of resection (P = 0.000). Progression-free survival ranged from 6 to 82 months, with a median value of 38 months and showed a significant relation with subtotal resection compared with biopsy (P = 0.006). Recurrence was less in patients who received radiotherapy and was statistically significant (P = 0.007). CONCLUSIONS: Long-term survival is possible for patients with atypical central neurocytomas treated with surgery and postoperative radiation. Multivariate analysis confirmed that gross total resection was an independent prognostic factor for survival. Adjuvant radiotherapy reduces tumor recurrence, especially after incomplete surgery.

Recurrent mandibular ameloblastoma in soft tissue and rib graft 17 years after initial presentation.

BACKGROUND: Ameloblastoma is the commonest odontogenic tumour of epithelial origin with a high incidence for developing local recurrence. We present a patient who developed local recurrence in both soft tissue and bone graft 17 years after the initial presentation. CASE PRESENTATION: A 75-year-old female with a previous history of right hemimandibulectomy and rib reconstruction for ameloblastoma in 1999 presented to our centre with a large cystic mouth floor swelling, biopsy from which revealed recurrent ameloblastoma. The patient underwent excision of the recurrent mass en bloc with the cystic swelling through oral and cervical approaches. The patient was discharged after 5 days with an uneventful postoperative course and with a free 2-year follow-up from further recurrence. CONCLUSION: Ameloblastoma is a locally aggressive tumour for which wide local excision with adequate margins is the best management approach. Recurrence of ameloblastoma even after adequate resection is not uncommon, and its management is considered a surgical challenge. A very long time may pass between the initial presentation and the development of recurrence.

Male Breast Huge Malignant Phyllodes.

Introduction: Phyllodes tumors are rare breast tumors. The best treatment is wide local excision with 1 cm safety margin unless metastatic. The three pathological types (benign, borderline and malignant were reported in men. Case presentation: A 73year-old male with huge left breast swelling extending from the clavicle to the left hypochondriac region. Core needle biopsy suggested malignant phyllodes tumor. Postcontrast CT revealed a huge mass seen at the left anterolateral chest wall measuring about (22 x 25 x 26 cm). Simple mastectomy was performed en bloc with the tumor. The microscopic examination led to the diagnosis of high grade malignant phyllodes. IHC showed diffuse positive vimentin, CD10 and negative CK in the neoplastic cells. The patient lost follow up for three months.Then he was presented with fungating local recurrence with bilateral metastatic pulmonary. The patient underwent palliative excision. After the second surgery, he was prepared for palliative chemoradiotherapy but the patient died one month later at home. Discussion and conclusions: Very few cases of phyllodes tumor were reported in men. Pathologically, phyllodes tumors are subdivided into three types: benign, borderline and malignant according to mitotic frequency, nature of margins, stromal growth, cellularity and atypia. Malignant phyllodes tumors tend to spread via hematological route mainly to the lung, then to the bone. Phyllodes tumors even benign type tend to recur even after complete excision with higher tendency for malignant cases. Wide local excision is the standard of care for phyllodes tumors with or without adjuvant radiotherapy in malignant lesions- with no proved value for chemotherapy or hormonal therapy.

Effect of omega-3 fatty acids administered as monotherapy or combined with artemether on experimental Schistosoma mansoni infection.

Schistosomiasis is on the top list of endemic diseases in sub-Saharan Africa. Praziquantel is the drug of choice for treatment of human schistosomiasis. Yet, the sole dependence on the drug raises concerns about the potential for increased drug resistance, which would subsequently result in searching for alternative preventive chemotherapy options, ideally among natural compounds. Therefore, we conducted this work to assess the effect of omega-3 polyunsaturated fatty acids [(ω-3) PUFAs] monotherapy or combined therapy with artemether (ART) against Schistosoma mansoni infection in a mouse model. A total of 42 mice were divided into 4 groups and infected with 50 ± 5 S. mansoni cercariae for 10 weeks. Mice were treated orally with either (ω-3) PUFAs as 273 mg/ kg, 4 times/ week throughout the experiment, ART as a single dose of 400 mg/ kg, 3 weeks post-infection, or combined ART + (ω-3) PUFAs using the same respective treatment regimen, while infected untreated mice were served as controls. The study explored that combined administration of (ω-3) PUFAs and ART has the best schistosomicidal efficacy as it significantly reduced liver and spleen indices, worm count, egg burdens, and granulomas count as well as diameter. Besides, the combined regimen was associated with a significant decrease in both hepatic nitric oxide and serum interleukin-4 level. The results highlighted the possibility of using (ω-3) PUFA combined with ART as a novel anti-schistosomal combination therapy. However, further researches should be conducted to clarify the possible synergistic mechanism/s between the two natural compounds.

Syndecan-1 could be added to hormonal receptors and HER2/neu in routine assessment of invasive breast carcinoma, relation of its expression to prognosis and clinicopathological parameters.

INTRODUCTION: Syndecan-1 is heparan sulfate proteoglycans (HSPGs) that is used as coreceptors for signaling of growth factors. The comprehensive effect of syndecan-1 is to augment receptor stimulation at little ligand concentrations. THE GOAL OF THIS RESEARCH: is to study syndecan-1 expression in breast carcinoma and its value in predicting the prognosis in comparison to other clinicopathological parameters. MATERIAL &METHODS: immunohistochemistry study for syndecan-1 is done on 103 cases of invasive breast carcinoma. Its expression is assessed and correlated to other clinicopathological parameters and prognosis. RESULTS: overexpression was significantly related to high histologic grade (p = 0.001), large tumor size (p = 0.043), HER2-positive status (p = 0.001), and ER&PR-negative status (p = 0.001). It was also have a negative impact on the overall survival (p=0.012) and disease free survival (p = 0.009). Syndecan-1 expression showed weak positive correlation with Her 2 expression (Correlation Coefficient (co): 0.332, p = 0.001). CONCLUSION: syndecan-1 is a good predictor of poor overall survival and recurrence/ metastasis free survival. It is associated with aggressive phenotype as HER2 enriched and Triple negative rather than luminal subtypes of breast carcinoma. So it can be added to the hormonal receptors and HER 2 assay in the routine management of invasive breast cancer after confirmation on a more larger study.

Expression levels of ß-catenin and galectin-3 in meningioma and their effect on brain invasion and recurrence: a tissue microarray study.

OBJECTIVE: Meningiomas are neoplasms that arise from the meninges of the central nervous system (CNS). They constitute about 25.6% of CNS tumors diagnosed in Egypt. Some morphological variants of meningiomas display aggressive behavior, leading to brain-invasive growth pattern. Although meningiomas are usually treated by complete surgical excision, the risk of postoperative recurrence remains. Hence, additional biomarkers for predicting aggressive behavior must be discovered. This study aims to explore the clinical and biological relevance of the protein expression levels of ß-catenin and galectine-3 in meningioma and to understand the pathobiology of this neoplasm. METHODS: This retrospective study was carried out on 153 cases of meningioma by using tissue microarrays and immunohistochemistry for ß-catenin and galectine-3. RESULTS: High ß-catenin expression was significantly associated with transitional and meningiotheliomatous meningiomas, low tumor grade, low recurrence rate, and low incidence of brain invasion. Meanwhile, high galectin-3 expression was associated with brain invasion, recurrence, high tumor grade, and tumor type. Logistic regression analysis indicated that among all variables included in the model, ß-catenin and galactin-3 expression levels were significant predictors of tumor recurrence (P<0.001). CONCLUSIONS: Galectin-3 and ß-catenin are involved in meningioma recurrencebut not in brain invasion. These molecules could be important potential therapeutic targets and predictors for meningiomas.

Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.

The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.

Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.

Phenethyl isothiocyanate potentiates anti-tumour effect of doxorubicin through Akt-dependent pathway.

The present study aims to investigate the in vivo and in vitro anti-tumour properties of phenethyl isothiocyanate (PEITC) alone and in combination with doxorubicin (Dox). The anti-tumour activity was evaluated in vitro by MTT assay using cultured human breast cancer cell line (MCF-7) and human hepatoma cell line (HepG-2) cell lines. In vivo, Ehrlich solid tumour model was used. Tumour volume, weight and antioxidant parameters were determined. Immunohistochemistry analysis for active (cleaved) caspase-3 was also performed. We tested the effect of PEITC treatment on pAkt/Akt ratio, NF-κB p65 DNA binding activity and caspase-9 enzyme activity in both MCF-7 and HepG-2 cell lines. Effect of PEITC treatment on cell migration was assessed by wound healing assay. PEITC and/or Dox treatment significantly inhibited solid tumour volume and tumour weight when compared with control mice. PEITC treatment significantly reduced oxidative stress caused by Dox treatment as indicated by significant increase in total antioxidant capacity and decrease in malondialdehyde level. Microscopic examination of tumour tissues showed a significant increase in active (cleaved) caspase-3 expression in PEITC and/or Dox treated groups. PEITC showed a dose-dependent inhibition of MCF-7 and HepG-2 cellular viability. PEITC inhibited Akt and NF-κB activation and increased caspase-9 activity in a dose-dependent manner. PEITC treatment effectively inhibited both MCF-7 and HepG-2 cell migration. We can conclude that PEITC acts via multiple molecular targets to elicit anti-carcinogenic activity. PEITC/Dox combination therapy might be a potential novel strategy, which may benefit patients with breast and liver cancers.

CXCL10 antagonism and plasma sDPPIV correlate with increasing liver disease in chronic HCV genotype 4 infected patients.

Egypt has the highest prevalence of hepatitis C virus infection worldwide. CXCL10 is a potent chemoattractant that directs effector lymphocytes to sites of inflammation. It has been reported that plasma CXCL10 is processed by dipeptidylpeptidase IV (DPPIV) thus leading to the generation of an antagonist form. Using Luminex-based immunoassays we determined the concentration of different forms of CXCL10 (total, agonist, and antagonist). We also evaluated plasma soluble DPPIV (sDPPIV) concentration and plasma dipeptidylpeptidase (DPP) activity. Using flow cytometry and immunohistochemistry, we analyzed the distribution of lymphocyte subsets. Plasma CXCL10 was elevated in chronic HCV patients, however the agonist form was undetectable. Increased sDPPIV concentration and DPP activity supported the NH2-truncation of CXCL10. Finally, we demonstrated an increased frequency of CXCR3(+) cells in the peripheral blood, and low numbers of CXCR3(+) cells within the lobular regions of the liver. These findings generalize the observation of chemokine antagonism as a mechanism of immune modulation in chronic HCV patients and may help guide the use of new therapeutic immune modulators.

Bilharzial endocervical polyp.

Schistosomiasis still represents a major threat to women's health in many developing countries. The frequency in developed countries is increasing among immigrants and tourists who have a history of freshwater exposure in endemic areas. This is a case of 43-year-old immunocompetent Egyptian woman presented by abnormal vaginal bleeding. The gynecological examination revealed an endocervical polyp measuring 3 x 2 x 1 cm. Polypectomy was done. Histopathological examination revealed several granulomas containing viable eggs of Schistosoma hematobium. Schistosomiasis is rarely presented with endocervical polyp. In developing countries, schistosomiasis may be considered in differential diagnosis of patient with endocervical polyp.

An inexpensive method of small paraffin tissue microarrays using mechanical pencil tips.

BACKGROUND: Tissue microarray technology has provided a high throughput means of evaluating potential biomarkers in archival pathological specimens. This study was carried out in order to produce tissue microarray blocks using mechanical pencil tips without high cost. METHOD: Conventional mechanical pencil tips (Rotring Tikky II Mechanical Pencil 1.0 mm) were used to cut out 1 mm wax cylinders from the recipient block, creating from 36 to 72 holes. Three cores of tumor areas were punched out manually by using the mechanical pencil tips from donor paraffin embedded tissue blocks and transferred to the holes of the paraffin tissue microarrays. RESULTS: This technique was easy and caused little damage to the donor blocks. We successfully performed H&E slides and immunodetection without substantial tissue cylinder loss. CONCLUSION: Our mechanical pencil tip technique is the most inexpensive easy technique among the literature. It also takes a reasonable amount of time and reduces antibody consumption during immunohistochemistry.

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice.

The present study was designed to examine the potential preventive and curative effects of curcumin, resveratrol, imatinib, rosiglitazone, losartan and bosentan (BOS) on Schistosoma mansoni-induced liver fibrosis in mice. Induction of liver fibrosis was produced in male Swiss mice by subcutaneous injection of S. mansoni cercariae per mouse. Mice were left for 28 days before starting the experiment then mice were divided into two main groups. The first group was further subdivided into experimental groups and started drug treatment at day 28 after infection and continued for 2 weeks in order to evaluate the potential preventive effects of the mentioned drugs on S. mansoni-induced liver fibrosis. The second group of mice were left for 2 weeks and then treated with praziquantel for two consecutive days to eradicate the worms and so stop egg disposition and further fibrosis development. Mice were then subdivided into the experimental groups and drug treatment was started for 2 weeks to evaluate their efficacy to decrease the developed fibrosis. At the end of the experiment period, mice were killed and serum was collected for the estimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and albumin. Liver tissue was taken for the estimation of hepatic hydroxyproline content and histopathological examination to confirm the biochemical results. Results of the study indicate that curcumin and imatinib have potent antifibrotic activity both in suppressing and reversing S. mansoni-induced liver fibrosis, while resveratrol has beneficial effects only in suppressing the development of S. mansoni-induced liver fibrosis.