Prognostic significance of annexin A2 and tumor associated macrophages (TAMs) in metastatic renal cell carcinoma and their relation to Sunitinib resistance.

Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the main treatment for metastatic renal cell carcinoma (mRCC). Development of resistance is a major obstacle against therapy success. The aim of this study was to assess annexin A2 and CD163+ tumor associated macrophages (TAMs) immunohistochemical expression in 50 mRCC cases as regard to patients' prognosis and Sunitinib response. Also, to assess the correlation between annexin A2 and TAMs expression. High annexin A2 expression and TAMs density were associated with serum calcium level (P = 0.024 and 0.037, respectively), larger tumor size (P < 0.001), high tumor grade (P = 0.014 and <0.001, respectively), and the presence of tumor necrosis (P < 0.001). High annexin A2 and TAMs expressions were related to shorter patients' overall survival (P = 0.009 and 0.001, respectively) and progression-free survival (P = 0.003 and 0.001, respectively). Annexin A2 was correlated with TAMs density (r = 0.890). Annexin A2 and TAMs are associated with poor prognostic parameters in mRCC patients, including high nuclear grade, increased tumor size, and the presence of tumor necrosis, together with shorter patients' survivals and poor response to Sunitinib. Annexin A2 expression is correlated with TAMs density suggesting immunomodulatory role of annexin A2.

Nano-crystallization of flubendazole for enhanced dissolution rate and improved in vivo efficacy against Trichinella spiralis.

The aim was to enhance the dissolution rate and in vivo efficacy of flubendazole against trichinella spiralis. Flubendazole nanocrystals were developed by controlled anti-solvent recrystallization. Saturated flubendazole solution was prepared in DMSO. This was injected into phosphate buffer (pH 7.4) containing Aerosil 200, Poloxamer 407 or sodium lauryl sulphate (SLS) while mixing using paddle mixer. The developed crystals were separated from DMSO/aqueous system by centrifugation. The crystals were characterized using DSC, X-ray diffraction and electron microscopy. The crystals were suspended in Poloxamer 407 solution and dissolution rate was monitored. Optimal formulation was administered to Trichinella spiralis infected mice. Administration protocol attacked the parasite in intestinal, migrating and encysted phases. The crystals were spherical nanosized with formulation employing 0.2% Poloxamer 407 as stabilizer being optimum with size of 743.1 nm. DSC and X-ray supported particle size reduction with partial amorphization. Optimal formulation showed fast dissolution to deliver 83.1% after 5 min. Nanocrystals provided complete eradication of intestinal Trichinella and reduced larval count by 90.27 and 85.76% in migrating and encysted phases compared with marginal effect in case of unprocessed flubendazole. The efficacy was clearer from improved histopathological features of the muscles. The study introduced nano-crystallization for enhanced dissolution and in vivo efficacy of flubendazole.

Hypoxia-induced autophagy in triple negative breast cancer: association with prognostic variables, patients' survival and response to neoadjuvant chemotherapy.

Autophagy is a cellular response to diverse stresses within tumor microenvironment (TME) such as hypoxia. It enhances cell survival and triggers resistance to therapy. This study investigated the prognostic importance of HIF-1α and miR-210 in triple negative breast cancer (TNBC). Also, we studied the relation between beclin-1 and Bcl-2 and their prognostic relevance in triple negative breast cancer. Furthermore, the involvement of hypoxia-related markers, beclin-1 and Bcl-2 in mediating resistance to neoadjuvant chemotherapy (NACT) in TNBC was evaluated. Immunohistochemistry was performed to evaluate HIF-1α, beclin-1 and Bcl-2 expression whereas, miR-210 mRNA was detected by quantitative reverse transcription PCR (q-PCR) in 60 TNBC patients. High HIF-1α expression was related to larger tumors, grade III cases, positive lymphovascular invasion, advanced stage, high Ki-67 and poor overall survival (OS). High miR-210 and negative Bcl-2 expression were related to nodal metastasis, advanced stage and poor OS. High beclin-1 was associated with grade III, nodal metastasis, advanced stage and poor OS. Also, high beclin-1 and negative Bcl-2 were significantly associated with high HIF-1α and high miR-210. High HIF- 1α, miR-210 and beclin-1 as well as negative Bcl-2 were inversely related to pathologic complete response following NACT. High beclin-1 and lack of Bcl-2 are significantly related to hypoxic TME in TNBC. High HIF-1α, miR-210, and beclin-1 expression together with lack of Bcl-2 are significantly associated with poor prognosis as well as poor response to NACT. HIF-1α and miR-210 could accurately predict response to NACT in TNBC.

Prognostic role of annexin A2 and cancer-associated fibroblasts in advanced non-small cell lung cancer: Implication in epithelial-mesenchymal transition and gefitinib resistance.

BACKGROUND: Despite advances in treatment of non-small cell lung cancer (NSCLC), its prognosis remains dismal. Development of drug resistance is a major obstacle against success of targeted epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKI) therapy. This study aimed to assess the prognostic role of annexin A2 (ANXA2) expression, within both tumor cells and stroma, as well as cancer associated fibroblasts (CAFs) in NSCLC and to investigate their potential role in induction of epithelial mesenchymal transition (EMT) and resistance to gefitinib. METHOD: Immunohistochemistry was performed to evaluate tumoral and stromal ANXA2 expression and α-SMA-stained CAFs in 110 advanced NSCLC patients. Furthermore, STAT3 and E-cadherin mRNA expression was studied by quantitative reverse transcription PCR (qRT-PCR). RESULTS: Both tumoral and stromal ANXA2 as well as CAFs were significantly related to clinical stage IV and malignant pleural effusion, while tumoral ANXA2 was significantly related to poor tumor differentiation. EGFR mutation and high tumoral ANXA2 were independent factors for poor overall survival, whereas high stromal and tumoral ANXA2 and high CAFs were independent predictors for poor progression-free survival. Moreover, high ANXA2 and CAFs were significantly associated with high STAT3 and low E-cadherin mRNA expression. Focusing on EGFR mutated cases, gefitinib resistance was significantly associated with high tumoral and stromal ANXA2, high CAFs, high STAT3 and low E-cadherin. CONCLUSION: CAFs and ANXA2 could be considered as poor prognostic parameters in advanced NSCLC and are potential factors for gefitinib therapy resistance through EMT induction.

The impact of L-citrulline on murine intestinal cell integrity, immune response, and arginine metabolism in the face of Giardia lamblia infection.

Giardiasis is an intestinal protozoal disease caused by Giardia lamblia (G. lamblia) which is a major worldwide health problem due to development of resistance to commonly used drugs. Therefore, it is necessary to identify an effective drug for giardiasis. This study aimed to assess the therapeutic role of L-citrulline against giardiasis in experimental animals. 40 male Swiss Albino weaned rats were used in this study, divided into four groups. Group I: normal control; group II: infected un-treated; group III: infected and treated with L-citrulline and Group IV: infected and treated with metronidazole. The efficacy was evaluated by counting Giardia trophozoites in the intestinal mucosa and cysts in the stool of infected rats. Histopathological analyses, immunohistochemistry expression of inducible nitric oxide synthase (iNOS) in the small intestine tissues were performed. Along with, serum IL6, the intestinal arginase enzyme level and giardial flavohemoglobin (flavoHb) expression were measured. L-citrulline administration reduced the mean number of G. lamblia cysts and trophozoites, serum IL-6, and intestinal arginase enzyme levels. Furthermore, the intestinal brush border was restored, with a reduction in the inflammatory infiltrate and an increase in iNOS activity. Moreover, there was a significant decrease in flavoHb gene expression in both the L-citrulline and metronidazole treated groups. Thus L-citrulline is effective in NO production therefore it has a therapeutic potential in controlling giardiasis.