Downregulation of developmentally regulated endothelial cell locus-1 inhibits the growth of colon cancer

Developmentally regulated endothelial cell locus-1 (Del1) is an embryonic angiogenic factor expressed in early embryonic endothelial cells, but recently has been found to be expressed in some forms of cancers including colon and breast cancers, and melanoma, and human cancer cell lines. Overexpression of Del1 accelerates tumor growth by enhancing vascular formation, implying Del1 may be a potential target for anti-angiogenic cancer therapy. The study aims to investigate whether downregulation of Del1 could inhibit the growth of tumors established in nude Balb/c mice by subcutaneous implantation of human LS-174T colon cancer cells. The shRNA expression vectors targeting human Del1, and vascular endothelial growth factor (VEGF) were constructed. Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro. Gene transfection of VEGF-shRNA downregulated expression of both VEGF and Del1 in LS-174T cells in vivo and in vitro. Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation. Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer

New Polarization Basis for Polarimetric Phased Array Weather Radar: Theory and Polarimetric Variables Measurement

A novel scheme is developed for mitigating measurement biases in agile-beam polarimetric phased array weather radar. Based on the orthogonal Huygens source dual-polarized element model, a polarization measurement basis for planar polarimetric phased array radar (PPAR) is proposed. The proposed polarization basis is orthogonal to itself after a 90° rotation along the array’s broadside and can well measure the characteristics of dual-polarized element. With polarimetric measurements being undertaken in this polarization basis, the measurement biases caused by the unsymmetrical projections of dual-polarized element’s fields onto the local horizontal and vertical directions of radiated beam can be mitigated. Polarimetric variables for precipitation estimation and classification are derived from the scattering covariance matrix in horizontal and vertical polarization basis. In addition, the estimates of these parameters based on the time series data acquired with the new polarization basis are also investigated. Finally, autocorrelation methods for both the alternate transmission and simultaneous reception mode and the simultaneous transmission and simultaneous reception mode are developed

Estradiol, progesterone, testosterone profiles in human follicular fluid and cultured granulosa cells from luteinized pre-ovulatory follicles

BACKGROUND: The production of sex steroids by follicular cells is proposed to be influenced by the maturity of the incumbent oocyte. Thus steroid levels may reflect suitability of an oocyte for IVF. We examined follicular fluids and granulosa cell production of steroid from IVF patients in order to test the relationship between steroid levels and fertilization. METHODS: Follicular fluid and granulosa cells were extracted from 206 follicles of 35 women undergoing controlled ovarian stimulation. Follicular fluid was assayed for estradiol, progesterone and testosterone. Granulosa cells were cultured from individual follicles and their culture media assayed for production of these hormones after 24 hrs in vitro. Levels of steroids were correlated with follicular diameter, oocyte recovery and subsequent fertilization. RESULTS: Follicular fluid levels of progesterone were 6100 times higher than that of estradiol, and 16,900 times higher that of testosterone. Despite the size of follicle triggered after controlled luteinization, the levels of progesterone and testosterone were maintained at relatively constant levels (median 98.1 micromoles/L for progesterone, and 5.8 nanomoles/L for testosterone). However, estradiol levels were slightly lower in the larger follicles (follicular diameter 10-15 mm, median 25.3 nanomoles/L; follicles > = 15 mm, median 15.1 nanomoles/L; linear correlation r = -0.47, p < 0.0001). With respect to oocyte recovery, no steroid showed a significant association in follicular fluid levels. Similarly no difference in follicular fluid steroid levels was found for those oocytes that did or did not fertilize. Significant quantities of progesterone were produced by the granulosa cells but production was constant regardless of the size of follicle from which the cells originated. Estradiol levels were only detectable in 10 of 121 cultures examined, and testosterone in none. Interestingly, when an oocyte was present follicular estradiol levels correlated with progesterone levels. However, when absent, follicular estradiol levels correlated with testosterone levels but not with progesterone. CONCLUSIONS: The principle steroid product of luteinized pre-ovulatory granulosa is progesterone, a differentiation triggered by the gonadotropin surge. However, absolute steroid levels are associated with follicular size, not oocyte maturation/ability to fertilize

Therapeutic potential of delivering arsenic trioxide into HPV-infected cervical cancer cells using liposomal nanotechnology

Arsenic trioxide (ATO) has been used successfully to treat acute promyelocytic leukaemia, and since this discovery, it has also been researched as a possible treatment for other haematological and solid cancers. Even though many positive results have been found in the laboratory, wider clinical use of ATO has been compromised by its toxicity at higher concentrations. The aim of this study was to explore an improved method for delivering ATO using liposomal nanotechnology to evaluate whether this could reduce drug toxicity and improve the efficacy of ATO in treating human papillomavirus (HPV)-associated cancers. HeLa, C33a, and human keratinocytes were exposed to 5 μm of ATO in both free and liposomal forms for 48 h. The stability of the prepared samples was tested using inductively coupled plasma optical emission spectrometer (ICP-OES) to measure the intracellular arsenic concentrations after treatment. Fluorescent double immunocytochemical staining was carried out to evaluate the protein expression levels of HPV-E6 oncogene and caspase-3. Cell apoptosis was analysed by flow cytometry. Results showed that liposomal ATO was more effective than free ATO in reducing protein levels of HPV-E6 and inducing cell apoptosis in HeLa cells. Moreover, lower toxicity was observed when liposomal-delivered ATO was used. This could be explained by lower intracellular concentrations of arsenic. The slowly accumulated intracellular ATO through liposomal delivery might act as a reservoir which releases ATO gradually to maintain its anti-HPV effects. To conclude, liposome-delivered ATO could protect cells from the direct toxic effects induced by higher concentrations of intracellular ATO. Different pathways may be involved in this process, depending on local architecture of the tissues and HPV status

Tea polyphenols induced apoptosis of breast cancer cells by suppressing the expression of Survivin

To study the mechanism of tea polyphenols (TP)-induced apoptosis of breast cancer cells. Proliferation of MCF-7 and SK-BR-3 cells was evaluated by MTT assays. Cellular ultrastructure was examined by electron microscopy. Apoptosis was detected by TUNEL. PCNA, Cyclin D1, Cyclin E and Survivin expression was measured by Western blot. Cell proliferation was significantly inhibited by TP. Spindle and round cells were loosely distributed with increased particles after TP treatment. Increased cell size, frequent nuclear atypia and a collapse of apoptosis were observed. The nucleus was pushed towards one side, while the cytoplasm was rich in free ribosome. The membrane of mitochondria was thickening, and the cell apoptotic body was observed. TP treated cells experienced significantly enhanced apoptosis compared with 5-Fu treated or control groups. The expression of survivin was downregulated by TP. To conclude, TP can inhibit cell growth and induce apoptosis through downregulating the expression of survivin in breast cancer

Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation

Abstract Background Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients. Methods In a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3–144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence. Results Thirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2–139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU. Conclusions Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.http://deepblue.lib.umich.edu/bitstream/2027.42/110306/1/13046_2015_Article_120.pd

Baseline Staging Tests Based on Molecular Subtype is Necessary for Newly Diagnosed Breast Cancer

Background: Bone scanning (BS), liver ultrasonography (LUS), and chest radiography (CXR) are commonly recommended for baseline staging in patients with newly diagnosed breast cancer. The purpose of this study is to demonstrate whether these tests are indicated for specific patient subpopulation based on clinical staging and molecular subtype. Methods: A retrospective study on 5406 patients with newly diagnosed breast cancer was conducted to identify differences in occurrence of metastasis based on clinical staging and molecular subtypes. All patients had been evaluated by BS, LUS and CXR at diagnosis. Results: Complete information on clinical staging was available in 5184 patients. For stage I, II, and III, bone metastasis rate was 0%, 0.6% and 2.7%, respectively (P \u3c 0.01); liver metastasis rate was 0%, 0.1%, and 1.0%, respectively (P \u3c 0.01); lung metastasis rate was 0.1%, 0.1%, and 0.7%, respectively (P \u3c 0.01). Complete information on molecular subtype was available in 3411 patients. For Luminal A, Luminal B (HER2−), Luminal BH (HER2+), HER2+ overexpression, and Basal-like, bone metastasis rate was 1.4%, 0.7%, 2.5%, 2.7%, and 0.9%, respectively (P \u3c 0.05); liver metastasis rate was 0.1%, 0.1%, 1.0%, 1.1%, and 0.9%, respectively (P \u3c 0.01); lung metastasis rate was 0.20%, 0%, 0%, 0.27%, and 0.9%, respectively (P \u3c 0.05). cT (tumor size), cN (lymph node), PR (progesterone receptor), and HER2 status predicted bone metastasis (P \u3c 0.05). cT, cN, ER (estrogen receptor), PR, and HER2 status predicted liver metastasis (P \u3c 0.05). cT, cN, and PR status predicted lung metastasis (P \u3c 0.05). Conclusion: These data indicate that based on clinical staging and molecular subtypes, BS, LUS and CXR are necessary for patients with newly diagnosed breast cancer

Hydrogen Sulfide Attenuates Carbon Tetrachloride-Induced Hepatotoxicity, Liver Cirrhosis and Portal Hypertension in Rats

BACKGROUND : Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension.METHODS AND FINDINGS : Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine &gamma;-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-&alpha;, interleukin (IL)-1&beta;, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and &alpha;-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters.CONCLUSIONS :&nbsp; Exogenous H2S attenuates CCl4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H2S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.<br /