Effect of trans-2,3-dimethoxycinnamoyl azide on enhancing antitumor activity of romidepsin on human bladder cancer

PURPOSE: Romidepsin (FK228, depsipeptide, FR901228), a unique cyclic depsipeptide with a histone deacetylase inhibitor (HDACI) activity, is a potential cancer therapeutic agent and currently under clinical trials for several types of cancer. For bladder cancer, romidepsin seems to be a potent antitumor agent from our recent study. In this study, we further delineate a new agent that can enhance both HDACI and antitumor activity of romidepsin. EXPERIMENTAL DESIGN: We screened a chemical library to identify candidate(s) that could enhance romidepsin activity. Chemical synthesis and purification were carried out to produce pure compound to examine its biochemical and antitumor effect on bladder cancer cell lines both in vitro and in vivo. RESULTS: Tranilast, N-(acetoacetyl) anthranilic acid, was first identified as a lead compound from screening, and then, one of the analogues, 2,3-dimethoxycinnamoyl azide (DMCA), seems to be more potent than tranilast. Our data indicate that DMCA can potentiate the HDACI activity of romidepsin and other biological activities, such as cell cycle arrest and apoptosis; these effects were accompanied with the expression of various key cell cycle regulators in different bladder cancer cells. Consistently, DMCA can enhance the in vivo antitumor effect of romidepsin without causing any more weight loss than romidepsin alone. CONCLUSION: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.     

Increased levels of transforming growth factor-betal and -beta2 in the aqueous humor of patients with neovascular glaucoma.

BACKGROUND AND OBJECTIVE: To measure the concentrations of transforming growth factor-betal and beta2 (TGF-beta1 and TGF-beta2) in the aqueous humor of patients with neovascular glaucoma (NVG). PATIENTS AND METHODS: Patients were divided into four groups: NVG secondary to central retinal vein occlusion (group 1), NVG secondary to proliferative diabetic retinopathy (group 2), central retinal vein occlusion without rubeosis (group 3), and senile cataract (group 4). The total TGF-beta 1 and TGF-beta2 concentrations in the aqueous humor of the four groups were measured by enzyme linked immunosorbent assay. RESULTS: The mean concentrations of total TGF-betal were 600.7 +/-436.7 microg/mL in group 1, 802.0 +/-359.5 pg/mL in group 2, and undetectable in groups 3 and group 4 (P < .05). The mean concentrations of total TGF-beta2 were 6,307.9+/- 2,206.2 microg/mL in group 1, 5,908.0+/-2,033.2 microg/mL in group 2, 899.7+/- 425.6 microg/mL in group 3, and 385.7 +/-89.9 microg/mL in group 4. The total TGF-betal and TGF-beta2 concentrations in groups 1 and 2 were significantly higher than those in groups 3 and 4, whereas the total TGF-beta2 concentration in group 3 was significantly higher than that in group 4 (P < .05). There was no significant difference in the TGF-betal or TGF-beta2 concentrations between groups 1 and 2 (P> .05). CONCLUSIONS: The abnormally high concentrations of TGF-betal and TGF-beta2 in the aqueous humor of patients with NVG may explain some aspects of the pathogenesis of NVG and the high failure rate of filtering operations in NVG.     

Testing the fertility of the spermatozoa

The sperm count, an absolutely necessary examination, seems no longer sufficient to establish a prognosis of fertility. Fertilization in vitro, for a diagnostic purpose, would be the ideal examination, but because of the ethical and technical problems it raises, other tests have been developed. The test of spermatozoid survival at 24 hours in Menezzo's B2 medium and interspecific fertilization in vitro (hamster-test) are carried out on isolated spermatozoids according the FIV protocol. The survival test provides two parameters: the presence of mobility and the rate of retention of the mobility after 24 hours. With the hamster-test it is possible to study the penetration and decondensation of the spermatozoids in the ovocytes. The results obtained with the survival test show that the absence of gradual mobility and a retention rate below 25 p. cent after 24 hours, significantly affect the cleavage of ovocytes during FIV. These two parameters affect, in a similar fashion, the percentage of fertilized ovocytes in the hamster-test. The latter seems less specific than the survival test to establish a prognosis before FIV. However, it is interesting as it allows the study of the different stages of fertilization of spermatozoid samples, from the same ejaculation, under varied experimental conditions. These tests require a standardization and present a definite advantage during exploration prior to FIV, AIC.     

Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats

Agents that are ubiquitous in the environment and are knowninducers of mammary cancer in rodents can be regarded as potentialcauses of human cancer and need to be evaluated more completely.Therefore, the purpose of this study was to determine underidentical conditions the relative carcinogenic potency in themammary glands of rats of benzo[a]pyrene (B[a]P), 1-nitropyrene(1-NP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyidne (PhIP).Thirty-day-old female CD rats were gavaged once weekly for 8weeks with B[a]P, 1-NP or PhIP. Each compound was given at 50µmol/rat/week in 0.5 ml trioctanoin for a total dose of400 µmoul/rat. Forty-one weeks after the last carcinogenadministration, rats were killed. In the 1-NP-treated rats,treatment elicited primarily benign tumors. In contrast, theB[a]P- and PhIP-treated rats developed both malignant and benigntumors. The incidence of adenocarcinomas in rats treated withB[a]P or PhIP was comparable and significantly higher than thatin animals receiving trioctanoin only. The incidence of benigntumors (fibroadenomas, desmoplastic adenomas and adenomas) observedin animals treated with B[a]P or 1-NP was comparable and significantlyhigher than that in animals given PhIP or trioctanoin. Thisis the first report describing the carcinogenic activity ofPhIP, given by gavage, in the mammary gland of CD rats and rankingthe carcinogenic potency observed under identical conditions,of three agents (B[a]P     

Coronary artery "pseudothrombus" due to collateral flow artifact distal to left circumflex coronary stenosis

Since the complexity, morbidity, and costs of coronary interventions are increased when coronary thrombus is present, identification of the cause of an angiographic filling defect is potentially important. We present a case report and review our experience with a flow artifact that mimicked thrombus ("pseudothrombus") in the setting of a severe proximal stenosis in the left circumflex coronary artery.     

Prevention of radiocontrast-induced nephropathy with N-acetylcysteine in patients undergoing coronary angiography

OBJECTIVES: Acetylcysteine in patients undergoing computerized tomography with intravenous contrast reduces the incidence of acute renal dysfunction. We examined the effect of N-acetylcysteine in patients undergoing coronary angiography. METHODS: Fifty-five consecutive patients receiving 3 doses of N-acetylcysteine prior to cardiac catheterization were compared to 55 historical controls. All patients in both groups had baseline serum creatinine > 1.2 mg/dl and received intravenous hydration before and after the procedure. Serum creatinine levels at baseline and 48 hours after the procedure were compared. RESULTS: Univariate analysis of clinical variables revealed no significant differences between the groups except for a higher baseline creatinine in the treatment group (2.0 0.7 vs. 1.8 0.4 mg/dl; p = 0.04). There was no difference in the amount or type of contrast used. The mean change in creatinine after 48 hours was -0.4 0.3 versus +0.1 0.3 mg/dl for treatment and control groups (p < 0.001). In patients with baseline creatinine > 2 mg/dl, the benefit was larger (-0.4 0.4 vs. +0.5 0.3 mg/dl; p < 0.001). Multivariate analysis confirmed pre-treatment with N-acetylcysteine as an independent predictor of renal protection (p < 0.001). CONCLUSIONS: Prophylactic use of acetylcysteine prevented reduction of renal function after coronary angiography. The benefit was greater in patients with baseline serum creatinine > 2 mg/dl.     

Sleeve lobectomy for bronchogenic cancers: factors affecting survival

BACKGROUND: Sleeve lobectomy is a parenchyma-sparing procedure that is particularly valuable in patients with cardiac or pulmonary contraindications to pneumonectomy. The purpose of this study is to report our experience with sleeve lobectomy for bronchogenic cancer and to investigate factors associated with long-term survival. METHODS: Between January 1981 and June 2001, 169 patients underwent sleeve lobectomy for non-small-cell lung cancer (n = 139) or carcinoid tumor (n = 30), including 61 with a preoperative contraindication to pneumonectomy. Mean age was 59 +/- 14 years (range, 19 to 82 years). Vascular sleeve resection was performed in 11 patients. The remaining bronchial stump contained microscopic disease in 7 patients. RESULTS: Major bronchial anastomotic complications occurred in 6 (3.6%) patients: one was fatal postoperatively, three required reoperation, and two were managed conservatively. In the non-small-cell lung cancer group, operative mortality was 2.9% (4 of 139), and overall 5-year and 10-year survival rates were 52% and 28%, respectively. Six patients experienced local recurrence after complete resection. By multivariate analysis, two factors significantly and independently influenced survival: nodal status (N0 or N1 versus N2; p = 0.01) and microscopic invasion of the bronchial stump (p = 0.02). In the carcinoid tumor group, there were no operative deaths, and overall 5-year and 10-year survival rates were 100% and 92%, respectively. CONCLUSIONS: Sleeve lobectomy achieves local tumor control and is associated with low mortality and bronchial anastomotic complication rates. Long-term survival is excellent for carcinoid tumors. For patients with non-small-cell lung cancer, N2 disease or incomplete resection is associated with a worse prognosis; outcome is not affected by presence of a preoperative contraindication to pneumonectomy.     

Use of remote sensing and a geographical information system in a national helminth control programme in Chad

OBJECTIVE: To design and implement a rapid and valid epidemiological assessment of helminths among schoolchildren in Chad using ecological zones defined by remote sensing satellite sensor data and to investigate the environmental limits of helminth distribution. METHODS: Remote sensing proxy environmental data were used to define seven ecological zones in Chad. These were combined with population data in a geographical information system (GIS) in order to define a sampling protocol. On this basis, 20 schools were surveyed. Multilevel analysis, by means of generalized estimating equations to account for clustering at the school level, was used to investigate the relationship between infection patterns and key environmental variables. FINDINGS: In a sample of 1023 schoolchildren, 22.5% were infected with Schistosoma haematobium and 32.7% with hookworm. None were infected with Ascaris lumbricoides or Trichuris trichiura. The prevalence of S. haematobium and hookworm showed marked geographical heterogeneity and the observed patterns showed a close association with the defined ecological zones and significant relationships with environmental variables. These results contribute towards defining the thermal limits of geohelminth species. Predictions of infection prevalence were made for each school surveyed with the aid of models previously developed for Cameroon. These models correctly predicted that A. lumbricoides and T. trichiura would not occur in Chad but the predictions for S. haematobium were less reliable at the school level. CONCLUSION: GIS and remote sensing can play an important part in the rapid planning of helminth control programmes where little information on disease burden is available. Remote sensing prediction models can indicate patterns of geohelminth infection but can only identify potential areas of high risk for S. haematobium.