Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design,direct synthesis,crystal study and in vitro biological evaluation

Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a–d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC₅₀?=?9 and 12?μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC₅₀?=?21 and 29?μM, respectively) and MDA-MB-468 (IC₅₀?=?23 and 24?μM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d.     

Prominence of three diets on life table parameters for Chrysoperla carnea (Neuroptera: Chrysopidae) to mass rearing under laboratory conditions

Chrysoperla carnea (Steph.) is a general predator reared in industrial scale. Different eggs of moth were used to rear C. carnea, but stabled moth colony needed expensive equipment and is costly. In this research, we surveyed appropriate diet to mass rearing. For this purpose, 100 same old (24H) eggs of C. carnea, separately, were selected randomly from the mass culture of C. carnea which was reared on the egg of flour moth Anagasta kuehniella (Zeller), artificial diet and semi-artificial diet under laboratory conditions (25 ± 5°C, 65 ± 5% RH and L–D: 16–8). These results showed reduction process e_x (expectation of life table at age X) and the survival curve was convex (K-Strategy). Also L_x in appearing of adults that fed on egg of flour moth, artificial diet and semi-artificial diet were 0.76, 0.4 and 0.9 which implied that 24, 60 and 10% of cohort were dead before reaching adult stage. Eggs produced by each female were recorded daily until all females died. The parameters were estimated using Carey’s (1993) method. Gross (GRR) and net (R₀) reproductive rates of predator on A. kuehniella, artificial diet and semi artificial diets were 225.5 ± 3.45, 72.4 ± 3.5, 267.8 ± 4.8 and 180.12 ± 2.3, 24.33 ± 4.3, 254.05+3.3 (female/female/generation), respectively. Mean generation time (T), Doubling time (DT), Intrinsic rate of increase (r_m ) and Finite rate of increase (λ) of predator on A. kuehniella, artificial diet and semi artificial diet were 31.9 ± 0.71, 42.87 ± 0.45, 29.79 ± 0.57 (days); 4.27 ± 0.03, 9.36 ± 0.06, 3.74 ± 0.05 (days); 0.162 ± 0.001, 0.074 ± 0.003, 1.185 ± 0.002; and 1.175 ± 0.001, 1.076 ± 0.002, 1.203 ± 0.002 (female/female/day), respectively. This research indicated that semi-artificial diet is a suitable prey for the predator.     

Development of the braconid wasp Cotesia flavipes in two Crambids, Diatraea saccharalis and Eoreuma loftini: Evidence of host developmental disruption

Cotesia flavipes is an important gregarious larval endoparasitoid of several crambid stem borers, including Diatraea saccharalis. The suitability of two crambid species, Eoreuma loftini and D. saccharalis, pests of sugarcane and rice in Texas, for C. flavipes development was tested. The effect of parasitization by C. flavipes on encapsulation response was assessed in vivo in both D. saccharalis and E. loftini. The results indicated that the parasitoid developed and emerged successfully in D. saccharalis larvae. Although E. loftini larvae were readily parasitized by C. flavipes parasitoids, no wasp larvae hatched from the eggs in this host because eggs were encapsulated by the host's hemocytes. The developmental fate of the E. loftini larvae with encapsulated parasitoids was variable. Most died as abnormal fifth instars or as post-wandering prepupae, while a few developed normally to the pupal stage. In vivo experiments, there was a significant reduction in the percent of beads encapsulated in parasitized larvae in both hosts. However, the percent of beads showing melanization decreased significantly in parasitized D. saccharalis larvae but did not differ significantly in parasitized or unparasitized E. loftini larvae. Our results showed that D. saccharalis is a suitable host for C. flavipes whereas E. loftini is an unsuitable host. This study indicated that lepidopteran stem borers that are taxonomically, behaviorally, and ecologically very similar can differ in their ability to encapsulate a parasitoid species.     

Use of biochemical markers to monitor changes in bone turnover in cynomolgus monkeys

The ovariectomized old cynomolgus monkey is a recognized model of human osteoporosis, and the same species can be used for the assessment of the efficacy and potential toxicity of agents intended to prevent or treat osteoporosis. Several assays have been developed that can measure the same biochemical markers of bone turnover as are used in human patients for the diagnosis and treatment follow-up of bone-related diseases, including osteoporosis. The aim of the present study was to describe the results obtained with these assays in normal control monkeys, their variations with age and sex, and their sensitivity in monitoring the bone turnover induced by ovariectomy in old skeletally mature cynomolgus monkeys. Seven old cynomolgus monkeys were bilaterally ovariectomized and 13 age-matched monkeys were sham-operated. Bone mineral density and biochemical markers were measured before and at regular intervals after surgery for up to 20 months. Total alkaline phosphatase (total ALP), bone-specific alkaline phosphatase isoenzyme (bone ALP) and osteocalcin (OC) were highly correlated to the decrease in bone mineral density (BMD) induced by ovariectomy. Deoxypyridinoline (DPD) measured by enzyme-linked immunoassay was insensitive to the bone resorption induced by ovariectomy, but cross-linked N-telopeptide (NTX-I) was higher in ovariectomized monkeys than in control monkeys. These results demonstrate that reliable biochemical parameters are available to adequately monitor and provide insight into osteoclastic bone resorption and osteoblastic bone formation, the two components of bone turnover in this animal model, and can thus be used to assess the efficacy and toxicity of potential therapeutic agents.     

Repolarization Parameters Are Associated With Mortality In Chagas Disease Patients In The United States

Objective

The goal of this study was to examine the association between ECG repolarization parameters and mortality in Chagas disease (CD) patients living in the United States.

Methods

CD patients with cardiomyopathy (CM) and bundle branch block (BBB) or BBB alone were compared to age- and sex-matched controls. QT interval, QT dispersion (QTd), T wave peak to T wave end duration (Tp-Te) and T wave peak to T wave end dispersion ((Tp-Te)d) were measured. Presence of fractionated QRS (fQRS) was also assessed. The main outcome measure was the association between ECG parameters and mortality or need for cardiac transplant.

Results

A total of 18 CM and 13 BBB CD patients were studied with 97% originating from Mexico or Central America. QTd (60.0±15.0 ms vs 43.5±9.8 ms, P=0.0002), Tp-Te (102.6±29.3 ms vs 77.1±11.0 ms, P=0.0002) and (Tp-Te)d (39.5±9.4 ms vs 22.7±7.6 ms, P<0.0001) were prolonged in CD CM patients compared to CM controls. Chagas CM patients had more fQRS then controls (84.2±0.10% vs 33.3±0.11%, p=0.0005). QTd (59.9±15.0 ms vs 29.5±6.9 ms, P=0.0001) and (Tp-Te)d (40.0±15.9 ms vs 18.5±5.4 ms, p<0.0001) were longer in the CD BBB group compared to BBB controls. Univariate analysis showed QTd (56.9±15.0 ms vs 46.5±17.3 ms, p=0.0412) and (Tp-Te)d (36.8±13.5 ms vs 28.5±13.3 ms, p=0.0395) were associated with death and/or need for cardiac transplant.

Conclusion

Our results indicate that P-max and PD are useful electrocardiographic markers for identifying the β-TM-high-risk patients for AF onset, even when the cardiac function is conserved.     

Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment

Despite many advances and optimization in colon cancer treatment, tumor recurrence and metastases make the development of new therapies necessary. Colon cancer stem cells (CCSCs) are considered as the main triggering factor of cancer progression, recurrence, and metastasis. CCSCs as a result of accumulated genetic and epigenetic alterations and also complex interconnection with the tumor microenvironment (TME) can evolve and convert to full malignant cells. Mounting evidence suggests that in cancer therapy both CCSCs and non-CCSCs in TME have to be regarded to break through the limitation of current therapies. In this regard, stem cell capabilities of some non-CCSCs may arise inside the TME condition. Therefore, a deep knowledge of regulatory mechanisms, heterogeneity, specific markers, and signaling pathways of CCSCs and their interconnection with TME components is needed to improve the treatment of colorectal cancer and the patient's life quality. In this review, we address current different targeted therapeutic options that target cell surface markers and signaling pathways of CCSCs and other components of TME. Current challenges and future perspectives of colon cancer personalized therapy are also provided here. Taken together, based on the deep understanding of biology of CCSCs and using three-dimensional culture technologies, it can be possible to reach successful colon cancer eradication and improvise combination targeted therapies against CCSCs and TME.     

Isolation and identification of cuticular compounds from the mediterranean flour moth,Ephestia kuehniella Zeller (Lepidoptera: Pyralidae), their antibacterial activities and biological functions

Cuticular analysis of Ephestia kuehniella females by gas chromatography-mass spectrometry revealed the presence of four groups of chemical compounds including alkane, alcohol, aldehyde and fatty acid. The cuticular n-alkanes ranged from 12 to 18, 20, 23, 24 and 29 carbon atoms in the chain. The most abundant n-alkanes detected in the cuticular extracts were C₁₄ (14.98%) and C₁₈ (8.15%). Cuticular fatty acids included hexadecenoic acid, 9-octadecenoic acid and 9,12-octadecenoic acid. Two types of alcohol including, 2-methyl-Z,Z-3,13-octadecadienol and 9-methyl-Z-10-tetradecen-1-ol acetate, were found in the cuticular lipids of the females. Two aldehyde components, (E)-11-hexadecenal and 9,17-octadecadienal, were identified in the cuticular extract of E. kuehniella. Antibacterial activity of the cuticular compounds was tested against Bacillus subtilis, Bacillus thuringiensis and Escherichia coli. These compounds from the moths inhibited the growth of Gram-positive bacteria. The functional characteristics of the cuticular compounds operating as pheromones, species-associated compounds and host-resistant compounds to bacterial infection are discussed.     

Bifurcation asymmetry of the porcine coronary vasculature and its implications on coronary flow heterogeneity

The branching pattern of the coronary arteries and veins is asymmetric, i.e., many small vessels branch off of a large trunk such that the two daughter vessels at a bifurcation are of unequal diameters and lengths. One important implication of the geometric vascular asymmetry is the dispersion of blood flow at a bifurcation, which leads to large spatial heterogeneity of myocardial blood flow. To document the asymmetric branching pattern of the coronary vessels, we computed an asymmetry ratio for the diameters and lengths of all vessels, defined as the ratio of the daughter diameters and lengths, respectively. Previous data from silicone elastomer cast of the entire coronary vasculature including arteries, arterioles, venules, and veins were analyzed. Data on smaller vessels were obtained from histological specimens by optical sectioning, whereas data on larger vessels were obtained from vascular casts. Asymmetry ratios for vascular areas, volumes, resistances, and flows of the various daughter vessels were computed from the asymmetry ratios of diameters and lengths for every order of mother vessel. The results show that the largest orders of arterial and venous vessels are most asymmetric and the degree of asymmetry decreases toward the smaller vessels. Furthermore, the diameter asymmetry at a bifurcation is significantly larger for the coronary veins (1.7-6.8 for sinus veins) than the corresponding arteries (1.5-5.8 for left anterior descending coronary artery) for orders 2-10, respectively. The reported diameter asymmetry at a bifurcation leads to significant heterogeneity of blood flow at a bifurcation. Hence, the present data quantify the dispersion of blood flow at a bifurcation and are essential for understanding flow heterogeneity in the coronary circulation.     

Proteomic analysis of an orthotopic neuroblastoma xenograft animal model

Neuroblastoma is the most common extracranial solid tumour of childhood and comprises up to 50% of malignancies among infants. There is a great need of designing novel therapeutic strategies and proteome analysis is one approach for defining markers useful for tumour diagnosis, as well as molecular targets for novel experimental therapies. We started by comparing healthy adrenal glands (which are the election organs developing primary neuroblastoma, NB, tumours) and adrenal glands carrying primary NB tumours, taken from nude mice. Standard maps of healthy and tumour samples were generated by analysis with the PDQuest software. The comparison between such maps showed up- and down-regulation of 84 polypeptide chains, out of a total of 700 spots detected by a fluorescent stain, Sypro Ruby. Spots that were differentially expressed between the two groups, were analysed by MALDI-TOF mass spectrometry and 14 of these spots were identified so far. Among these proteins, of particular interest are the down-regulated proteins adrenodoxin (21-folds), carbonic anhydrase III (eight-folds) and aldose reductase related protein I (eight-folds), as well as the up-regulated protein peptidyl-propyl cis-trans isomerase A (five-folds). Moreover new proteins, which were absent in control samples, were expressed in tumour samples, such as nucleophosmin (NPM) and stathmin (oncoprotein 18).