Evaluation of the Antitumor Activity of Dacomitinib in Models of Human Bladder Cancer

Members of the human epidermal growth factor receptor (HER) family play a significant role in bladder cancer progression and may underlie the development of chemotherapy resistance. Dacomitinib is an irreversible tyrosine kinase inhibitor with structural specificity for the catalytic domains of epidermal growth factor receptor (EGFR), HER2 and HER4 that has exhibited vigorous efficacy against other solid tumors. We evaluated the antitumor activity of dacomitinib in human bladder cancer cell lines expressing varying levels of HER family receptors. These cell lines also were established as bladder cancer xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to assess dacomitinib activity in vivo. Significant cytotoxic and cytostatic effects were noted in cells expressing elevated levels of the dacomitinib target receptors with apoptosis and cell cycle arrest being the predominant mechanisms of antitumor activity. Cells expressing lower levels of HER receptors were much less sensitive to dacomitinib. Interestingly, dacomitinib was more active than either trastuzumab or cetuximab in vitro, and exhibited increased growth inhibition of bladder tumor xenografts compared with lapatinib. Pharmacodynamic effects of dacomitinib included decreased E-cadherin (E-cad) expression, reduction of EGFR and extracellular signal-regulated kinase (ERK) phosphorylation and reduced mitotic count. Dacomitinib also inhibited tumor growth in a chemotherapy-resistant xenograft and, when combined with chemotherapy in a sensitive xenograft, exhibited superior antitumor effects compared with individual treatments. Evaluation in xenograft-bearing mice revealed that this combination was broadly feasible and well tolerated. In conclusion, dacomitinib exhibited pronounced activity both as a single agent and when combined with chemotherapy in human bladder cancer models. Further investigation of dacomitinib in the preclinical and clinical trial settings is being pursued.     

Putting your eggs in several baskets: oviposition in a wasp that walks between several figs

The interaction between figs (Ficus spp., Moraceae) and their pollinator fig wasps (Hymenoptera: Agaonidae) is an obligate mutualism, but females of dioecious fig trees exploit fig wasps without providing rewards. Figs are closed inflorescences that typically trap pollinator females after entry, but some fig wasp species can re‐emerge (although wingless) and subsequently oviposit in and pollinate further figs. Using glasshouse populations, we examined the sex ratios and clutches laid by single foundresses of Kradibia tentacularis (Grandi) in their first and subsequent male figs of Ficus montana Blume, and how the probability of emergence and entering a second fig varied between seasons. A maximum of four figs were entered by any one foundress. Wingless foundresses were able to locate and enter figs up to 60 cm from the first fig they entered, but the probability of entry declined sharply with distance from that fig. The foundresses that re‐emerged produced slightly higher adult offspring totals than those that failed to re‐emerge. Clutch sizes of a single foundress in its first fig equalled those in all the subsequent figs combined, with clutch size per fig decreasing when more figs were entered. Smaller clutches had less female‐biased sex ratios. Figs were more numerous in summer than in winter, but the proportion of figs entered by only wingless foundresses remained unchanged. Movement between figs increases pollinator reproductive success in male figs, thereby encouraging foundresses that encounter a female tree to also move between and pollinate several female figs.     

The taxonomy and systematics of Apocynaceae: where we stand in 2012

In their most recent classification of Apocynaceae in 2000, Endress and Bruyns recognized five subfamilies of Apocynaceae (Rauvolfioideae, Apocynoideae, Periplocoideae, Secamonoideae and Asclepiadoideae). Subsequently, through various studies using molecular data, it has been shown that most tribes and subtribes of Rauvolfioideae were not monophyletic, and new tribes and subtribes have been erected to reflect improved phylogenetic understanding of the family: Aspidospermeae in Rauvolfioideae; Nerieae, Odontadenieae and Baisseeae in Apocynoideae; Fockeeae in Asclepiadoideae; and Orthosiinae in Asclepiadeae. Several genera in Rauvolfioideae have been reassigned to different tribes in order to improve the monophyly of these tribes. The sister group of Asclepiadoideae plus Secamonoideae is not Periplocoideae, as formerly assumed, but tribe Baisseeae. Periplocoideae are nested in Apocynoideae. However, tribal composition remains unclear in some parts of the family. Clade structure in Apocynaceae is now generally well understood. The principal challenges now lie in identifying characters that can reflect and articulate these clades in a formal classification. Species‐rich, recent radiations such as core Asclepiadinae in Africa and the Metastematinae in Latin America present particular problems in this regard. © 2013 The Linnean Society of London     

Variation in inflorescence size in a dioecious fig tree and its consequences for the plant and its pollinator fig wasp

The host-specific relationship between fig trees (Ficus) and their pollinator wasps (Agaonidae) is a classic case of obligate mutualism. Pollinators reproduce within highly specialised inflorescences (figs) of fig trees that depend on the pollinator offspring for the dispersal of their pollen. About half of all fig trees are functionally dioecious, with separate male and female plants responsible for separate sexual functions. Pollen and the fig wasps that disperse it are produced within male figs, whereas female figs produce only seeds. Figs vary greatly in size between different species, with female flower numbers varying from tens to many thousands. Within species, the number of female flowers present in each fig is potentially a major determinant of the numbers of pollinator offspring and seeds produced. We recorded variation in female flower numbers within male and female figs of the dioecious Ficus montana growing under controlled conditions, and assessed the sources and consequences of inflorescence size variation for the reproductive success of the plants and their pollinator (Kradibia tentacularis). Female flower numbers varied greatly within and between plants, as did the reproductive success of the plants, and their pollinators. The numbers of pollinator offspring in male figs and seeds in female figs were positively correlated with female flower numbers, but the numbers of male flowers and a parasitoid of the pollinator were not. The significant variation in flower number among figs produced by different individuals growing under uniform conditions indicates that there is a genetic influence on inflorescence size and that this character may be subject to selection.     

Morphological and molecular characterization of selected <Emphasis Type="Italic">Artemisia</Emphasis> species from Rawalakot,Azad Jammu and Kashmir

Artemisia is an important genus of Asteraceae and has a high number of taxa, ecological and economic importance. Its natural classification has not been achieved and the taxonomists are trying to solve the problem of its classification over the last two decades. The genus Artemisia can be divided into five large sections namely: Absinthium DC, Artemisia L., Dracunculus Besser, Seriphidium Besser and Tridentatae (Rybd.). In the present study, three species (A. vulgaris, A. roxburghiana and A. absinthium) belonging to groups Artemisia (A. vulgaris and A. roxburghiana) and Absinthium (A. absinthium) were collected from Rawalakot, Azad Jammu and Kashmir. The species were analyzed for the assessment of morphological and genetic diversity and relationship was estimated among and within the different species of Artemisia. The morphological and molecular data were analyzed using software NTSYS (Numerical Taxonomy and Multivariate Analysis System) pc version 2.01. For molecular study, random amplification of polymorphic DNA (RAPD) was used to detect genetic variations among the species. Out of the ten random primers used, nine have given amplification profiles. A total 611 bands were produced by all the primers, of which 419 were polymorphic and level of polymorphism was detected to be 68% across all the samples of studied species. Based on the results obtained, it has been observed that there is a wide range of diversity both at morphological and molecular level among and within the species. Further, mixed pattern of grouping in cluster analysis was found, indicating the close affinities of species with each other.     

Molecular characterization of dengue and chikungunya virus strains circulating in New Delhi,India

Dengue and chikungunya are acute viral infections with overlapping clinical symptoms. Both diseases are transmitted by common mosquito vectors resulting in their co‐circulation in a region. Molecular and serological tests specific for both dengue and chikungunya infections were performed on 87 acute phase blood samples collected from patients with suspected dengue/chikungunya infections in Delhi from September to December, 2011. RT‐PCR and IgM ELISA were performed to detect dengue virus (DENV) and chikungunya virus (CHIKV). NS1 and IgG ELISA were also performed to detect DENV specific antigen and secondary DENV infection. DENV infection was detected in 49%, CHIKV infection in 29% and co‐infection with DENV and CHIKV in 10% of the samples by RT‐PCR. DENV serotypes 1, 2 and 3 were detected in this study. Nine DENV‐1 strains, six DENV‐2 strains and 20 CHIKV strains were characterized by DNA sequencing and phylogenetic analysis of their respective envelope protein genes. DENV‐1 strains grouped in the American African genotype, DENV‐2 strains in the Cosmopolitan genotype and CHIKV strains in the East Central South African genotype by phylogenetic analysis. This is one of the few studies reporting the phylogeny of two dengue virus serotypes (DENV‐1 and DENV‐2) and CHIKV. Surveillance and monitoring of DENV and CHIKV strains are important for design of strategies to control impending epidemics.     

Lipid productivity and fatty acid composition-guided selection of Chlorella strains isolated from Malaysia for biodiesel production

The need to develop biomass-based domestic production of high-energy liquid fuels (biodiesel) for transportation can potentially be addressed by exploring microalgae with high lipid content. Selecting the strains with adequate oil yield and quality is of fundamental importance for a cost-efficient biofuel feedstock production based on microalgae. This work evaluated 29 strains of Chlorella isolated from Malaysia as feedstock for biodiesel based on volumetric lipid productivity and fatty acid profiles. Phylogenetic studies based on 18S rRNA gene revealed that majority of the strains belong to true Chlorella followed by Parachlorella. The strains were similarly separated into two groups based on fatty acid composition. Of the 18 true Chlorella strains, Chlorella UMACC187 had the highest palmitic acid (C16:0) content (71.3?±?4.2 % total fatty acids, TFA) followed by UMACC84 (70.1?±?0.7 %TFA), UMACC283 (63.8?±?0.7 %TFA), and UMACC001 (60.3?±?4.0 %TFA). Lipid productivity of the strains at exponential phase ranged from 34.53 to 230.38 mg L^?1 day^?1, with Chlorella UMACC050 attaining the highest lipid productivity. This study demonstrated that Chlorella UMACC050 is a promising candidate for biodiesel feedstock production.     

Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Copper (II) Complex against Ethanol-Induced Acute Gastric Lesions in Rats

Background

Copper is an essential element in various metabolisms. The investigation was carried out to evaluate acute gastroprotective effects of the Copper (II) complex against ethanol-induced superficial hemorrhagic mucosal lesions in rats.

Methodology/Principal Findings

Rats were divided into 7 groups. Groups 1 and 2 were orally administered with Tween 20 (10% v/v). Group 3 was orally administered with 20 mg/kg omeprazole (10% Tween 20). Groups 4–7 received 10, 20, 40, and 80 mg/kg of the complex (10% Tween 20), respectively. Tween 20 (10% v/v) was given orally to group 1 and absolute ethanol was given orally to groups 2–7, respectively. Rats were sacrificed after 1 h. Group 2 exhibited severe superficial hemorrhagic mucosal lesions. Gastric wall mucus was significantly preserved by the pre-treatment complex. The results showed a significant increase in glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), and Prostaglandin E2 (PGE₂) activities and a decrease in malondialdehyde (MDA) level. Histology showed marked reduction of hemorrhagic mucosal lesions in groups 4–7. Immunohistochemical staining showed up-regulation of Hsp70 and down-regulation of Bax proteins. PAS staining of groups 4–7 showed intense stain uptake of gastric mucosa. The acute toxicity revealed the non-toxic nature of the compound.

Conclusions/Significance

The gastroprotective effect of the Copper (II) complex may possibly be due to preservation of gastric wall mucus; increase in PGE₂ synthesis; GSH, SOD, and NO up-regulation of Hsp70 protein; decrease in MDA level; and down-regulation of Bax protein.