Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and-D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and-D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and-D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer. © 2012 USCAP, Inc All rights reserved

Macroeconomic adjustment policies, health sector reform, and health care : an investigation of the macro - micro linkages

Meeting: MIMAP Annual Conference, Palawan, P

Low Genetic Differentiation in the Populations of the Malabar Carp Labeo dussumieri as revealed by Allozymes, Microsatellites and RAPD

The population structure of Labeo dussumieri, an endangered and endemic cyprinid from three riverine locations in the Western Ghats, India was investigated using allozyme, microsatellite and RAPD markers. L. dussumieri samples were obtained from Meenachil, Manimala and Pamba River basins, Kerala. Fourteen (46.7%) out of 30 allozyme loci, seven microsatellite loci and 12 RAPD Operon decamers gave polymorphic pattern. Six allozyme loci (AAT-2*, EST-4*, GLDH*, GPI-2*, G6PDH* and LDH-2*) and three microsatellite loci (LdussG1, MFW19 and Bgon22) exhibited consistent significant deviation from Hardy-Weinberg Equilibrium expectations in different populations after probability level (P<0.05) was adjusted for sequential Bonferroni correction. All the three marker types demonstrated concordant results and various estimates revealed genetic variability within the subpopulations but surprisingly low level (= 0.0034 to 0.0081) of genetic differentiation among L. dussumieri from different river samples. AMOVA analysis also indicated low differentiation among subpopulations. No evidence for a recent genetic bottleneck was observed in L. dussumieri populations based on allozyme and microsatellite data set analysis. Meenachil, Manimala and Pamba Rivers open in to the southern end of Vembanad Lake in Kerala and are connected to each other in the lower reaches through an extensive network of natural canals. Common ancestry in the prehistoric period; and possible mixing of fish populations resulting in high gene flow across the rivers through the lake and interconnecting canals could have been responsible for the lack of significant allelic heterogeneity among the L. dussumieri populations. The stocks from the three rivers do not require different management strategies and for propagation assisted river ranching programme of this species, large effective breeding population can be developed by mixing individuals from three river

A molecular approach to reveal the genetic identity of parrot mussel and other sympatric mussel species distributed along the Kerala coast

Two commercially important mussel species are recorded from the Indian coast: green mussel Perna viridis (Linnaeus, 1758) and brown mussel P. indica (Kuriakose and Nair, 1976). Apart from this, a third type referred to as parrot mussel, which has shell shape of brown mussel, but with green shell colouration and suspected to be the hybrid of the above two species has also been reported from Kollam coast of Kerala, where both the species co-occur. In the present work, genetic identity of parrot and sympatric mussel species was determined using protein and genomic DNA markers. Protein markers viz. Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE) and allozymes and the genomic DNA marker Random Amplified Polymorphic DNA (RAPD) were used for determining genetic identity of the three mussel groups. The green and brown mussels could be clearly differentiated using SDS PAGE. The parrot mussel protein pattern was similar to that of brown mussel, except for an additional band of molecular weight 48.7 Kda which is unique to brown mussel. Genus specific protein bands for Perna viz. 66 Kda, 43 Kda and 14.3 Kda, were detected in this study. Allozyme electrophoresis also followed a similar pattern. Of the 10 allozyme loci studied, seven revealed speciesspecific diagnostic differences between P.viridis and P.indica. They were AAT-1* (Aspartate Amino Transferase-1*), AAT-2*, ME (Malic Enzyme)*, PGM-2*(Phospo Gluco Mutase-2*), EST-1* (Esterase- 1*), EST-2*, IcDH* (Isocitrate Dehydrogenase)*. Parrot mussel shared all the alleles of brown mussel, and no hybrid pattern was observed. Species-specific alleles clearly differentiated green mussel from both brown and parrot mussel. The genetic distance of green mussel from brown mussel, estimated from allozyme data was 1.1145 and with parrot mussel it was 1.105. The genetic distance between parrot mussel and brown mussel was negligibly low (0.0005). Using allozyme and RAPD data, the Nei’s Unbiased Measures of genetic distance were calculated and the dendograms prepared based on these values clearly depicted the separation of parrot mussel from green mussel as well as the close resemblance of parrot mussel with brown mussel. The higher gene flow (1.1539) determined using RAPD marker also hints that brown and parrot mussel may be acting as single interbreeding population. Hence this study using molecular tools to test the genetic identity of parrot mussel has helped to conclude that parrot mussel is only a morphotype of brown mussel and not a true hybrid of the two

Empiric Radiotherapy for Lung Cancer Collaborative Group multi-institutional evidence-based guidelines for the use of empiric stereotactic body radiation therapy for non-small cell lung cancer without pathologic confirmation

The standard of care for managing early stage non-small cell lung cancer (NSCLC) is definitive surgical resection. Stereotactic body radiation therapy (SBRT) has become the standard treatment for patient who are medically inoperable, and it is increasingly being considered as an option in operable patients. With the growing use of screening thoracic CT scans for patients with a history of heavy smoking, as well as improved imaging capabilities, the discovery of small lung nodes has become a common dilemma. As a result, clinicians are increasingly faced with managing lung nodules in patients in whom diagnostic biopsy is not safe or feasible. Herein, we describe the scope of the problem, tools available for predicting the probability that a lung nodule is a malignancy, staging procedures, benefits of pathology-proven and empiric SBRT, considerations of safety based on location of the lesion of concern, and overall efficacy of SBRT

Paniya Voices: A Participatory Poverty and Health Assessment among a marginalized South Indian tribal population

<p>Abstract</p> <p>Background</p> <p>In India, indigenous populations, known as <it>Adivasi </it>or Scheduled Tribes (STs), are among the poorest and most marginalized groups. 'Deprived' ST groups tend to display high levels of resignation and to lack the capacity to aspire; consequently their health perceptions often do not adequately correspond to their real health needs. Moreover, similar to indigenous populations elsewhere, STs often have little opportunity to voice perspectives framed within their own cultural worldviews. We undertook a study to gather policy-relevant data on the views, experiences, and priorities of a marginalized and previously enslaved tribal group in South India, the Paniyas, who have little 'voice' or power over their own situation.</p> <p>Methods/design</p> <p>We implemented a Participatory Poverty and Health Assessment (PPHA). We adopted guiding principles and an ethical code that promote respect for Paniya culture and values. The PPHA, informed by a vulnerability framework, addressed five key themes (health and illness, well-being, institutions, education, gender) using participatory approaches and qualitative methods. We implemented the PPHA in five Paniya colonies (clusters of houses in a small geographical area) in a <it>gram panchayat </it>(lowest level decentralized territorial unit) to generate data that can be quickly disseminated to decision-makers through interactive workshops and public forums.</p> <p>Preliminary findings</p> <p>Findings indicated that the Paniyas are caught in multiple 'vulnerability traps', that is, they view their situation as vicious cycles from which it is difficult to break free.</p> <p>Conclusion</p> <p>The PPHA is a potentially useful approach for global health researchers working with marginalized communities to implement research initiatives that will address those communities' health needs in an ethical and culturally appropriate manner.</p

DNA barcoding Indian marine fishes

DNA barcoding has been adopted as a global bio-identification system for animals in recent years. A major national programme on DNA barcoding of fish and marine life was initiated in India by the authors during 2006 and 115 species of marine fish covering Carangids, Clupeids, Scombrids, Groupers, Sciaenids, Silverbellies, Mullids, Polynemids and Silurids representing 79 Genera and 37 Families from the Indian Ocean have been barcoded for the first time using cytochrome c oxidase I gene (COI) of the mtDNA. The species were represented by multiple specimens and a total of 397 sequences were generated. After amplification and sequencing of 707 base pair fragment of COI, primers were trimmed which invariably generated a 655 base pair barcode sequence. The average Kimura two parameter (K2P) distances within species, genera, families, orders were 0.30%, 6.60%, 9.91%, 16.00%, respectively. In addition to barcode-based species identification system, phylogenetic relationships among the species have also been attempted. The neighbour-joining tree revealed distinct clusters in concurrence with the taxonomic status of the species

A systematic review of population health interventions and Scheduled Tribes in India

<p>Abstract</p> <p>Background</p> <p>Despite India's recent economic growth, health and human development indicators of Scheduled Tribes (ST) or <it>Adivasi </it>(India's indigenous populations) lag behind national averages. The aim of this review was to identify the public health interventions or components of these interventions that are effective in reducing morbidity or mortality rates and reducing risks of ill health among ST populations in India, in order to inform policy and to identify important research gaps.</p> <p>Methods</p> <p>We systematically searched and assessed peer-reviewed literature on evaluations or intervention studies of a population health intervention undertaken with an ST population or in a tribal area, with a population health outcome(s), and involving primary data collection.</p> <p>Results</p> <p>The evidence compiled in this review revealed three issues that promote effective public health interventions with STs: (1) to develop and implement interventions that are low-cost, give rapid results and can be easily administered, (2): a multi-pronged approach, and (3): involve ST populations in the intervention.</p> <p>Conclusion</p> <p>While there is a growing body of knowledge on the health needs of STs, there is a paucity of data on how we can address these needs. We provide suggestions on how to undertake future population health intervention research with ST populations and offer priority research avenues that will help to address our knowledge gap in this area.</p