Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS

Expression of the neural stem cell markers NG2 and L1 in human angiomyolipoma: are angiomyolipomas neoplasms of stem cells?

Angiomyolipomas are benign tumors of the kidney which express phenotypes of smooth muscle, fat, and melanocytes. These tumors appear with increased frequency in the autosomal dominant disorder tuberous sclerosis and are the leading cause of morbidity in adults with tuberous sclerosis. While benign, these tumors are capable of provoking life threatening hemorrhage and replacement of the kidney parenchyma, resulting in renal failure. The histogenesis of these tumors is currently unclear, although currently, we believe these tumors arise from perivascular epithelioid cells of which no normal counterpart has been convincingly demonstrated. Recently, stem cell precursors have been recognized that can give rise to smooth muscle and melanocytes. These precursors have been shown to express the neural stem cell marker NG2 and L1. In order to determine whether angiomyolipomas, which exhibit smooth muscle and melanocytic phenotypes, express NG2 and L1, we performed immunocytochemistry on a cell line derived from a human angiomyolipoma, and found that these cells are uniformly positive. Immunohistochemistry of human angiomyolipoma specimens revealed uniform staining of tumor cells, while renal cell carcinomas revealed positivity only of angiogenic vessels. These results support a novel histogenesis of angiomyolipoma as a defect in differentiation of stem cell precursors

Honokiol, a Small Molecular Weight Natural Product, Inhibits Angiogenesis in Vitro and Tumor Growth in Vivo

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent

A landscape-level assessment of Asian elephant habitat, its population and elephant-human conflict in the Anamalai hill ranges of southern Western Ghats, India

Spatial information at the landscape scale is extremely important for conservation planning, especially in the case of long-ranging vertebrates. The biodiversity-rich Anamalai hill ranges in the Western Ghats of southern India hold a viable population for the long-term conservation of the Asian elephant. Through rapid but extensive field surveys we mapped elephant habitat, corridors, vegetation and land-use patterns, estimated the elephant population density and structure, and assessed elephant-human conflict across this landscape. GIS and remote sensing analyses indicate that elephants are distributed among three blocks over a total area of about 4600 km(2). Approximately 92% remains contiguous because of four corridors; however, under 4000 km2 of this area may be effectively used by elephants. Nine landscape elements were identified, including five natural vegetation types, of which tropical moist deciduous forest is dominant. Population density assessed through the dung count method using line transects covering 275 km of walk across the effective elephant habitat of the landscape yielded a mean density of 1.1 (95% Cl = 0.99-1.2) elephant/km(2). Population structure from direct sighting of elephants showed that adult male elephants constitute just 2.9% and adult females 42.3% of the population with the rest being subadults (27.4%), juveniles (16%) and calves (11.4%). Sex ratios show an increasing skew toward females from juvenile (1:1.8) to sub-adult (1:2.4) and adult (1:14.7) indicating higher mortality of sub-adult and adult males that is most likely due to historical poaching for ivory. A rapid questionnaire survey and secondary data on elephant-human conflict from forest department records reveals that villages in and around the forest divisions on the eastern side of landscape experience higher levels of elephant-human conflict than those on the western side; this seems to relate to a greater degree of habitat fragmentation and percentage farmers cultivating annual crops in the east. We provide several recommendations that could help maintain population viability and reduce elephant-human conflict of the Anamalai elephant landscape. (C) 2013 Deutsche Gesellschaft far Saugetierkunde. Published by Elsevier GmbH. All rights reserved

Application of integrated petroleum reservoir study for intervention and field development program in western onshore field, India

In this research, an integrated reservoir study is performed in the J#Field (J-Oil Field) of western onshore, India to evaluate its additional reserves expectations and implement field developments plan using waterflood pilot program. The target strata includes two formations of Paleogene, which is about 3600 ft, namely G#Fm (G-Formation) of the Eocene and T#Fm (T-Formation) of Oligocene, subdivided into 11 zones. Based on these results, an attempt was made to construct of an optimization plan to exploit it, taking into account that the field is producing since 1947, with a cumulative production of 183.5 MMbbl and an overall recovery factor of 28% until January 2016. On the basis of the potential evaluation and geological modeling, blocks J48 and J45 were simulated, and the remaining oil distribution characteristics in two blocks were studied after history match. The work includes the stratigraphic studies, seismic study, logging interpretation, sedimentary facies modeling, three dimensional geological modeling, simulations for waterflooding, and future field development plans

Mosquito diversity in Keeriparai and Mundanthurai hill ranges of the Western Ghats, southern India

After a gap of 25 years the Centre for Research in Medical Entomology (CRME) surveyed the mosquito biodiversity in the tail-end hill ranges of the Western Ghats, viz., Kanyakumari (Keeriparai) and Tirunelveli districts (Kalakkad-Mundanthurai Tiger Reserve (KMTR) and Courtallam) of Tamil Nadu between July 2010 and June 2013.  The altitude of the hills ranged from 100–950 m covered by evergreen forests.  A major emphasis was given to collect the immature stages of mosquitoes, from various breeding habitats, viz., slow flowing streams, spring pool, rocky pool, leaf axils, latex cup, tree hole, bamboo stumps, etc.  Altogether 4602 immature individuals were collected, reared individually to be identified at the adult stage.  A total of 3583 specimens belonging to 50 species classified under 21 genera and 18 subgenera were recorded.  The major vector species found in these hill ranges were Stegomyia aegypti, S. albopicta (Dengue and Chikungunya), Culex bitaeniorhynchus, C. tritaeniorhynchus (Japanese encephalitis), Downsiomyia nivea (diurnally subperiodic filariasis) and Anopheles mirans (Simian malaria) vectors were recorded. </div

Mosquito diversity in Keeriparai and Mundanthurai hill ranges of the Western Ghats, southern India

After a gap of 25 years the Centre for Research in Medical Entomology (CRME) surveyed the mosquito biodiversity in the tail-end hill ranges of the Western Ghats, viz., Kanyakumari (Keeriparai) and Tirunelveli districts (Kalakkad-Mundanthurai Tiger Reserve (KMTR) and Courtallam) of Tamil Nadu between July 2010 and June 2013.  The altitude of the hills ranged from 100–950 m covered by evergreen forests.  A major emphasis was given to collect the immature stages of mosquitoes, from various breeding habitats, viz., slow flowing streams, spring pool, rocky pool, leaf axils, latex cup, tree hole, bamboo stumps, etc.  Altogether 4602 immature individuals were collected, reared individually to be identified at the adult stage.  A total of 3583 specimens belonging to 50 species classified under 21 genera and 18 subgenera were recorded.  The major vector species found in these hill ranges were Stegomyia aegypti, S. albopicta (Dengue and Chikungunya), Culex bitaeniorhynchus, C. tritaeniorhynchus (Japanese encephalitis), Downsiomyia nivea (diurnally subperiodic filariasis) and Anopheles mirans (Simian malaria) vectors were recorded. </div