bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1
Authors: Shen H.-C. Jennifer , He Mei , Powell Anathea , Adem Asha , Lorang Dominique , Heller Charles , Grover Amelia C. , Ylaya Kris , Hewitt Stephen M. , Marx Stephen J. , Spiegel Allen M. , Libutti Steven K. 
Published: February 2009

Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutations in the MEN1 tumor suppressor gene. Whereas the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the remaining wild-type MEN1 allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrine specificity of the MEN1 syndrome, we evaluated biallelic loss of Men1 by inactivating Men1 in pancreatic progenitor cells using the Cre-lox system. Men1 deletion in progenitor cells that differentiate into exocrine and endocrine pancreas did not affect normal pancreas morphogenesis and development. However, mice having homozygous inactivation of the Men1 in pancreas developed endocrine tumors with no exocrine tumor manifestation, recapitulating phenotypes seen in the MEN1 patients. In the absence of menin, the endocrine pancreas showed increase in cell proliferation, vascularity, and abnormal vascular structures; such changes were lacking in exocrine pancreas. Further analysis revealed that these endocrine manifestations were associated with up-regulation in vascular endothelial growth factor expression in both human and mouse MEN1 pancreatic endocrine tumors. Together, these data suggest the presence of cell-specific factors for menin and a permissive endocrine environment for MEN1 tumorigenesis in endocrine pancreas. Based on our analysis, we propose that menin's ability to maintain cellular and microenvironment integrity might explain the endocrine- restrictive nature of the MEN1 syndrome. [Cancer Res 2009;69(5):1858–66]
Targeted Cancer Therapeutics
Authors: Hait William N. 
Published: February 2009

Abstract
Targeted therapies can be defined as drugs developed against a specific target based on its important biological function in cancer. In contrast, nontargeted therapies are drugs identified by phenotypic screening of natural products or chemical libraries against established cancer cell lines or preclinical animal models without a priori knowledge of the target. Targeted therapies are designed to selectively inhibit a target that is abnormal in malignant compared with normal tissues; these drugs often affect proximal events in signaling pathways that drive abnormal growth and have relatively low toxicity. In contrast, nontargeted therapies affect proteins or nucleic acids that may or may not be abnormal in malignant compared with normal tissues; these drugs often target the downstream consequences of activated signaling pathways, e.g., DNA synthesis and microtubule assembly, and are toxic. Whereas targeted therapies are highly effective in selected hematopoietic malignancies, most have shown limited efficacy against complex solid tumors. In contrast, nontargeted drugs include some of the most effective yet most toxic drugs in the oncology pharmacopoeia. In the future, advances in genomics, proteomics, biology, biomarkers, chemistry, and protein engineering will coalesce to accelerate the development of increasingly selective and effective targeted therapies. Understanding the target in context will help identify biomarkers predictive of response. Finally, a detailed understanding of the target's structure and function will help anticipate and identify mechanism of drug resistance and help design drugs and combinations of drugs that retain activity. [Cancer Res 2009;69(4):1263–7]
Anti–Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors
Authors: Li Betty , VanRoey Melinda , Wang Changyu , Chen Tseng-hui Timothy , Korman Alan , Jooss Karin 
Published: February 2009

Abstract
Purpose: The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)–secreting tumor cell immunotherapy, which is known to stimulate potent and long-lasting antigen-specific immune responses, in combination with PD-1 blockade, which has been shown to augment cellular immune responses.
Experimental Design: Survival studies were done in the B16 melanoma and CT26 colon carcinoma tumor models. Immune monitoring studies were done in the B16 model. GM-CSF–secreting tumor cell immunotherapy was administered s.c. and the anti–PD-1 antibody was administered i.p.
Results: The studies reported here show that combining PD-1 blockade with GM-CSF–secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with strong antigen-specific T-cell responses detected by tetramer staining and an in vivo CTL assay, higher secretion levels of proinflammatory cytokines by splenocytes, and the persistence of functional CD8+ T cells in the tumor microenvironment. Furthermore, in the biweekly multiple treatment setting, repeated antigen-specific T-cell expansion was only observed following administration of the cellular immunotherapy with the PD-1 blockade and not when the cellular immunotherapy or PD-1 blockade was used as monotherapy.
Conclusion: The combination of PD-1 blockade with GM-CSF–secreting tumor cell immunotherapy leads to significantly improved antitumor responses by augmenting the tumor-reactive T-cell responses induced by the cellular immunotherapy. Readministration of the cellular immunotherapy with the anti–PD-1 antibody in subsequent immunotherapy cycles was required to reactivate these T-cell responses.
Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells
Authors: Gallia Gary L. , Tyler Betty M. , Hann Christine L. , Siu I-Mei , Giranda Vincent L. , Vescovi Angelo L. , Brem Henry , Riggins Gregory J. 
Published: February 2009

Abstract
A commonly activated signaling cascade in many human malignancies, including glioblastoma multiforme, is the Akt pathway. This pathway can be activated via numerous upstream alterations including genomic amplification of epidermal growth factor receptor, PTEN deletion, or PIK3CA mutations. In this study, we screened phosphatidylinositol 3-kinase/Akt small-molecule inhibitors in an isogenic cell culture system with an activated Akt pathway secondary to a PIK3CA mutation. One small molecule, A-443654, showed the greatest selective inhibition of cells with the mutant phenotype. Based on these findings, this inhibitor was screened in vitro against a panel of glioblastoma multiforme cell lines. All cell lines tested were sensitive to A-443654 with a mean IC50 of ∼150 nmol/L. An analogue of A-443654, methylated at a region that blocks Akt binding, was on average 36-fold less active. Caspase assays and dual flow cytometric analysis showed an apoptotic mechanism of cell death. A-443654 was further tested in a rat intracranial model of glioblastoma multiforme. Animals treated intracranially with polymers containing A-443654 had significantly extended survival compared with control animals; animals survived 79% and 43% longer than controls when A-443654-containing polymers were implanted simultaneously or in a delayed fashion, respectively. This small molecule also inhibited glioblastoma multiforme stem-like cells with similar efficacy compared with traditionally cultured glioblastoma multiforme cell lines. These results suggest that local delivery of an Akt small-molecule inhibitor is effective against experimental intracranial glioma, with no observed resistance to glioblastoma multiforme cells grown in stem cell conditions. [Mol Cancer Ther 2009;8(2):386–93]
Blood flow and Vd (water): both biomarkers required for interpreting the effects of vascular targeting agents on tumor and normal tissue
Authors: Kötz Barbara , West Catharine , Saleem Azeem , Jones Terry , Price Patricia 
Published: February 2009

Abstract
Positron emission tomography studies with oxygen-15–labeled water provide in vivo quantitative tissue perfusion variables—blood flow and fractional volume of distribution of water [Vd (water)]. To investigate the relationship between perfusion variables and the effect of vascular-targeting agents on vasculature, we measured tissue perfusion in tumors, spleen, kidney, and liver before and after treatment with combretastatin-A4-phosphate, a combination of nicotinamide and carbogen (N/C), and interferon (IFN). We observed that mean tumor blood flow and Vd (water) was lower than in kidney, liver, and spleen at baseline. Blood flow and Vd (water) were related in tumor (r = 0.62; P = 0.004) at baseline, but not in other normal tissues evaluated, where minimal variations in Vd (water) were observed over a wide range of blood flow. Despite the relationship between blood flow and Vd (water) in tumors before intervention, vascular-targeting agent–induced changes in these perfusion variables were not correlated. In contrast, changes in blood flow and Vd (water) correlated in kidney and spleen after N/C and in kidney after combretastatin-A4-phosphate. The close relation between blood flow and Vd (water) in tumors but not normal tissue may reflect barriers to fluid exchange in tumors because of necrosis and/or increased interstitial fluid pressure and underlies the importance and interdependence of these positron emission tomography perfusion variables under these conditions. As blood flow and Vd (water) signify different aspects of tissue perfusion, the differential effects of interventions on both variables, flow and Vd (water), should therefore be reported in future studies. [Mol Cancer Ther 2009;8(2):303–9]
Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4
Authors: Samarin Jana , Rehm Margot , Krueger Bettina , Waschke Jens , Goppelt-Struebe Margarete 
Published: February 2009

Abstract
Incubation of microvascular endothelial cells with combretastatin A-4 phosphate (CA-4P), a microtubule-destabilizing compound that preferentially targets tumor vessels, altered cell morphology and induced scattering of Golgi stacks. Concomitantly, CA-4P up-regulated connective tissue growth factor (CTGF/CCN2), a pleiotropic factor with antiangiogenic properties. In contrast to the effects of other microtubule-targeting agents such as colchicine or nocodazole, up-regulation of CTGF was only detectable in sparse cells, which were not embedded in a cell monolayer. Furthermore, CA-4P induced CTGF expression in endothelial cells, forming tube-like structures on basement membrane gels. Up-regulation of CTGF by CA-4P was dependent on Rho kinase signaling and was increased when p42/44 mitogen-activated protein kinase was inhibited. Additionally, FoxO transcription factors were identified as potent regulators of CTGF expression in endothelial cells. Activation of FoxO transcription factors by inhibition of phosphatidylinositol 3-kinase/AKT signaling resulted in a synergistic increase in CA-4P-mediated CTGF induction. CA-4P-mediated expression of CTGF was thus potentiated by the inhibition of kinase pathways, which are targets of novel antineoplastic drugs. Up-regulation of CTGF by low concentrations of CA-4P may thus occur in newly formed tumor vessels and contribute to the microvessel destabilization and antiangiogenic effects of CA-4P observed in vivo. (Mol Cancer Res 2009;7(2):180–8)
Annual dynamics of sperm production and storage in the Mediterranean Gecko, Hemidactylus turcicus, in the southeastern United States
Authors: Eckstut Mallory E. , Lemons Erica Rottmann , Sever David M. 
Published: February 2009

Abstract
The Mediterranean Gecko, Hemidactylus turcicus, is an invasive species found
in warmer regions throughout the world, including the southern United
States. In Louisiana, H. turcicus appears to be free of competition and has
been rapidly expanding its range in the past several decades. However, in
Florida and Texas, H. turcicus is heavily out-competed by closely related
competitors that do not occur in Louisiana, including H. frenatus, of which
a substantial amount of reproductive morphology and ecology is known.
Although the reproductive cycle of H. turcicus has been studied in Florida
and Louisiana, little is known about the seasonal variation of their oviduct
and if they are capable of storing sperm, which can have substantial
implications for reproductive competition. We analysed sperm production,
storage and seasonal variation in the testes and oviducts of H. turcicus
using light and electron microscopy. Previous studies found that female H.
frenatus store sperm in the uterine-infundibular region for up to 36 weeks,
and that their oviducts are active year-round. In H. turcicus, we found that
sperm are stored in the uterine-infundibular region of the oviduct, and
sperm are stored from May through August. Hemidactylus turcicus has one
breeding season per year, producing three to four clutches between May and
August, but between September and February minimal activity occurs in the
oviduct. Additionally, male H. turcicus are producing sperm throughout the
entire reproductive season, but whether females utilize stored sperm to
fertilize eggs or if they mate continually throughout the spring and summer
is unknown.
Variation of body size, age structure and growth of a temperate frog, Rana chensinensis, over an elevational gradient in Northern China
Authors: Ma Xiaoyan , Tong Lina , Lu Xin 
Published: February 2009

Abstract
Identifying the patterns of body size, age and growth in relation to
environments may help us to understand the evolution of life history of
organisms. This study compared the variability in these demographic traits
of a temperate frog, Rana chensinensis, among populations from Northern
China located at three elevations (567, 1470 and 1700 m) with distinct mean
annual temperature (12.1, 5.8 and 3.9°C). Overall, frogs from higher
elevations tended to be larger in body size, partially because despite
shorter growing seasons, they lived longer as a result of delayed maturity.
However, discordance with the expected cline was detected between
neighboring populations and the variation was sex specific. Adult females
became significantly older and larger as elevation varied from 567 m to 1470
m, but the two traits no longer increased with an elevational shift from
1470 m to 1700 m. Adult males at 1470 m were similar in age and size to
animals at 567 m but significantly younger and smaller than those at 1700 m.
This suggested that sexes could be exposed to different pressures along
elevation gradients with females being stronger than males in life history
responses to the elevation-induced environmental change. We also showed that
factors other than age also contributed to size differences both among
populations and between the sexes.
Mitochondrial phylogeography of Testudo graeca in the Western Mediterranean: Old complex divergence in North Africa and recent arrival in Europe
Authors: Fritz Uwe , Harris D. James , Fahd Soumia , Rouag Rachid , Graciá Martínez Eva , Giménez Casalduero Andrés , Široký Pavel , Kalboussi Mohsen , Jdeidi Tarek B. , Hundsdörfer Anna K. 
Published: February 2009

Abstract
We investigated the mitochondrial phylogeography of spur-thighed tortoises
(Testudo graeca) in the Western Mediterranean. In North Africa, four major
lineages (A-D) occur that together constitute a well-supported clade
corresponding to one of the six major clades within T. graeca; the North
African clade is sister to a Caucasian clade representing the subspecies T.
g. armeniaca. Phylogenetic relationships between the North African lineages
are badly resolved. Lineage A is distributed in Tunisia and adjacent
Algeria, lineage B in Algeria and northern Morocco, lineage C in the Libyan
Cyrenaica Peninsula, and lineage D north of the High Atlas Mts. and in the
Souss Valley (southern Morocco). Lineage B is subdivided into two subgroups,
B1 (eastern Morocco and Algeria) and B2 (north-western Morocco). Italian
tortoises harbour haplotypes of lineage A, Spanish tortoises of subgroup B1.
Based on a relaxed molecular clock calibrated with fossil evidence, the six
major mtDNA clades of T. graeca are estimated to have diverged approximately
4.2-1.8 Ma ago; the split between the clades representing the eastern
subspecies T. g. ibera and T. g. terrestris is younger than the split
between Western Mediterranean tortoises and T. g. armeniaca. The Western
Mediterranean lineages A-D were dated to have diverged at least 1.4-1.1 Ma
ago; B1 and B2 split approximately 0.7 Ma ago. Our results suggest that
Italian and Spanish tortoises were either introduced or originated from
trans-oceanic dispersal in historic or prehistoric times. Spur-thighed
tortoises invaded North Africa probably across Near Eastern landbridges that
emerged in the Late Tertiary. Their diversification in North Africa seems to
be correlated with habitat aridization cycles during the Pleistocene. The
ranges of the Western Mediterranean lineages largely correspond to the
distribution of morphologically defined subspecies in North Africa, with
exception of T. g. graeca and T. g. whitei, and of T. g. lamberti and T. g.
marokkensis, which are not differentiated. We propose to lump the first two
subspecies under the name of T. g. graeca and the latter under the name of
T. g. marokkensis. The complex differentiation of spur-thighed tortoises in
North Africa implies that the model of a bipartite east-west
differentiation, as proposed for other Maghrebian amphibians and reptiles,
may be too simplistic, reflecting incomplete locality sampling rather than
actual phylogeographic differentiation.
Measuring species diversity to determine land-use effects on reptile and amphibian assemblages
Authors: Hutchens Stan , DePerno Christopher 
Published: February 2009

AbstractPopulations of herpetofauna are declining globally primarily due to land-use practices (e.g., silviculture or conversion to agriculture) and declines require monitoring of all herpetofauna communities. Therefore, forest management plans for Bull Neck Swamp, a pocosin wetland in North Carolina, USA, initiated an inventory of the herpetofauna community. Our objectives were to: (1) derive diversity measures for four designated habitat preserves (i.e., Atlantic whitecedar [Chamaecyparis thyoides], Pond pine [Pinus serotina], Non-riverine Swamp, and Shoreline/Islands) and a Forest manageable area, (2) determine if there were benefits to habitat preserves for the herpetofauna community, and (3) provide recommendations for future monitoring. We employed 11 different sampling techniques across the four habitat preserves and Forest manageable area. Species richness estimates and similarity indices were derived using EstimateS 8.0. For post hoc comparisons, we derived species distributions with the Nestedness Temperature Calculator Program. Observed species richness ranged from 7 to 32 species (S = 13 to 44) and abundances ranged from 99 to 873 individuals. Similarity indices suggested species compositions were similar among habitats. Further, nestedness temperature (T = 12.6°C) indicated an even species distribution among assemblages. Comparable similarity indices among habitats, an even species distribution, and habitat continuity suggested management practices would have little impact on the herpetofauna community. Nevertheless, future management practices should be carefully considered and planned to mitigate effects to individual species. We recommend studies employ species richness, relative abundance, species composition, and distribution as conservation tools when inventorying or monitoring herpetofauna communities.
Genetic differentiation in two European tree frog (Hyla arborea) metapopulations in contrasted landscapes of western Switzerland
Authors: Dubey Sylvain , Ursenbacher Sylvain , Pellet Jérôme , Fumagalli Luca 
Published: February 2009

Abstract
The survival of threatened species as the European tree frog (Hyla arborea)
is strongly dependent on the genetic variability within populations, as well
as gene flow between them. In Switzerland, only two sectors in its western
part still harbour metapopulations. The first is characterised by a very
heterogeneous and urbanized landscape, while the second is characterised by
a uninterrupted array of suitable habitats. In this study, six
microsatellite loci were used to establish levels of genetic differentiation
among the populations from the two different locations. The results show
that the metapopulations have: (i) weak levels of genetic differentiation
(FST within metapopulation ≈ 0.04), (ii) no difference in levels of genetic
structuring between them, (iii) significant (p = 0.019) differences in terms
of genetic diversity (Hs) and observed heterozygozity (Ho), the
metapopulation located in a disturbed landscape showing lower values. Our
results suggest that even if the dispersal of H. arborea among contiguous
ponds seems to be efficient in areas of heterogeneous landscape, a loss of
genetic diversity can occur.
Body temperature, size, nuptial colouration and mating success in male Moor Frogs (Rana arvalis)
Authors: Hettyey Attila , Herczeg Gábor , Laurila Anssi , Crochet Pierre-André , Merilä Juha 
Published: February 2009

Abstract
Variation in colouration has rarely been related to sexual selection in
anuran amphibians, even though such a relationship has been proven for many
other vertebrate taxa. Male and female Moor Frogs (Rana arvalis) have a
cryptic brown colour pattern, but males develop a conspicuous blue nuptial
colouration during the reproductive season. To investigate the possibility
that colouration plays a role in sexual selection in this species, we
studied the temporal variation in blue colouration, determined if body size
or body temperature affected blueness and investigated if blueness of males
could be related to their mating success. Results confirmed previous
observations that males develop and maintain blue colouration for only a
very few nights during peak reproductive activity. Colouration of males was
unrelated to body size, but males exhibiting higher body temperatures were
somewhat bluer than males with lower body temperatures. Further, males in
amplexus had higher body temperatures than non-mated males. Finally, mating
success was positively related to blueness in small males, whereas in large
males no such relationship was detected. While our results align with the
hypothesis that the bright blue colouration of males may be a target of
sexual selection, alternative explanations are also discussed.
The complete mitochondrial DNA genome of Eremias brenchleyi (Reptilia: Lacertidae) and its phylogeny position within squamata reptiles
Authors: Rui Jinlong , Wang Yuting , Nie Liuwang 
Published: February 2009

Abstract
Squamata is the most diversified reptilian order that has been traditionally
classified into three suborders – Lacertilia, Serpentes and Amphisbaenia in
which Lacertilia have about 16-19 families. But the phylogenetic
relationships among major groups of Lacertilia remain controversial. In this
paper, the complete mitochondrial DNA sequence of Eremias brenchleyi was
determined by using long-and-accurate PCR (LA-PCR). The mtDNA sequence is 19
542 bp, making it the longest mitochondrial genome in squamates species
reported so far. It shows the typical vertebrate arrangement of genes. The
control region of E. brenchleyi was characterized by two conspicuous 65 bp
and 56 bp tandem repeats at its 5′ and 3′ terminus respectively. In order to
study the higher level relationships of squamates, the phylogenetic study
including all currently available squamates mitochondrial sequences was
carried out. We obtained a relationship of 16 families of lizards
(Lacertidae, Scincidae, Iguanidae, Chameleonidae, Agamidae, Trogonophidae,
Bipedidae, Shinisauridae, Helodermatidae, Amphisbaenidae, Gekkonidae,
Varanidae, Anguidae, Xantusiidae, Rhineuridae, Cordylidae) and 8 families of
Serpentes. The internal relationships within this group yielded high
bootstrap support and were more congruent with morphological analyses.