bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression
Authors: Duvvuri Umamaheswar , Shiwarski Daniel J. , Xiao Dong , Bertrand Carol , Huang Xin , Edinger Robert S. , Rock Jason R. , Harfe Brian D. , Henson Brian J. , Kunzelmann Karl , Schreiber Rainer , Seethala Raja S. , Egloff Ann Marie , Chen Xing , Lui Vivian W. , Grandis Jennifer R. , Gollin Susanne M. 
Published: May 2012

Abstract
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal–regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN. Cancer Res; 72(13); 3270–81. ©2012 AACR.
Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment
Authors: Nüesch Jürg P.F. , Lacroix Jeannine , Marchini Antonio , Rommelaere Jean 
Published: May 2012

AbstractRodent parvoviruses (PV) are recognized for their intrinsic oncotropism and oncolytic activity, which contribute to their natural oncosuppressive effects. Although PV uptake occurs in most host cells, some of the subsequent steps leading to expression and amplification of the viral genome and production of progeny particles are upregulated in malignantly transformed cells. By usurping cellular processes such as DNA replication, DNA damage response, and gene expression, and/or by interfering with cellular signaling cascades involved in cytoskeleton dynamics, vesicular integrity, cell survival, and death, PVs can induce cytostasis and cytotoxicity. Although productive PV infections normally culminate in cytolysis, virus spread to neighboring cells and secondary rounds of infection, even abortive infection or the sole expression of the PV nonstructural protein NS1, is sufficient to cause significant tumor cell death, either directly or indirectly (through activation of host immune responses). This review highlights the molecular pathways involved in tumor cell targeting by PVs and in PV-induced cell death. It concludes with a discussion of the relevance of these pathways to the application of PVs in cancer therapy, linking basic knowledge of PV–host cell interactions to preclinical assessment of PV oncosuppression. Clin Cancer Res; 18(13); 3516–23. ©2012 AACR.
Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer
Authors: Mohan Helen M. , Aherne Carol M. , Rogers Ailin C. , Baird Alan W. , Winter Des C. , Murphy Evelyn P. 
Published: May 2012

Abstract
Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-κB, phosphoinositide 3-kinase/AKT, c-jun-NH2-kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-ϒ). The subcellular location of NR4A “nuclear receptors” is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation. Clin Cancer Res; 18(12); 3223–8. ©2012 AACR.
Optimal egg size in a suboptimal environment: reproductive ecology of female Sonora mud turtles (Kinosternon sonoriense) in central Arizona, USA
Authors: Lovich Jeffrey E. , Madrak Sheila V. , Drost Charles A. , Monatesti Anthony J. , Casper Dennis , Znari Mohammed 
Published: May 2012

We studied the reproductive ecology of female Sonora mud turtles (Kinosternon sonoriense) at Montezuma Well, a chemically-challenging natural wetland in central Arizona, USA. Females matured between 115.5 and 125 mm carapace length (CL) and 36-54% produced eggs each year. Eggs were detected in X-radiographs from 23 April-28 September (2007-2008) and the highest proportion (56%) of adult females with eggs occurred in June and July. Clutch frequency was rarely more than once per year. Clutch size was weakly correlated with body size, ranged from 1-8 (mean = 4.96) and did not differ significantly between years. X-ray egg width ranged from 17.8-21.7 mm (mean 19.4 mm) and varied more among clutches than within. Mean X-ray egg width of a clutch did not vary significantly with CL of females, although X-ray pelvic aperture width increased with CL. We observed no evidence of a morphological constraint on egg width. In addition, greater variation in clutch size, relative to egg width, suggests that egg size is optimized in this hydrologically stable but chemically-challenging habitat. We suggest that the diversity of architectures exhibited by the turtle pelvis, and their associated lack of correspondence to taxonomic or behavioral groupings, explains some of the variation observed in egg size of turtles.
Simulated Local and Remote Biophysical Effects of Afforestation over the Southeast United States in Boreal Summer*
Authors: Chen Guang-Shan , Notaro Michael , Liu Zhengyu , Liu Yongqiang 
Published: May 2012

Abstract
Afforestation has been proposed as a climate change mitigation strategy by sequestrating atmospheric carbon dioxide. With the goal of increasing carbon sequestration, a Congressional project has been planned to afforest about 18 million acres by 2020 in the Southeast United States (SEUS), the Great Lake states, and the Corn Belt states. However, biophysical feedbacks of afforestation have the potential to counter the beneficial climatic consequences of carbon sequestration. To assess the potential biophysical effects of afforestation over the SEUS, the authors designed a set of initial value ensemble experiments and long-term quasi-equilibrium experiments in a fully coupled Community Climate System Model, version 3.5 (CCSM3.5). Model results show that afforestation over the SEUS not only has a local cooling effect in boreal summer [June–August (JJA)] at short and long time scales but also induces remote warming over adjacent regions of the SEUS at long time scales. Precipitation, in response to afforestation, increases over the SEUS (local effect) and decreases over adjacent regions (remote effect) in JJA. The local surface cooling and increase in precipitation over SEUS in JJA are hydrologically driven by the changes in evapotranspiration and latent heat flux. The remote surface warming and decrease in precipitation over adjacent regions are adiabatically induced by anomalous subsidence. Our results suggest that the planned afforestation efforts should be developed carefully by taking account of short-term (local) and long-term (remote) biophysical effects of afforestation.
Extreme Rainstorm Events over the Northwest Himalayas during 1875–2010
Authors: Nandargi S. , Dhar O. N. 
Published: May 2012

AbstractA significant part of northern India is covered by the Himalayas, where a number of major Indian rivers originate. In the present study, a detailed analysis of rainstorms that affected the northwest region of the Himalayas has been made to assess the orographic effect of the Himalayas on precipitation in this region during the 135 years from 1875 to 2010. The study showed that the northwest Himalayas have experienced five most-severe rainstorms whose rain depths have not been surpassed so far. These severe rainstorms caused heavy to very heavy rainfall over the region that led to tremendous destruction to crops, communications, and livestock. Severe rainstorms have not occurred during the 2001–10 decade. It is also noticed that severe floods in this region have not occurred because of a “break monsoon situation” in the middle or eastern Himalayas.
Comments on “On the Steadiness of Separating Meandering Currents”
Authors: Nof Doron , Zharkov Volodymyr , Arruda Wilton , Pichevin Thierry , Van Gorder Stephen , Paldor Nathan 
Published: May 2012

Abstract
Using integration constraints and scale analysis, van Leeuwen and De Ruijter focused on the steady aspect of the downstream flow in the momentum imbalance articles of Nof and Pichevin appearing in the 1990s and later on. They correctly pointed out that when the steady downstream flow is exactly geostrophic then it must obey the additional downstream (critical) condition (where u is the speed, g′ is the reduced gravity, and h is the thickness). They then further argue that this additional condition provides “a strong limitation on the generality of their results.” These results for steady flows have been incorrectly generalized by the typical reader to eddy generating unsteady flows, which was the focus of Nof and Pichevin.
The current authors argue that, although the van Leeuwen and De Ruijter condition of is valid for a purely geostrophic and steady flow downstream, it is inapplicable even for the steady aspect of the Nof and Pichevin solutions because the assumption of a purely geostrophic flow (i.e., and ) was never made at any downstream cross section in Nof and Pichevin. Instead, the familiar assumption of a cross-stream geostrophic balance in a boundary current, which is slowly varying in the downstream direction, as well as time, has been made (i.e., , , and small but nonzero). Perhaps the current authors originally were not as clear about that as they should have been, but this implies that the basic state around which van Leeuwen and De Ruijter expanded their steady Taylor series does not exist in Nof and Pichevin; consequently, their expansion fails to say anything about both the time-dependent and the time-independent Nof and Pichevin. In the current authors’ view, the “strong limitation” that they allude to does not exist.
The Unusual Behavior and Precipitation Pattern Associated with Tropical Storm Ignacio (1997)
Authors: Wood Kimberly M. , Ritchie Elizabeth A. 
Published: May 2012

Abstract
A case study of eastern North Pacific Tropical Storm Ignacio (1997), which brought rainfall to the southwestern United States as a tropical cyclone and to the northwestern United States as an extratropical cyclone, is presented. This tropical cyclone formed from a region of disturbed weather, rather than a tropical wave, outside the typical eastern North Pacific genesis region and intensified into a tropical storm coincident with the passage of an upper-tropospheric trough. Moisture transported from Ignacio along an outflow jet associated with the trough resulted in precipitation in Mexico and the southwestern United States. As Ignacio moved north and away from the trough, this tropical cyclone weakened and eventually underwent extratropical transition over the open ocean, in contrast to climatological eastern North Pacific tropical cyclone behavior. Ignacio then strengthened as an extratropical cyclone due to favorable baroclinic conditions and the passage of another upper-tropospheric trough before making landfall on the northern coast of California, bringing rain to the northwestern United States. Ignacio’s remnant moisture eventually merged into a slow-moving midlatitude low pressure system that developed after interacting with the extratropical remnant of Hurricane Guillermo.
Structure of a Narrow Cold Front in the Boundary Layer: Observations versus Model Simulation
Authors: Sinclair Victoria A. , Niemelä Sami , Leskinen Matti 
Published: May 2012

Abstract
A narrow and shallow cold front that passed over Finland during the night 30–31 October 2007 is analyzed using model output and observations primarily from the Helsinki Testbed. The aim is to describe the structure of the front, especially within the planetary boundary layer, identify how this structure evolved, and determine the ability of a numerical model to correctly predict this structure. The front was shallow with a small (2.5–3 K) temperature decrease associated with it, which is attributed to the synoptic evolution of the cold front from a frontal wave on a mature, trailing cold front in a region of weak upper-level forcing and where the midtroposphere was strongly stratified. Within the boundary layer, the frontal surface was vertical and the frontal zone was narrow (&lt;8 km). The small cross-front scale was probably a consequence of the weak frontolytical turbulent mixing occurring at night, at high latitudes, combined with strong, localized frontogenetic forcing driven by convergence. The model simulated the mesoscale evolution of the front well, but overestimated the width of the frontal zone. Within the boundary layer, the model adequately predicted the stratification and near-surface temperatures ahead of, and within, the frontal zone, but failed to correctly predict the thermal inversion that developed in the stably stratified postfrontal air mass. This case study highlights the complex structure of fronts both within the nocturnal boundary layer, and in a location far from regions of cyclogenesis, and hence the challenges that both forecasters and operational models face.
Common mental disorders in immigrant and second-generation respondents: Results from the Israel-based World Mental Health Survey
Authors: Nakash Ora , Levav Itzhak , Gal Gilad 
Published: May 2012

Background: The contrasting social status of ethnic groups differentially impacts the mental health of their members. This may be the case in Israel despite its egalitarian ideology. However, studies are a few and limited in scope. Aim: To study mental health disparities between immigrant and second-generation disadvantaged and advantaged Jewish groups. Methods: Data were extracted from the Israel World Mental Health Survey. This included the Composite International Diagnostic Interview and the General Health Questionnaire. We compared 547 first-generation immigrants born in North Africa/Asia and 708 born in Europe/America; and 707 second-generation immigrants of North African/Asian origin and 449 of European/American origin. Results: The prevalence rate of common mental disorders in the preceding year was approximately double for respondents of North African/Asian origin compared with their European/American counterparts following adjustment for socio-demographic confounders. Inmigrants: North African/Asian 12.4%, SE = 1.5; European/American 6.4%, SE = 1.0 (AOR = 2.1, 95% CI 1.4–3.4). Second generation: North African/Asian 10.1%, SE = 1.2; European/American 5.4%, SE = 1.1 (AOR = 1.7, 95% CI 1.1–3.2). Significant differences in emotional distress mean scores were observed only among second-generation respondents: North African/Asian respondents reported higher emotional distress ( M = 18.7, SE = 0.5) compared with European/American ( M = 17.3, SE = 0.4) (Wald F = 13.31, p < .001). Conclusions: Results showed disparities in the mental health measures in both generations. It is likely that social causation factors, such as restricted opportunities in the context of higher aspirations, partially account for the findings.
Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10
Authors: Oakley Kevin , Han Yufen , Vishwakarma Bandana A. , Chu Su , Bhatia Ravi , Gudmundsson Kristbjorn O. , Keller Jonathan , Chen Xiongfong , Vasko Vasyl , Jenkins Nancy A. , Copeland Neal G. , Du Yang 
Published: May 2012

AbstractAcquisition of self-renewal capability by myeloid progenitors to become leukemic stem cells during myeloid leukemia development is poorly understood. Here, we show that Setbp1 overexpression efficiently confers self-renewal capability to myeloid progenitors in vitro, causing their immortalization in the presence of stem cell factor and IL-3. Self-renewal after immortalization requires continuous Setbp1 expression. We also found that Hoxa9 and Hoxa10 mRNA are present at dramatically higher levels in Setbp1-immortalized cells compared with other immortalized cells, and are induced shortly after Setbp1 expression in primary myeloid progenitors. Suppression of either gene in Setbp1-immortalized cells drastically reduces their colony-forming capability. Interestingly, Setbp1 protein associates with Hoxa9 and Hoxa10 promoters in chromatin immunoprecipitation assays in these cells, suggesting that both are direct transcriptional targets of Setbp1. Setbp1 also promotes self-renewal of myeloid progenitors in vivo as its coexpression with BCR/ABL transforms primary mouse myeloid progenitors, generating aggressive leukemias in recipient mice resembling chronic myelogenous leukemia (CML) myeloid blast crisis. Increased SETBP1 mRNA levels were also detected in a subset of CML advanced phase/blast crisis patients with high levels of HOXA9 and HOXA10 expression. Thus, Setbp1 activation represents a novel mechanism conferring self-renewal capability to myeloid progenitors in myeloid leukemia development.
Augmented annotation and orthologue analysis for Oryctolagus cuniculus: Better Bunny
Authors: Craig Douglas B , Kannan Sujatha , Dombkowski Alan A 
Published: May 2012

Abstract

Background
The rabbit is an important model organism used in a wide range of biomedical research. However, the rabbit genome is still sparsely annotated, thus prohibiting extensive functional analysis of gene sets derived from whole-genome experiments. We developed a web-based application that provides augmented annotation and orthologue analysis for rabbit genes. Importantly, the application allows comprehensive functional analysis through the use of orthologous relationships.

Results
Using data extracted from several public bioinformatics repositories we created Better Bunny, a database and query tool that extensively augments the available functional annotation for rabbit genes. Using the complete set of target genes from a commercial rabbit gene expression microarray as our benchmark, we are able to obtain functional information for 88 % of the genes on the microarray. Previously, functional information was available for fewer than 10 % of the rabbit genes.

Conclusions
We have developed a freely available, web-accessible bioinformatics tool that enables investigators to quickly and easily perform extensive functional analysis of rabbit genes (http://cptweb.cpt.wayne.edu). The software application fills a critical void for a wide range of biomedical research that relies on the rabbit model and requires characterization of biological function for large sets of genes.
Exploring drug combinations in genetic interaction network
Authors: Wang Yin-Ying , Xu Ke-Jia , Song Jiangning , Zhao Xing-Ming 
Published: May 2012

Abstract

Background
Drug combination that consists of distinctive agents is an attractive strategy to combat complex diseases and has been widely used clinically with improved therapeutic effects. However, the identification of efficacious drug combinations remains a non-trivial and challenging task due to the huge number of possible combinations among the candidate drugs. As an important factor, the molecular context in which drugs exert their functions can provide crucial insights into the mechanism underlying drug combinations.

Results
In this work, we present a network biology approach to investigate drug combinations and their target proteins in the context of genetic interaction networks and the related human pathways, in order to better understand the underlying rules of effective drug combinations. Our results indicate that combinatorial drugs tend to have a smaller effect radius in the genetic interaction networks, which is an important parameter to describe the therapeutic effect of a drug combination from the network perspective. We also find that drug combinations are more likely to modulate functionally related pathways.

Conclusions
This study confirms that the molecular networks where drug combinations exert their functions can indeed provide important insights into the underlying rules of effective drug combinations. We hope that our findings can help shortcut the expedition of the future discovery of novel drug combinations.
High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity
Authors: Yang Runkuan , Zhang Shutian , Cotoia Antonella , Oksala Niku , Zhu Shengtao , Tenhunen Jyrki 
Published: May 2012

Abstract

Background
Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose.

Methods
Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses.

Results
24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.

Conclusion
HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.