bluuebunny/crossref_metadata_2025_split huggingface dataset:
CANCER: NINETEENTH CENTURY SCIENCE — TWENTIETH CENTURY TECHNOLOGY
Authors: Potter John D. 
Published: August 2010

AbstractCancer is a major cause of death in western societies. Overall, there has been no decline in the incidence and little improvement in survival for twenty years. Hundreds of millions of dollars are regularly spent on cancer research. It is argued that much research effort is misdirected as a consequence of a limited view of the nature of the cancer process and the influences on it. Preoccupation with a nineteenth century view of the genesis of cancer and a twentieth‐century high‐technology approach to treatment has prevented the proper exploration of the determinants of cancer, and the development of different therapeutic modes. Several models of the cancer process are examined. A model which considers human populations, human behaviour (including social and economic factors) and the interactive nature of the biologic response of living organisms to the environment is developed. Some of the implications of this model for research and therapy are discussed.
RECENT MORTALITY TRENDS IN THE ADULT AUSTRALIAN POPULATION AND ITS PRINCIPAL ETHNIC GROUPINGS
Authors: Dunt David R. 
Published: August 2010

AbstractSecular trends in mortality rates for ‘Allcauses’ and for nine very common diseases were analysed for age group 25–64 in Australia from 1966 to 1976. Substantial decline occurred for All‐causes and for most of the nine selected diseases. Trends were independent of changes in the ethnic composition of the population during this period. Continental Europeans, with the notable exception of Southern European females, have not experienced this downward trend in rates during the study period. Their considerable lead in mortality rates that existed in 1966 over native‐born Australians has consequently been eroded. Trends for Southern European males and females were similar to trends in their countries of origin both for Allcauses and for ischaemic heart disease during this period.
CRITIQUE OF OCCUPATIONAL HEALTH MONITORING IN AUSTRALIA
Authors: Mathews J. A. 
Published: August 2010

AbstractThe procedures used to collect data relating to occupational health in Australia are reviewed and a critique is offered of their adequacy in presenting a comprehensive picture of occupational health. Attention is focused on the death certification process and on the role of the cancer and perinatal statistics units. Proposals are offered for overhauling the social procedures for collecting public health data, with a view to providing a better base for preventive strategies.
COMMENTARY: BEHAVIOURAL SCIENCE IS NOT SPOKEN HERE ‐ WHERE ARE THE INTERPRETERS?
Authors: Kamien M. 
Published: August 2010

AbstractSome of the current problems with health care in Australia are due to the reluctance of orthodox medicine to incorporate a behavioural science perspective into its biomedical fabric. This narrow view of medicine is partly maintained by the failure of the behavioural scientists to address themselves to the study of mainstream medical practice in Australian society.
USABLE KNOWLEDGE AND EXPERTISE: SETTING THE AGENDA FOR TOBACCO REFORM
Authors: Peachment Allan 
Published: August 2010

AbstractIn some areas of public policy where reform is sought the assumed advantages of emphasising expert and professional knowledge should be reconsidered. Other approaches to problem solving ‐ interaction and social learning ‐ may have much to offer and the important role played by ordinary knowledge should be examined. The medical lobby's support for the Western Australian Government's failed attempt to pass its Tobacco (Promotion and Sale) Bill is examined as a case in point. That the lobby's emphasis on expert knowledge aimed mainly towards a parliamentary context may have been an important factor in the Bill's defeat. With the Bill's possible reintroduction into State Parliament consideration of other areas of knowledge, in addition to medical research, would enable reformers to exercise greater control over the political agenda.
DOES BULK BILLING CAUSE ABUSE OF MEDICARE?
Authors: Richardson J. 
Published: August 2010

AbstractMedicare data are examined to determine whether there is an association between bulk billing and the ‘abuse’ of Medicare. It is found that, with the exception of one group — ‘GP‐Specialist’, there is no systematic relationship between bulk billing and increased medical incomes. Neither GP gross income nor total fees per patient vary significantly with the proportion of items bulk billed. By contrast, there is a significant and systematic increase in total fees per patient as medical incomes increase.
COMMENTARY: A BLIND EYE: COMMUNITY HEALTH SERVICES IN REMOTE AREAS OF AUSTRALIA
Authors: Cramer Jennifer 
Published: August 2010

AbstractCommunity health services to remote Australian communities are frequently overlooked by health policy and planning authorities, despite the particular health and social problems confronting these communities. Nurses are the main providers of health care in isolated regions where they must perform an extended primary health care role. It is assumed that a nurse in the community can fulfil multiple and continuous roles in clinical care, and public health. In the absence of administrative expertise the isolated community health service functions more often by reflex action than design. Essential factors in the development of health services to remote communities include evaluation of current practices and staff utilisation. Greater accountability for funding would enforce regular reviews. Deliberate health services planning must be flexible to community changes and consider appropriate alternatives to the prevailing curative focus.
PREGNANCY OUTCOMES IN BOURKE 1983–1985
Authors: Harris Mark 
Published: August 2010

AbstractAll pregnancies to Bourke residents ending over the three years from 1983 to 1985 (a total of 340) were retrospectively studied. Bourke Aboriginal women were more fertile and fell pregnant at a younger age than their non‐Aboriginal counterparts. Aborigines had eight times the perinatal mortality, much of which was still birth associated with syphilis. Syphilis occurred in 16 per cent of Aboriginal pregnancies reaching 20 weeks gestation but there were none among non‐Aboriginal pregnancies.The birth rate of Aborigines has declined to almost half that of 1964–72, probably as a result of more accessible contraception. The birth weight of Aboriginal babies has also decreased coincidentally with an increase in tobacco smoking, unemployment and obesity among young Aboriginal adults. Improvements in the morbidity associated with Aboriginal pregnancies will require changes in education and the social inequality that exists in Bourke.
Epigenetic Silencing of miR-137 Is an Early Event in Colorectal Carcinogenesis
Authors: Balaguer Francesc , Link Alexander , Lozano Juan Jose , Cuatrecasas Miriam , Nagasaka Takeshi , Boland C. Richard , Goel Ajay 
Published: August 2010

Abstract
Global downregulation of microRNAs (miRNA) is a common feature in colorectal cancer (CRC). Whereas CpG island hypermethylation constitutes a mechanism for miRNA silencing, this field largely remains unexplored. Herein, we describe the epigenetic regulation of miR-137 and its contribution to colorectal carcinogenesis. We determined the methylation status of miR-137 CpG island in a panel of six CRC cell lines and 409 colorectal tissues [21 normal colonic mucosa from healthy individuals (N-N), 160 primary CRC tissues and their corresponding normal mucosa (N-C), and 68 adenomas]. TaqMan reverse transcription-PCR and in situ hybridization were used to analyze miR-137 expression. In vitro functional analysis of miR-137 was performed. Gene targets of miR-137 were identified using a combination of bioinformatic and transcriptomic approaches. We experimentally validated the miRNA:mRNA interactions. Methylation of the miR-137 CpG island was a cancer-specific event and was frequently observed in CRC cell lines (100%), adenomas (82.3%), and CRC (81.4%), but not in N-C (14.4%; P &lt; 0.0001 for CRC) and N-N (4.7%; P &lt; 0.0001 for CRC). Expression of miR-137 was restricted to the colonocytes in normal mucosa and inversely correlated with the level of methylation. Transfection of miR-137 precursor in CRC cells significantly inhibited cell proliferation. Gene expression profiling after miR-137 transfection discovered novel potential mRNA targets. We validated the interaction between miR-137 and LSD-1. Our data indicate that miR-137 acts as a tumor suppressor in the colon and is frequently silenced by promoter hypermethylation. Methylation silencing of miR-137 in colorectal adenomas suggests it to be an early event, which has prognostic and therapeutic implications. Cancer Res; 70(16); 6609–18. ©2010 AACR.
CD73: A Novel Target for Cancer Immunotherapy
Authors: Zhang Bin 
Published: August 2010

Abstract
The promise of cancer immunotherapy has not been translated into clinical successes, in large part because of tumor-associated immune suppression that blocks effective antitumor immunity. Recent findings show a tumor-induced immunosuppressive mechanism, whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine, which promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling. Results with small molecule inhibitors, or monoclonal antibodies targeting CD73 in murine tumor models, suggest that targeted CD73 therapy is an important alternative and realistic approach to effective control of tumor growth. In particular, it helps T-cell–based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating T lymphocytes, and subsequently lead to improved survival in cancer patients. Cancer Res; 70(16); 6407–11. ©2010 AACR.
Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy
Authors: Wright John J. 
Published: August 2010

Abstract
Clinical trials evaluating combinations of targeted agents with bortezomib, the first-in-class proteasome inhibitor, have been initiated, with the objective of enhancing its single agent activity in hematologic malignancies (myeloma, mantle cell lymphoma), as well as expanding its efficacy in solid tumors. In most cases, preclinical studies have provided a supportive rationale for designing these doublet combination studies. Novel, small molecule–targeted agents being investigated with bortezomib in clinical trials include protein deacetylase inhibitors, kinase inhibitors, farnesyltransferase inhibitors, heat-shock protein 90 inhibitors, pan-Bcl-2 family inhibitors, and other classes of targeted inhibitors. Preliminary clinical data, available from a number of ongoing trials, suggest that most of these combinations are well tolerated and some have promising clinical efficacy that will require subsequent confirmation. Translational studies, conducted as part of the trials, may provide important insights into the putative mechanism of action delineated by preclinical studies of the combinations. The emergence of novel proteasome inhibitors may also expand the opportunities for optimizing these combination therapies. There is potential for an increasingly broad clinical trials program to investigate this therapeutic approach in a range of tumor types, as well as to consider additional agents in sequence or in combination. Clin Cancer Res; 16(16); 4094–104. ©2010 AACR.
Accumulation of Foxp3+ T Regulatory Cells in Draining Lymph Nodes Correlates with Disease Progression and Immune Suppression in Colorectal Cancer Patients
Authors: Deng Liufu , Zhang Haizeng , Luan Yan , Zhang Jianfeng , Xing Qiao , Dong Shuxiao , Wu Xiaoran , Liu Mingyue , Wang Shengdian 
Published: August 2010

Abstract
Purpose: To assess the relation of Foxp3+ regulatory T cells (Treg) in tumor draining lymph nodes (TDLNs) with tumor progression and immune suppression in colorectal cancer (CRC).
Experimental Design: Flow cytometry was used to analyze the densities of Tregs in lymphocytes of TDLNs, peripheral blood, and tumors from 34 patients with CRC. The frequency of Tregs was compared and evaluated for the association with disease stage. The effect of Tregs on the function of CD8+ T cells was investigated by IFN-γ production.
Results: The density of Foxp3+ Tregs in TDLNs was dramatically higher than that in peripheral blood lymphocytes, but significantly lower than that in tumor-infiltrating lymphocytes. Importantly, the frequency of Foxp3+ Tregs in TDLNs, rather than that in tumors and peripheral blood, was positively correlated with disease stage. In addition, the functions of CD8+ T cells were impaired in TDLNs compared with peripheral blood lymphocytes and were restored after Treg depletion.
Conclusions: Foxp3+ Tregs in TDLNs are more correlated with disease progression and potentially influence CD8+ T-cell functions. This study suggests that the frequency of Tregs in TDLNs may provide a valuable prognostic tool in the treatment of CRC. Clin Cancer Res; 16(16); 4105–12. ©2010 AACR.
Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth
Authors: Okamoto Takashi , Inozume Takashi , Mitsui Hiroshi , Kanzaki Mirei , Harada Kazutoshi , Shibagaki Naotaka , Shimada Shinji 
Published: August 2010

Abstract
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is common in many human and murine cancer cells, and its activation leads to cellular transformation. STAT3 pathway inhibitors have been reported to suppress cancer growth. To investigate the antitumor effects of inhibiting the STAT3-mediated signaling cascade in the cancer microenvironment, using a molecular-targeting approach, we focused on the gene associated with retinoid-IFN-induced mortality 19 (GRIM-19). GRIM-19 has been reported to interact physically with STAT3 and inhibit STAT3-dependent signal transduction. We used the nona-arginine (R9)-protein transduction domain (R9-PTD) as a protein carrier to induce high levels of GRIM-19 expression in vitro and in vivo. We generated an R9-PTD–containing GRIM-19 fusion protein (rR9-GRIM19) and successfully induced overexpression in the cytoplasm of cancer cells. Analysis of the expression of downstream molecules of STAT3 confirmed that in vitro rR9-GRIM19 treatment of constitutively activated STAT3 (STAT3c) cancer cells significantly reduced STAT3-dependent transcription. Moreover, intratumoral injections of rR9-GRIM19 in STAT3c cancer-bearing mice significantly suppressed tumor growth. These results suggest that intratumoral injections of rR9-GRIM19 have potential as a novel anticancer therapy in STAT3c cancer due to their ability to inhibit STAT3-mediated signal transduction without major systemic side effects. Mol Cancer Ther; 9(8); 2333–43. ©2010 AACR.
Targeted Inhibition of Src Kinase Signaling Attenuates Pancreatic Tumorigenesis
Authors: Nagaraj Nagathihalli S. , Smith J. Joshua , Revetta Frank , Washington M. Kay , Merchant Nipun B. 
Published: August 2010

Abstract
Elevated Src expression correlates with malignant potential and metastatic disease in many tumors including pancreatic cancer. We sought to characterize the molecular effects of Src kinase inhibition with dasatinib (BMS-354825), a novel, multitargeted kinase inhibitor that targets Src family kinases in pancreatic ductal adenocarcinoma (PDA). We identified sensitive and resistant PDA cell lines to dasatinib treatment and tested the molecular effects of Src inhibition in vitro and in vivo. We show for the first time that cellular localization of Src expression affects survival in patients with PDA. Pancreatic tumors with increased membranous expression of Src resulted in decreased survival compared with tumors that had increased cytoplasmic Src expression. Src kinase inhibition with dasatinib markedly inhibits cell proliferation, migration, invasion, cell cycle progression and anchorage-independent growth, and stimulates apoptosis. This was accompanied by decreased phosphorylation of Src, focal adhesion kinase, paxillin, AKT, signal transducers and activators of transcription 3 (STAT3), extracellular signal–regulated kinase, and mitogen-activated protein kinase (MAPK), as well as decreased cyclin D1 expression in a time- and concentration-dependent manner. Furthermore, small interfering RNA to Src results in a significant decrease in cell proliferation, invasion, and migration of pancreatic cancer cells. Dasatinib treatment also inhibits in vivo pancreatic tumor growth. Mechanisms of resistance to Src inhibition seem to be related to a lack of inhibition of STAT3 and MAPK signaling. These results establish a mechanistic rationale for Src inhibition with dasatinib as a therapeutic target in the treatment of pancreatic cancer and identify potential biomarkers of resistance to Src inhibition. Mol Cancer Ther; 9(8); 2322–32. ©2010 AACR.
Galectin-3 Promotes Chronic Activation of K-Ras and Differentiation Block in Malignant Thyroid Carcinomas
Authors: Levy Ran , Grafi-Cohen Meital , Kraiem Zaki , Kloog Yoel 
Published: August 2010

AbstractAnaplastic thyroid carcinomas are deadly tumors that are highly invasive, particularly into the bones. Although oncogenic Ras can transform thyroid cells into a severely malignant phenotype, thyroid carcinomas do not usually harbor ras gene mutations. Therefore, it is not known whether chronically active Ras contributes to thyroid carcinoma cell proliferation, although galectin-3 (Gal-3), which is strongly expressed in thyroid carcinomas but not in benign tumors or normal glands, is known to act as a K-Ras chaperone that stabilizes and drives K-Ras.GTP nanoclustering and signal robustness. Here, we examined the possibility that thyroid carcinomas expressing high levels of Gal-3 exhibit chronically active K-Ras. Using cell lines representing three types of malignant thyroid tumors—papillary, follicular, and anaplastic—we investigated the possible correlation between Gal-3 expression and active Ras content, and then examined the therapeutic potential of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib) for thyroid carcinoma. Thyroid carcinoma cells strongly expressing Gal-3 showed high levels of K-Ras.GTP expression, and K-Ras.GTP transmitted strong signals to extracellular signal-regulated kinase. FTS disrupted interactions between Gal-3 and K.Ras, strongly reduced K-Ras.GTP and phospho-extracellular signal-regulated kinase expression, and enhanced the expression of the cell cycle inhibitor p21 as well as of the thyroid transcription factor 1, which is involved in thyroid cell differentiation. FTS also inhibited anaplastic thyroid carcinoma cell proliferation in vitro and tumor growth in nude mice. We conclude that wild-type K-Ras.GTP in association with Gal-3 contributes to thyroid carcinoma malignancy and that Ras inhibition might be a useful treatment strategy against these deadly tumors. Mol Cancer Ther; 9(8); 2208–19. ©2010 AACR.
Sorafenib Activates CD95 and Promotes Autophagy and Cell Death via Src Family Kinases in Gastrointestinal Tumor Cells
Authors: Park Margaret A. , Reinehr Roland , Häussinger Dieter , Voelkel-Johnson Christina , Ogretmen Besim , Yacoub Adly , Grant Steven , Dent Paul 
Published: August 2010

Abstract
Sorafenib and vorinostat interact in a synergistic fashion to kill carcinoma cells by activating CD95; the present studies have determined how sorafenib and vorinostat individually contribute to CD95 activation. Sorafenib (3–6 μmol/L) promoted a dose-dependent increase in Src Y416, ERBB1 Y845 and CD95 Y232/Y291 phosphorylation, and Src Y527 dephosphorylation. Low levels of sorafenib-induced (3 μmol/L) CD95 tyrosine phosphorylation did not promote surface localization whereas sorafenib (6 μmol/L), or sorafenib (3 μmol/L) and vorinostat (500 nmol/L) treatment promoted higher levels of CD95 phosphorylation which correlated with DISC formation, receptor surface localization, and autophagy. CD95 (Y232F, Y291F) was not tyrosine phosphorylated and was unable to localize plasma membrane or induce autophagy. Knockdown/knockout of Src family kinases abolished sorafenib-induced CD95 tyrosine phosphorylation, DISC formation, and the induction of cell death and autophagy. Knockdown of platelet-ived growth factor receptor-β enhanced Src Y416 and CD95 tyrosine phosphorylation, which correlated with elevated CD95 plasma membrane levels and autophagy, and with a reduced ability of sorafenib to promote CD95 membrane localization. Vorinostat increased reactive oxygen species levels, and in a delayed NFκB-dependent fashion, those of FAS ligand and CD95. Neutralization of FAS-L did not alter the initial rapid drug-induced activation of CD95; however, neutralization of FAS-L reduced sorafenib + vorinostat toxicity by ∼50%. Thus, sorafenib contributes to CD95 activation by promoting receptor tyrosine phosphorylation, whereas vorinostat contributes to CD95 activation via the initial facilitation of reactive oxygen species generation and subsequently of FAS-L expression. Mol Cancer Ther; 9(8); 2220–31. ©2010 AACR.
Selective control of amino acid metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae
Authors: Zaborske John M , Wu Xiaochen , Wek Ronald C , Pan Tao 
Published: August 2010

Abstract

Background
When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. Activated Gcn2p up-regulates the general amino acid control pathway through phosphorylation of the translational initiation factor eIF2. In Saccharomyces cerevisiae, Gcn2p is the only kinase that phosphorylates eIF2 to regulate translation through this mechanism. We addressed changes in yeast growth and tRNA aminoacylation, or charging, during amino acid depletion in the presence and absence of GCN2. tRNA charging was measured using a microarray technique which simultaneously measures all cytosolic tRNAs. A fully prototrophic strain, and its isogenic gcn2 Δ counterpart, were used to study depletion for each of the 20 amino acids, with a focus on Trp, Arg, His and Leu, which are metabolically distinct and together provide a good overview on amino acid metabolism.

Results
While the wild-type strain had no observable phenotype upon depletion for any amino acid, the gcn2 Δ strain showed slow growth in media devoid of only Trp or Arg. Consistent with the growth phenotypes, profiles of genome-wide tRNA charging revealed significant decrease in cognate tRNA charging only in the gcn2 Δ strain upon depletion for Trp or Arg. In contrast, there was no change in tRNA charging during His and Leu depletion in either the wild-type or gcn2 Δ strains, consistent with the null effect on growth during loss of these amino acids. We determined that the growth phenotype of Trp depletion is derived from feedback inhibition of aromatic amino acid biosynthesis. By removing Phe and Tyr from the media in addition to Trp, regular growth was restored and tRNATrp charging no longer decreased. The growth phenotype of Arg depletion is derived from unbalanced nitrogen metabolism. By supplementing ornithine upon Arg depletion, both growth and tRNAArg charging were partially restored.

Conclusion
Under mild stress conditions the basal activity of Gcn2p is sufficient to allow for proper adaptation to amino acid depletion. This study highlights the importance of the GCN2 eIF2 kinase pathway for maintaining metabolic homeostasis, contributing to appropriate tRNA charging and growth adaptation in response to culture conditions deficient for the central amino acids, tryptophan and arginine.