bluuebunny/crossref_metadata_2025_split huggingface dataset:
The do-not-resuscitate order: associations with advance directives, physician specialty and documentation of discussion 15 years after the Patient Self-Determination Act
Authors: Morrell E D , Brown B P , Qi R , Drabiak K , Helft P R 
Published: August 2008

Background:Since the passage of the Patient Self-Determination Act, numerous policy mandates and institutional measures have been implemented. It is unknown to what extent those measures have affected end-of-life care, particularly with regard to the do-not-resuscitate (DNR) order.Methods:Retrospective cohort study to assess associations of the frequency and timing of DNR orders with advance directive status, patient demographics, physician’s specialty and extent of documentation of discussion on end-of-life care.Results:DNR orders were more frequent for patients on a medical service than on a surgical service (77.34% vs 64.20%, p = 0.02) and were made earlier in the hospital stay for medicine than for surgical patients (adjusted mean ratio of time from DNR orders to death versus total length of stay 0.30 for internists vs 0.21 for surgeons, p = 0.04). 22.18% of all patients had some form of an advance directive in their chart, yet this variable had no impact on the frequency or timing of DNR ordering. Documentation of DNR discussion was significantly associated with the frequency of DNR orders and the time from DNR to death (2.1 days with no or minimal discussion vs 2.8 days with extensive discussion, p<0.01).Conclusions:The physician’s specialty continues to have a significant impact on the frequency and timing of DNR orders, while advance directive status still has no measurable impact. Additionally, documentation of end-of-life discussions is significantly associated with varying DNR ordering rates and timing.
Sustained Ca2+signaling and delayed internalization associated with endothelin receptor heterodimers linked through a PDZ fingerThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Evans Nathan J. , Walker Jeffery W. 
Published: August 2008

G protein-coupled receptors (GPCRs), including endothelin receptor A (ETA) and B (ETB), may form dimers or higher-order oligomers that profoundly influence signaling. Here we examined a PDZ finger motif within the C-terminus of ETAand its role in heterodimerization with ETB, and in homodimerization with itself, when expressed in HEK293 cells. Receptor dimerization was monitored by (i) fluorescence resonance energy transfer (FRET) between cyan fluorescent protein (CFP) (FRET donor) and tetracysteine/FlAsH (FRET acceptor) fused to the C-termini of ET receptors, and (ii) coimmunoprecipitation of ET receptors after mild detergent solubilization. Mutations in a PDZ finger motif at threonine403/serine404 eliminated FRET and reduced coimmunoprecipitation of heterodimers and homodimers. Functional consequences were evaluated by measuring mobilization of intracellular Ca2+and internalization of receptors in response to a 10 nmol/L ET-1 challenge. PDZ mutations converted a sustained Ca2+signal mediated by ETA:ETBheterodimers into a transient response, similar to that observed for homodimers or monomers. Heterodimers containing PDZ mutations were seen to internalize in a similar time domain (approximately 5 min) to the transient Ca2+elevation and with similar kinetics to internalization of ETAhomodimers or monomers. Without the PDZ mutations, heterodimers did not internalize over 15 min, suggesting the intriguing possibility that sustained Ca2+signaling was a consequence (at least in part) of delayed internalization. The results are consistent with structural models of ETA-receptor dimerization that place threonine403/serine404 of the PDZ finger motif at the interaction interface between heterodimers and homodimers. Sustained Ca2+signaling and delayed endocytosis of ETA:ETBheterodimers argues strongly for a unique dimer interface that impacts transmembrane signaling and internalization.
Endothelin: 20 years from discovery to therapyThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Barton Matthias , Yanagisawa Masashi 
Published: August 2008

Since its identification as an endothelial cell-derived vasoconstrictor peptide in 1988, endothelin-1, the predominant member of the endothelin peptide family, has received considerable interest in basic medical science and in clinical medicine, which is reflected by more than 20 000 scientific publications on endothelin research in the past 20 years. The story of endothelin is unique as the gene sequences of endothelin receptors and the first receptor antagonists became available within only 4 years of the identification of the peptide sequence.The first clinical study in patients with congestive heart failure was published only 3 years thereafter. Yet, despite convincing experimental evidence of a pathogenetic role for endothelin in development, cell function, and disease, many initial clinical studies on endothelin antagonism were negative. In many of these studies, study designs or patient selection were inadequate. Today, for diseases such as pulmonary hypertension, endothelin antagonist treatment has become reality in clinical medicine, and ongoing clinical studies are evaluating additional indications, such as renal disease and cancer. Twenty years after the discovery of endothelin, its inhibitors have finally arrived in the clinical arena and are now providing us with new options to treat disease and prolong the lives of patients. Possible future indications include resistant arterial hypertension, proteinuric renal disease, cancer, and connective tissue diseases.
Lysosomotropic drugs inhibit maturation of transforming growth factor-β
Authors: Basque Julie , Martel Marc , Leduc Richard , Cantin André M. 
Published: August 2008

Transforming growth factor-β (TGFβ) is synthesized as a precursor protein, pro-TGFβ, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of the trans-Golgi network (TGN)/endosome system may suppress pro-TGFβ processing and decrease TGFβ secretion. This hypothesis was tested in human A549 alveolar epithelial and T98G glioblastoma cell lines and in C57BL/6 mice. Inhibition of furin-like activity with decanoyl-RVKR chloromethylketone suppressed pro-TGFβ processing, thereby significantly reducing the levels of secreted TGFβ. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFβ processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFβ. Reduced levels of secreted TGFβ were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFβ. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFβ processing.
PIK3CA Mutations and Copy Number Gains in Human Lung Cancers
Authors: Yamamoto Hiromasa , Shigematsu Hisayuki , Nomura Masaharu , Lockwood William W. , Sato Mitsuo , Okumura Naoki , Soh Junichi , Suzuki Makoto , Wistuba Ignacio I. , Fong Kwun M. , Lee Huei , Toyooka Shinichi , Date Hiroshi , Lam Wan L. , Minna John D. , Gazdar Adi F. 
Published: August 2008

Abstract
We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non–small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference–mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance. [Cancer Res 2008;68(17):6913–21]
EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing's Sarcoma
Authors: Ban Jozef , Bennani-Baiti Idriss M. , Kauer Max , Schaefer Karl-Ludwig , Poremba Christopher , Jug Gunhild , Schwentner Raphaela , Smrzka Oskar , Muehlbacher Karin , Aryee Dave N.T. , Kovar Heinrich 
Published: August 2008

AbstractAlthough p53 is the most frequently mutated gene in cancer, half of human tumors retain wild-type p53, whereby it is unknown whether normal p53 function is compromised by other cancer-associated alterations. One example is Ewing's sarcoma family tumors (ESFT), where 90% express wild-type p53. ESFT are characterized by EWS-FLI1 oncogene fusions. Studying 6 ESFT cell lines, silencing of EWS-FLI1 in a wild-type p53 context resulted in increased p53 and p21WAF1/CIP1 levels, causing cell cycle arrest. Using a candidate gene approach, HEY1 was linked to p53 induction. HEY1 was rarely expressed in 59 primary tumors, but consistently induced upon EWS-FLI1 knockdown in ESFT cell lines. The NOTCH signaling pathway targets HEY1, and we show NOTCH2 and NOTCH3 to be expressed in ESFT primary tumors and cell lines. Upon EWS-FLI1 silencing, NOTCH3 processing accompanied by nuclear translocation of the activated intracellular domain was observed in all but one p53-mutant cell line. In cell lines with the highest HEY1 induction, NOTCH3 activation was the consequence of JAG1 transcriptional induction. JAG1 modulation by specific siRNA, NOTCH-processing inhibition by either GSI or ectopic NUMB1, and siRNA-mediated HEY1 knockdown all inhibited p53 and p21WAF1/CIP1 induction. Conversely, forced expression of JAG1, activated NOTCH3, or HEY1 induced p53 and p21WAF1/CIP1. These results indicate that suppression of EWS-FLI1 reactivates NOTCH signaling in ESFT cells, resulting in p53-dependent cell cycle arrest. Our data link EWS-FLI1 to the NOTCH and p53 pathways and provide a plausible basis both for NOTCH tumor suppressor effects and oncogenesis of cancers that retain wild-type p53. [Cancer Res 2008;68(17):7100–9]
Chondroitin Sulfate E Fragments Enhance CD44 Cleavage and CD44-Dependent Motility in Tumor Cells
Authors: Sugahara Kazuki N. , Hirata Takako , Tanaka Toshiyuki , Ogino Shinji , Takeda Mitsuhiro , Terasawa Hiroaki , Shimada Ichio , Tamura Jun-ichi , ten Dam Gerdy B. , van Kuppevelt Toin H. , Miyasaka Masayuki 
Published: August 2008

Abstract
During tumor cell invasion, certain extracellular matrix (ECM) components such as hyaluronan (HA) are degraded into small oligosaccharides, which are detected in patients. We previously reported that such HA oligosaccharides induce the proteolytic cleavage of an ECM-binding molecule CD44 from tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we report that chondroitin sulfate E (CSE), another component of the tumor ECM, strongly enhances CD44 cleavage and tumor cell motility when degraded into oligosaccharides. CSE and its degradation products were detected in pancreatic ductal adenocarcinoma. In CD44-expressing pancreatic tumor cells, degraded forms of CSE but not intact CSE enhanced CD44 cleavage; enzymatic digestion of such low-molecular weight CSE (LMW-CSE) abrogated this enhancement. Among the LMW-CSE preparations examined, 3-kDa CSE most potently induced CD44 cleavage. Nuclear magnetic resonance analysis showed that the 3-kDa-CSE bound to CD44, and that blocking such binding abrogated the CD44 cleavage induction. LMW-CSE also induced prominent filopodia formation and cytoskeletal changes in tumor cells; these effects were also abrogated by blocking the LMW-CSE binding to CD44. Chemically synthesized CSE hexasaccharides also enhanced the CD44 cleavage and tumor cell motility in a CD44-dependent manner. We conclude that the degraded forms of CSE modulate cell adhesion and migration by interacting with tumor-cell CD44, suggesting that the degradation products of tumor-associated ECMs that interact with CD44 play a significant role in CD44-mediated tumor progression. [Cancer Res 2008;68(17):7191–9]
Molecular Basis for the Induction of an Angiogenesis Inhibitor, Thrombospondin-1, by 5-Fluorouracil
Authors: Zhao Hong-Ye , Ooyama Akio , Yamamoto Masatatsu , Ikeda Ryuji , Haraguchi Misako , Tabata Sho , Furukawa Tatsuhiko , Che Xiao-Fang , Zhang Shaoxuan , Oka Toshinori , Fukushima Masakazu , Nakagawa Masayuki , Ono Mayumi , Kuwano Michihiko , Akiyama Shin-ichi 
Published: August 2008

Abstract
5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in chemotherapy against various solid tumors. 5-FU dose-dependently increased the expression levels of intrinsic antiangiogenic factor thrombospondin-1 (TSP-1) in human colon carcinoma KM12C cells and human breast cancer MCF7 cells. We investigated the molecular basis for the induction of TSP-1 by 5-FU in KM12C cells. Promoter assays showed that the region with the Egr-1 binding site is critical for the induction of TSP-1 promoter activity by 5-FU. The binding of Egr-1 to the TSP-1 promoter was increased in KM12C cells treated with 5-FU. Immunofluorescence staining revealed that 5-FU significantly increased the level of Egr-1 in the nuclei of KM12C cells. The suppression of Egr-1 expression by small interfering RNA decreased the expression level of TSP-1. Furthermore, 5-FU induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27). Blockade of the p38 MAPK pathway by SB203580 remarkably inhibited the phosphorylation of HSP27 induced by 5-FU and decreased the induction of Egr-1 and TSP-1 by 5-FU in KM12C cells. These findings suggest that the p38 MAPK pathway plays a crucial role in the induction of Egr-1 by 5-FU and that induced Egr-1 augments TSP-1 promoter activity, with the subsequent production of TSP-1 mRNA and protein. [Cancer Res 2008;68(17):7035–41]
Tissue Prostate-Specific Antigen Facilitates Refractory Prostate Tumor Progression via Enhancing ARA70-Regulated Androgen Receptor Transactivation
Authors: Niu Yuanjie , Yeh Shuyuan , Miyamoto Hiroshi , Li Gonghui , Altuwaijri Saleh , Yuan Jianqun , Han Ruifa , Ma Tengxiang , Kuo Hann-Chorng , Chang Chawnshang 
Published: August 2008

Abstract
Despite being well recognized as the best biomarker for prostate cancer, pathophysiologic roles of prostate-specific antigen (PSA) remain unclear. We report here that tissue PSA may be involved in the hormone-refractory prostate cancer progression. Histologic analyses show that the increased tissue PSA levels are correlated with lower cell apoptosis index and higher cell proliferation rate in hormone-refractory tumor specimens. By stably transfecting PSA cDNA into various prostate cancer cell lines, we found that PSA could promote the growth of androgen receptor (AR)-positive CWR22rv1 and high-passage LNCaP (hormone-refractory prostate cancer cells) but not that of AR-negative PC-3 and DU145 cells. Surprisingly, the protease activity of PSA is not crucial for PSA to stimulate growth and promote AR transactivation. We further showed that increased PSA could enhance ARA70-induced AR transactivation via modulating the p53 pathway that results in the decreased apoptosis and increased cell proliferation in prostate cancer cells. Knockdown of PSA in LNCaP and CWR22rv1 cells causes cell apoptosis and cell growth arrest at the G1 phase. In vitro colony formation assay and in vivo xenografted tumor results showed the suppression of prostate cancer growth via targeting PSA expression. Collectively, our findings suggest that, in addition to being a biomarker, PSA may also become a new potential therapeutic target for prostate cancer. PSA small interfering RNA or smaller molecules that can degrade PSA protein may be developed as alternative approaches to treat the prostate cancer. [Cancer Res 2008;68(17):7110–9]
Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells
Authors: Deng Wen , Tsao Sai Wah , Kwok Yvonne K. , Wong Esther , Huang Xiao Ru , Liu Si , Tsang Chi M. , Ngan Hextan Y.S. , Cheung Annie N.Y. , Lan Hui Yao , Guan Xin-Yuan , Cheung Annie L.M. 
Published: August 2008

Abstract
Uterine cervical cancer, the second most frequently occurring cancer in women worldwide, is tightly associated with the expression of high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] oncogenes E6 and E7 and characteristically exhibits chromosomal instability. However, the mechanisms underlying chromosomal instability in cervical cancer are still not fully understood. In this study, we observed that two of three human cervical epithelial cell lines expressing HPV16 E6E7 became immortalized without extensive chromosomal instability and crisis. The introduction of transforming growth factor (TGF)-β1, a multiple functional cytokine/growth factor, in the culture medium induced crisis, which was associated with massive chromosomal end-to-end fusions and other structural aberrations. The distributions of structural aberrations on individual chromosomes were significantly correlated with the profiles of telomere signal–free ends. The immortalized cells that emerged from the TGF-β1–induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-β1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-β1 on chromosomal instability. Interestingly, another HPV16 E6E7–expressing cervical cell line that experienced crisis and telomere dysfunction under ordinary culture condition had a higher level of autocrine TGF-β1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-β1 pathway by an inhibitor of TGF-β1 receptor type I prevented the crisis and telomere-mediated chromosomal instability. In addition, more dramatic telomere shortening was observed in cervical intraepithelial neoplasias having higher expression of TGF-β1 in vivo. These results together suggest an important role of TGF-β1 in the early process of cervical carcinogenesis. [Cancer Res 2008;68(17):7200–9]
Manipulation of [11C]-5-Hydroxytryptophan and 6-[18F]Fluoro-3,4-Dihydroxy-l-Phenylalanine Accumulation in Neuroendocrine Tumor Cells
Authors: Neels Oliver C. , Koopmans Klaas P. , Jager Pieter L. , Vercauteren Laya , van Waarde Aren , Doorduin Janine , Timmer-Bosscha Hetty , Brouwers Adrienne H. , de Vries Elisabeth G.E. , Dierckx Rudi A.J.O. , Kema Ido P. , Elsinga Philip H. 
Published: August 2008

Abstract
[11C]-5-Hydroxytryptophan ([11C]HTP) and 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine ([18F]FDOPA) are used to image neuroendocrine tumors with positron emission tomography. The precise mechanism by which these tracers accumulate in tumor cells is unknown. We aimed to study tracer uptake via large amino acid transporters, peripheral decarboxylation (inhibited by carbidopa), and intracellular breakdown by monoamine oxidase (MAO). [11C]HTP and [18F]FDOPA tracer accumulation was assessed in a human neuroendocrine tumor cell line, BON. The carbidopa experiments were done in a tumor-bearing mouse model. Intracellular [11C]HTP accumulation was 2-fold higher than that of [18F]FDOPA. Cellular transport of both tracers was inhibited by amino-2-norbornanecarboxylic acid. The MAO inhibitors clorgyline and pargyline increased tracer accumulation in vitro. Carbidopa did not influence tracer accumulation in vitro but improved tumor imaging in vivo. Despite lower accumulation in vitro, visualization of [18F]FDOPA is superior to [11C]HTP in the neuroendocrine pancreatic tumor xenograft model. This could be a consequence of the serotonin saturation of BON cells in the in vivo model. [Cancer Res 2008;68(17):7183–90]
RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose
Authors: Hamatani Kiyohiro , Eguchi Hidetaka , Ito Reiko , Mukai Mayumi , Takahashi Keiko , Taga Masataka , Imai Kazue , Cologne John , Soda Midori , Arihiro Koji , Fujihara Megumu , Abe Kuniko , Hayashi Tomayoshi , Nakashima Masahiro , Sekine Ichiro , Yasui Wataru , Hayashi Yuzo , Nakachi Kei 
Published: August 2008

Abstract
A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAFV600E point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAFV600E mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (Ptrend = 0.002). In contrast, BRAFV600E mutation was less frequent in cases exposed to higher radiation dose (Ptrend &lt; 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAFV600E mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis. [Cancer Res 2008;68(17):7176–82]