bluuebunny/crossref_metadata_2025 huggingface dataset:
PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients
Authors: He Youji , Van't Veer Laura J. , Mikolajewska-Hanclich Izabela , van Velthuysen Marie-Louise F. , Zeestraten Eliane C.M. , Nagtegaal Iris D. , van de Velde Cornelis J.H. , Marijnen Corrie A.M.
Published: November 2009

Purpose: Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients.

Experimental Design: We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial.

Results: PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9), 81 (33.9), and 5 (2.1) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8 versus 9.4; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95 confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage.

Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects. (Clin Cancer Res 2009;15(22):695662)
Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies
Authors: Hong David S. , Sebti Said M. , Newman Robert A. , Blaskovich Michelle A. , Ye Lei , Gagel Robert F. , Moulder Stacy , Wheler Jennifer J. , Naing Aung , Tannir Nizar M. , Ng Chaan S. , Sherman Steven I. , El Naggar Adel K. , Khan Rabia , Trent Jon , Wright John J. , Kurzrock Razelle
Published: November 2009

Purpose: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.

Experimental Design: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).

Results: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had 50 reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months).

Conclusions: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations. (Clin Cancer Res 2009;15(22):70618)
Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib
Authors: Bello Carlo L. , Mulay Marilyn , Huang Xin , Patyna Shem , Dinolfo Melissa , Levine Steven , Van Vugt Andrew , Toh Melvin , Baum Charles , Rosen Lee
Published: November 2009

Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.

Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread.

Results: Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QTcF) of 5.6 ms [90 confidence interval (CI), 1.9-9.3]. Sunitinib QTcF changes correlated with exposure, but not Tmax. Maximum mean time-matched, placebo-adjusted QTcF was 9.6 ms (90 CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90 CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QTcF >500 ms. Concomitant granisetron produced no significant QTcF prolongation. Sunitinib-related adverse events were as previously described.

Conclusions: Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer. (Clin Cancer Res 2009;15(22):704552)
Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Vaccination with an Allogeneic Whole-Cell Melanoma Vaccine
Authors: Faries Mark B. , Hsueh Eddy C. , Ye Xing , Hoban Mary , Morton Donald L.
Published: November 2009

Purpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.

Experimental Design: Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined.

Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.

Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution. (Clin Cancer Res 2009;15(22):702935)
Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial
Authors: Slingluff Craig L. , Petroni Gina R. , Olson Walter C. , Smolkin Mark E. , Ross Merrick I. , Haas Naomi B. , Grosh William W. , Boisvert Marc E. , Kirkwood John M. , Chianese-Bullock Kimberly A.
Published: November 2009

Purpose: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites.

Experimental Design: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class Irestricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DRrestricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 g GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN- ELIspot assay and tetramer analysis. Clinical outcomes were recorded.

Results: CD8+ T-cell response rates to the 12 MHC class Irestricted melanoma peptides (by day 50) with or without GM-CSF were 34 and 73, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 versus 77; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95 confidence interval) were 76 (67-83) and 52 (43-61), respectively, with too few events to assess differences by study group.

Conclusions: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. (Clin Cancer Res 2009;15(22):703644)
A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
Authors: Damiano Vincenzo , Garofalo Sonia , Rosa Roberta , Bianco Roberto , Caputo Rosa , Gelardi Teresa , Merola Gerardina , Racioppi Luigi , Garbi Corrado , Kandimalla Ekambar R. , Agrawal Sudhir , Tortora Giampaolo
Published: November 2009

Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment.

Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers.

Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling.

Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):692130)
Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor- and PTGS2
Authors: Dougherty Urszula , Cerasi Dario , Taylor Ieva , Kocherginsky Masha , Tekin Ummuhan , Badal Shamiram , Aluri Lata , Sehdev Amikar , Cerda Sonia , Mustafi Reba , Delgado Jorge , Joseph Loren , Zhu Hongyan , Hart John , Threadgill David , Fichera Alessandro , Bissonnette Marc
Published: November 2009

Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined.

Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR.

Results: Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P < 0.05) and cancer incidence (43.9 versus 16.7; P < 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon.

Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)
Getting Knit-PI3Ky: PIK3CA Mutation Status to Direct Multimodality Therapy?
Authors: Myers Andrea P. , Meyerhardt Jeffrey A. , Cantley Lewis C.
Published: November 2009

There is high morbidity associated with local recurrence of rectal cancer. However, the adjuvant therapies given to prevent such recurrences also have significant side effects and associated risks. The ability to select patients with the highest risk of recurrence and greatest therapeutic response will improve rectal cancer care. (Clin Cancer Res 2009;15(22):674850)
Immunostimulation Versus Immunosuppression after Multiple Vaccinations: the Woes of Therapeutic Vaccine Development
Authors: Eggermont Alexander M.M.
Published: November 2009

Three articles in this issue of Clinical Cancer Research show how multiple vaccinations can lead to immunosuppression. Moreover, two studies in patients show that granulocyte macrophage colony-stimulating factor (GM-CSF) as an adjuvant immunostimulant to different kind of vaccines can lead to adverse outcome in terms of relapse-free and overall survival. Modulation of regulatory T-cell activity may be required to overcome this outcome and may be crucial for the successful development of therapeutic vaccines. (Clin Cancer Res 2009;15(22):67457)
Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells
Authors: Gueron Geraldine , De Siervi Adriana , Ferrando Mercedes , Salierno Marcelo , De Luca Paola , Elguero Belen , Meiss Roberto , Navone Nora , Vazquez Elba S.
Published: November 2009

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here, we investigated the regulated expression of HO-1 and its functional consequences in PCa. We studied the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgen-insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared with MDA PCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. Furthermore, overexpression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, small interfering RNA–mediated silencing of HO-1 expression in MDA PCa2b cells resulted in increased proliferation and invasion. Using reverse transcription-quantitative PCR–generated gene array, a set of inflammatory and angiogenic genes were upregulated or downregulated in response to HO-1 overexpression identifying matrix metalloprotease 9 (MMP9) as a novel downstream target of HO-1. MMP9 production and activity was downregulated by HO-1 overexpression. Furthermore, PC3 cells stably transfected with HO-1 (PC3HO-1) and controls were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth and MMP9 expression was significantly reduced in PC3HO-1 tumors compared with control xenografts. Taken together, these results implicate HO-1 in PCa cell migration and proliferation suggesting its potential role as a therapeutic target in clinical settings. (Mol Cancer Res 2009;7(11):1745–55)
Upregulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large-Cell Lung Cancer
Authors: Hillion Joelle , Wood Lisa J. , Mukherjee Mita , Bhattacharya Raka , Di Cello Francescopaolo , Kowalski Jeanne , Elbahloul Ossama , Segal Jodi , Poirier John , Rudin Charles M. , Dhara Surajit , Belton Amy , Joseph Biju , Zucker Stanley , Resar Linda M.S.
Published: November 2009

Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we show that HMGA1 is an important oncogene that drives transformation in undifferentiated, large-cell carcinoma. First, we show that the HMGA1 gene is overexpressed in lung cancer cell lines and primary human lung tumors. Forced overexpression of HMGA1 induces a transformed phenotype with anchorage-independent cell growth in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA1 expression blocks anchorage-independent cell growth in the H1299 metastatic, undifferentiated, large-cell human lung carcinoma cells. We also show that the matrix metalloproteinase-2 (MMP-2) gene is a downstream target upregulated by HMGA1 in large-cell carcinoma cells. In chromatin immunoprecipitation experiments, HMGA1 binds directly to the MMP-2 promoter in vivo in large-cell lung cancer cells, but not in squamous cell carcinoma cells. In large-cell carcinoma cell lines, there is a significant, positive correlation between HMGA1 and MMP-2 mRNA. Moreover, interfering with MMP-2 expression blocks anchorage-independent cell growth in H1299 large-cell carcinoma cells, indicating that the HMGA1–MMP-2 pathway is required for this transformation phenotype in these cells. Blocking MMP-2 expression also inhibits migration and invasion in the H1299 large-cell carcinoma cells. Our findings suggest an important role for MMP-2 in transformation mediated by HMGA1 in large-cell, undifferentiated lung carcinoma and support the development of strategies to target this pathway in selected tumors. (Mol Cancer Res 2009;7(11):1803–12)
p34SEI-1 Inhibits Doxorubicin-Induced Senescence through a Pathway Mediated by Protein Kinase C-δ and c-Jun-NH2-Kinase 1 Activation in Human Breast Cancer MCF7 Cells
Authors: Lee Sae Lo Oom , Hong Seung-Woo , Shin Jae-Sik , Kim Jin Sun , Ko Seong-Gyu , Hong Nam-Joo , Kim Dae Jin , Lee Wang-Jae , Jin Dong-Hoon , Lee Myeong-Sok
Published: November 2009

In this study, we describe a novel function of the p34SEI-1 protein, which is both an oncogenic protein and a positive regulator of the cell cycle. The p34SEI-1 protein was found to inhibit doxorubicin-induced senescence. We investigated the molecular mechanisms of the inhibitory effect of p34SEI-1 on senescence. First, we found that the activation of protein kinase C-δ (PKC-δ), which is cleaved into a 38 kDa active form from a 78 kDa pro-form, induced after doxorubicin treatment, was inhibited by p34SEI-1. Furthermore, p34SEI-1 induced the ubiquitination of PKC-δ. Yet, there is no interaction between p34SEI-1 and PKC-δ. We also found that the phosphorylation of c-Jun-NH2-kinase 1 (JNK1) induced after doxorubicin treatment was suppressed by p34SEI-1, but not in JNK2. Consistently, pharmacologic or genetic inactivation of either PKC-δ or JNK1 was found to inhibit doxorubicin-induced senescence. In addition, the genetic inactivation of PKC-δ by PKC-δ small interfering RNA resulted in an inhibition of JNK1 activation, but PKC-δ expression was not inactivated by JNK1 small interfering RNA, implying that the activation of JNK1 could be dependently induced by PKC-δ. Therefore, p34SEI-1 inhibits senescence by inducing PKC-δ ubiquitination and preventing PKC-δ–dependent phosphorylation of JNK1. [Mol Cancer Res 2009;7(11):1845–53]
Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein
Authors: Thulin Åsa , Ringvall Maria , Dimberg Anna , Kårehed Karin , Väisänen Timo , Väisänen Marja-Riitta , Hamad Osama , Wang Jian , Bjerkvig Rolf , Nilsson Bo , Pihlajaniemi Taina , Åkerud Helena , Pietras Kristian , Jahnen-Dechent Wilhelm , Siegbahn Agneta , Olsson Anna-Karin
Published: November 2009

The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain. Using a combination of immunohistochemistry and mass spectrometry, we here provide biochemical evidence for the presence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons. Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+. Previous studies have shown that zinc-dependent binding of the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis. We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor, which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion. (Mol Cancer Res 2009;7(11):1792–802)
Caveolin-1 Promotes Autoregulatory, Akt-Mediated Induction of Cancer-Promoting Growth Factors in Prostate Cancer Cells
Authors: Li Likun , Ren Chengzhen , Yang Guang , Goltsov Alexei A. , Tabata Ken-ichi , Thompson Timothy C.
Published: November 2009

Caveolin-1 (cav-1) and the cancer-promoting growth factors vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor 2 (FGF2) are often found to be upregulated in advanced prostate cancer and other malignancies. However, the relationship between cav-1 overexpression and growth factor upregulation remains unclear. This report presents, to our knowledge, the first evidence that in prostate cancer cells, a positive autoregulatory feedback loop is established in which VEGF, TGF-β1, and FGF2 upregulate cav-1, and cav-1 expression, in turn, leads to increased levels of VEGF, TGF-β1, and FGF2 mRNA and protein, resulting in enhanced invasive activities of prostate cancer cells, i.e., migration and motility. Our results further show that cav-1–enhanced mRNA stability is a major mechanism underlying the upregulation of these cancer-promoting growth factors, and that PI3-K-Akt signaling is required for forming this positive autoregulatory feedback loop.(Mol Cancer Res 2009;7(11):1781–91)
Pulse Wave Analysis of the Aortic Pressure Waveform in Severe Left Ventricular Systolic Dysfunction
Authors: Denardo Scott J. , Nandyala Ramavathi , Freeman Gregory L. , Pierce Gary L. , Nichols Wilmer W.
Published: November 2009

Background—

The effect of moderate left ventricular systolic dysfunction (LVSD) on ventricular/vascular coupling and the aortic pressure waveform (AoPW) has been well described, but the effect of severe LVSD has not.

Methods and Results—

We used noninvasive, high-fidelity tonometry of the radial artery and a mathematical transfer function to generate the AoPW in 25 treated patients with LVSD (mean LV ejection fraction, 24±8.8%; range, 11% to 40%; 21 patients <30%). Pulse wave analysis of the AoPW was used to characterize ventricular/vascular coupling and compared with pulse wave analysis performed in 25 normal subjects matched for age, gender, height, body mass index, and heart rate. Measurements obtained using pulse wave analysis in LVSD patients indicated features of poor LV stroke performance and also reduced indices of arterial stiffness: increased travel time of the pressure wave (147±10 ms versus 132±21 ms;
P
<0.001); decreased systolic duration of reflected wave (134±24 ms versus 167±26 ms;
P
<0.001); ejection duration (277±22 ms versus 299±25 ms;
P
<0.008); percent systolic duration (32±5.3% versus 35±4.0%;
P
<0.02); aortic systolic pressure (100±16 mm Hg versus 121±16 mm Hg;
P
<0.001); unaugmented pressure (24±6.3 mm Hg versus 32±6.4 mm Hg;
P
<0.001); augmented pressure (4.8±3.1 mm Hg versus 9.6±4.5 mm Hg;
P
<0.001); pulse pressure (28±7.4 mm Hg versus 42±9.5 mm Hg;
P
<0.001); augmentation index (12±6.6% versus 23±7.6%;
P
<0.006); wasted LV effort (5.3±2.8×10
2
dyne sec/cm
2
versus 17±10×10
2
dyne sec/cm
2
;
P
<0.001); systolic pressure time index (17±4.1×10
2
mm Hg-sec/min versus 23±4.2×10
2
mm Hg sec/min;
P
<0.001); and pressure systolic area (383±121 mm Hg sec/min versus 666±150 mm Hg sec/min;
P
<0.001).

Conclusions—

Severe LVSD causes measurable changes in the AoPW. Standardization of AoPW findings in LVSD patients may allow for the clinical use of radial artery pulse wave analysis to noninvasively determine the severity of dysfunction and aid in logical therapy.
Recent National Trends in Readmission Rates After Heart Failure Hospitalization
Authors: Ross Joseph S. , Chen Jersey , Lin Zhenqiu , Bueno Héctor , Curtis Jeptha P. , Keenan Patricia S. , Normand Sharon-Lise T. , Schreiner Geoffrey , Spertus John A. , Vidán Maria T. , Wang Yongfei , Wang Yun , Krumholz Harlan M.
Published: November 2009

Background—

In July 2009, Medicare began publicly reporting hospitals’ risk-standardized 30-day all-cause readmission rates (RSRRs) among fee-for-service beneficiaries discharged after hospitalization for heart failure from all the US acute care nonfederal hospitals. No recent national trends in RSRRs have been reported, and it is not known whether hospital-specific performance is improving or variation in performance is decreasing.

Methods and Results—

We used 2004–2006 Medicare administrative data to identify all fee-for-service beneficiaries admitted to a US acute care hospital for heart failure and discharged alive. We estimated mean annual RSRRs, a National Quality Forum-endorsed metric for quality, using 2-level hierarchical models that accounted for age, sex, and multiple comorbidities; variation in quality was estimated by the SD of the RSRRs. There were 570 996 distinct hospitalizations for heart failure in which the patient was discharged alive in 4728 hospitals in 2004, 544 550 in 4694 hospitals in 2005, and 501 234 in 4674 hospitals in 2006. Unadjusted 30-day all-cause readmission rates were virtually identical over this period: 23.0% in 2004, 23.3% in 2005, and 22.9% in 2006. The mean and SD of RSRRs were also similar: mean (SD) of 23.7% (1.3) in 2004, 23.9% (1.4) in 2005, and 23.8% (1.4) in 2006, suggesting similar hospital variation throughout the study period.

Conclusions—

National mean and RSRR distributions among Medicare beneficiaries discharged after hospitalization for heart failure have not changed in recent years, indicating that there was neither improvement in hospital readmission rates nor in hospital variations in rates over this time period.
Interventional Therapy of Bifurcation Lesions
Authors: Korn Hubertus v. , Yu Jiangtao , Ohlow Marc A. , Huegl Burkhard , Schulte Walter , Wagner Andreas , Wassmer Gernot , Gruene Stefan , Petek Oliver , Lauer Bernward
Published: November 2009

Background—

Treatment of bifurcations is a complex problem. The clinical value of treating side branches is an unsolved problem in the field of interventional cardiology.

Methods and Results—

We initiated a prospective randomized controlled trial. One hundred and ten patients with bifurcations were randomly assigned to 2 arms: Stenting of the main branch (MB, Taxus-stent, paclitaxel-eluting stents) and mandatory side branch (SB) percutaneous coronary intervention (PCI; kissing balloons) with provisional SB stenting (therapy A), or stenting of the MB (paclitaxel-eluting stents) with provisional SB-PCI only when the SB had a thrombolysis in myocardial infarction flow <2 (therapy B). The primary end point was target lesion revascularization. The mean ages were 66.8 years (A) versus 65.1 years (B,
P
=0.4), 71.4% (A) versus 77.8% were men (
P
=0.4), patients with diabetes were present in 25.0% versus 25.9% (
P
=0.9). The MB was left anterior descending artery in 80.4% versus 81.5% (A versus B,
P
=0.9). The SB-PCI and kissing balloon-PCI were performed according to the study protocol in 82.1%/73.2% versus 16.7%/13.0% (
P
<0.05 for both), while changing of the intended therapy was necessary in 17.9% versus 16.7% (A versus B,
P
=0.9). A final thrombolysis in myocardial infarction flow 3 (MB) was reached in all patients (groups A and B), final thrombolysis in myocardial infarction flow 3 (SB) was observed in 96.4% versus 88.9% (A versus B,
P
=0.3). Radiation time (min) and contrast medium (mL) were 14.2/210 (group A) versus 7.8/151.6 (group B;
P
for both <0.05). Six month – follow up: major adverse cardiac events was 23.2% (A) versus 24.1% (B,
P
=0.9), target lesion revascularization was 17.9% (A) versus 14.8% (B,
P
=0.7), and late lumen loss (MB) was 0.2 mm (A) versus 0.3 mm (B,
P
=0.5). In group B, no PCI of the SB was done during follow up.

Conclusion—

A simple strategy using paclitaxel-eluting stents with only provisional SB-PCI may be of equal value to a more complex strategy with mandatory SB-PCI.

Clinical Trial Registration—

URL: http://www.controlled.trials.com. Unique identifier: ISRCTN22637771.
Insight Into the Dynamics of the Coronary Sinus/Great Cardiac Vein and the Mitral Annulus
Authors: del Valle-Fernández Raquel , Jelnin Vladimir , Panagopoulos Georgia , Ruiz Carlos E.
Published: November 2009

Background—

Implantation of devices into the coronary sinus (CS)/great cardiac vein (GCV) to reshape the mitral annulus (MA) is being investigated, despite these structures not being within the same plane and coronary arteries frequently traversing between them. Furthermore, dynamic changes in their relationship have never been studied. We analyzed the CS/GCV dimensions and its relationship with the MA and the coronary arteries.

Methods and Results—

Of 390 consecutive computed tomography angiographies reviewed, 56 met the inclusion criteria. Mean age of the patients was 68.9�13.1 years (26.8% men). The dimensions of the CS/GCV and the distance between this structure and the MA were measured at 10 different spatial points along the CS/GCV trajectory and at 3 different time points along the cardiac cycle (phases 0%, 40%, and 75% of the RR interval) by using curved multiplanar reconstruction technique. The CS/GCV was larger in phase 40% than in phase 75% and was smallest in phase 0% (
P
<0.001). The distance between the CS/GCV and the MA was longest in phase 40% and shortest in phase 0% (
P
=0.013). The diameter of the MA was measured in oblique 2- and 4-chamber reconstructions, being largest in phase 0% and smallest in phase 40% (
P
=0.019). A coronary artery traversed between the CS/GCV and the MA in 85.7% of the patients.

Conclusions—

This study demonstrated dynamic changes in the relationship between the CS/GCV and the MA and also that coronary arteries frequently traverse between both structures. Whether these findings are of clinical relevance for patients undergoing percutaneous mitral annuloplasty needs to be prospectively evaluated.
Outcomes for Patients With ST-Elevation Myocardial Infarction in Hospitals With and Without Onsite Coronary Artery Bypass Graft Surgery
Authors: Hannan Edward L. , Zhong Ye , Racz Michael , Jacobs Alice K. , Walford Gary , Cozzens Kimberly , Holmes David R. , Jones Robert H. , Hibberd Mary , Doran Donna , Whalen Deborah , King Spencer B.
Published: November 2009

Background—

The benefit of primary percutaneous coronary interventions (P-PCI) for patients with ST-elevation myocardial infarction (STEMI) has been well documented. However, controversy still exists as to whether PCI should be expanded to hospitals without coronary artery bypass graft surgery.

Methods and Results—

Patients who were discharged after PCI for STEMI between January 1, 2003, and December 12, 2006, in P-PCI centers (hospitals with no coronary artery bypass graft surgery, and PCI only for patients with STEMI) were propensity matched with patients in full service centers, and mortality and subsequent revascularization rates were compared. For patients undergoing PCI, there were no differences for in-hospital/30-day mortality (2.3% for P-PCI centers versus 1.9% for full service centers [
P
=0.40]), emergency coronary artery bypass graft surgery immediately after PCI (0.06% versus 0.35%,
P
=0.06), 3-year mortality (7.1% versus 5.9%,
P
=0.07), or 3-year subsequent revascularization (23.8% versus 21.5%,
P
=0.52). P-PCI centers had a lower same/next day coronary artery bypass graft rate (0.23% versus 0.69%,
P
=0.046) and higher repeat target vessel PCI rates (12.1% versus 9.0%,
P
=0.003). For patients with STEMI who did not undergo PCI, P-PCI centers had higher in-hospital mortality (28.5% versus 22.3%; adjusted odds ratio, 1.38; 95% CI, 1.10 to 1.75).

Conclusions—

No differences between P-PCI centers and full service centers were found in in-hospital/30-day mortality, the need for emergency surgery, 3-year mortality or subsequent revascularization, but P-PCI centers had higher repeat target vessel PCI rates and higher mortality rates for patients who did not undergo PCI. P-PCI centers should be monitored closely, including the monitoring of patients with STEMI who did not undergo PCI.
Predictors of Survival From Out-of-Hospital Cardiac Arrest
Authors: Sasson Comilla , Rogers Mary A.M. , Dahl Jason , Kellermann Arthur L.
Published: November 2009

Background—

Prior studies have identified key predictors of out-of-hospital cardiac arrest (OHCA), but differences exist in the magnitude of these findings. In this meta-analysis, we evaluated the strength of associations between OHCA and key factors (event witnessed by a bystander or emergency medical services [EMS], provision of bystander cardiopulmonary resuscitation [CPR], initial cardiac rhythm, or the return of spontaneous circulation). We also examined trends in OHCA survival over time.

Methods and Results—

An electronic search of PubMed, EMBASE, Web of Science, CINAHL, Cochrane DSR, DARE, ACP Journal Club, and CCTR was conducted (January 1, 1950 to August 21, 2008) for studies reporting OHCA of presumed cardiac etiology in adults. Data were extracted from 79 studies involving 142 740 patients. The pooled survival rate to hospital admission was 23.8% (95% CI, 21.1 to 26.6) and to hospital discharge was 7.6% (95% CI, 6.7 to 8.4). Stratified by baseline rates, survival to hospital discharge was more likely among those: witnessed by a bystander (6.4% to 13.5%), witnessed by EMS (4.9% to 18.2%), who received bystander CPR (3.9% to 16.1%), were found in ventricular fibrillation/ventricular tachycardia (14.8% to 23.0%), or achieved return of spontaneous circulation (15.5% to 33.6%). Although 53% (95% CI, 45.0% to 59.9%) of events were witnessed by a bystander, only 32% (95% CI, 26.7% to 37.8%) received bystander CPR. The number needed to treat to save 1 life ranged from 16 to 23 for EMS-witnessed arrests, 17 to 71 for bystander-witnessed, and 24 to 36 for those receiving bystander CPR, depending on baseline survival rates. The aggregate survival rate of OHCA (7.6%) has not significantly changed in almost 3 decades.

Conclusions—

Overall survival from OHCA has been stable for almost 30 years, as have the strong associations between key predictors and survival. Because most OHCA events are witnessed, efforts to improve survival should focus on prompt delivery of interventions of known effectiveness by those who witness the event.
Structure of the Atmospheric Boundary Layer in the Vicinity of a Developing Upslope Flow System: A Numerical Model Study
Authors: Serafin Stefano , Zardi Dino
Published: November 2009

The development of a morning upslope flow is studied by means of idealized numerical simulations. In particular, two cases are examined: a plane slope connecting a lower plain and an elevated plateau and a symmetric mountain in the middle of a uniform plain. The analysis examines various steepness cases and aims at understanding the processes occurring in the area of transition between the upslope flow region and the convective boundary layers (CBLs) growing nearby. A characteristic sequence of events is recognized in the simulations, and their relationship with the along-slope variability of the thermal energy and turbulent kinetic energy budgets is studied. Features occurring after the onset of the upslope wind include a transient depression in the boundary layer depth at the base of the slope and the formation of elevated turbulent layers above the CBL, caused by the divergence of turbulent flow from a thermal plume at the slope top. Numerical evidence agrees well with the results of previous experiments, including both field campaigns and water tank models. It is observed that the occurrence of streamwise inhomogeneities in the upslope flow field favors the occurrence of a multilayered vertical structure of the CBL near heated slopes. Multiple layering appears to be a transient feature, only persisting until sufficient heating causes the merging of the CBL with the overlying elevated turbulent layers. The analysis suggests that the slope steepness is an important factor in determining the speed at which the boundary layer structure near a slope evolves in time: in particular, the development of the wind system appears to occur faster in the vicinity of a steeper slope.
Validation of a High-Resolution Regional Climate Model for the Alpine Region and Effects of a Subgrid-Scale Topography and Land Use Representation
Authors: Im E-S. , Coppola E. , Giorgi F. , Bi X.
Published: November 2009

A mosaic-type parameterization of subgrid-scale topography and land use (SubBATS) is applied for a high-resolution regional climate simulation over the Alpine region with a regional climate model (RegCM3). The model coarse-gridcell size in the control simulation is 15 km while the subgridcell size is 3 km. The parameterization requires disaggregation of atmospheric variables from the coarse grid to the subgrid and aggregation of surface fluxes from the subgrid to the coarse grid. Two 10-yr simulations (1983–92) are intercompared, one without (CONT) and one with (SUB) the subgrid scheme. The authors first validate the CONT simulation, showing that it produces good quality temperature and precipitation statistics, showing in particular a good performance compared to previous runs of this region. The subgrid scheme produces much finer detail of temperature and snow distribution following the topographic disaggregation. It also tends to form and melt snow more accurately in response to the heterogeneous characteristics of topography. In particular, validation against station observations shows that the SUB simulation improves the model simulation of the surface hydrologic cycle, in particular snow and runoff, especially at high-elevation sites. Finally, two experiments explore the model sensitivity to different subgrid disaggregation assumptions, namely, the temperature lapse rate and an empirical elevation-based disaggregation of precipitation.
Relating Convective and Stratiform Rain to Latent Heating
Authors: Tao Wei-Kuo , Lang Stephen , Zeng Xiping , Shige Shoichi , Takayabu Yukari
Published: November 2009

The relationship among surface rainfall, its intensity, and its associated stratiform amount is established by examining observed precipitation data from the Tropical Rainfall Measuring Mission (TRMM) Precipitation Radar (PR). The results show that for moderate–high stratiform fractions, rain probabilities are strongly skewed toward light rain intensities. For convective-type rain, the peak probability of occurrence shifts to higher intensities but is still significantly skewed toward weaker rain rates. The main differences between the distributions for oceanic and continental rain are for heavily convective rain. The peak occurrence, as well as the tail of the distribution containing the extreme events, is shifted to higher intensities for continental rain. For rainy areas sampled at 0.5° horizontal resolution, the occurrence of conditional rain rates over 100 mm day−1 is significantly higher over land. Distributions of rain intensity versus stratiform fraction for simulated precipitation data obtained from cloud-resolving model (CRM) simulations are quite similar to those from the satellite, providing a basis for mapping simulated cloud quantities to the satellite observations.

An improved convective–stratiform heating (CSH) algorithm is developed based on two sources of information: gridded rainfall quantities (i.e., the conditional intensity and the stratiform fraction) observed from the TRMM PR and synthetic cloud process data (i.e., latent heating, eddy heat flux convergence, and radiative heating/cooling) obtained from CRM simulations of convective cloud systems. The new CSH algorithm-derived heating has a noticeably different heating structure over both ocean and land regions compared to the previous CSH algorithm. Major differences between the new and old algorithms include a significant increase in the amount of low- and midlevel heating, a downward emphasis in the level of maximum cloud heating by about 1 km, and a larger variance between land and ocean in the new CSH algorithm.
Reduction of Middle-Atmospheric Forecast Bias through Improvement in Satellite Radiance Quality Control
Authors: Kim Young-Joon , Campbell William F. , Swadley Steven D.
Published: November 2009

This article discusses a practical problem faced in operational atmospheric forecasting and data assimilation, and efforts to improve forecast quality through the choice of quality control parameters. The need to utilize as much data as possible must be carefully balanced against the need to reject observations deemed erroneous because they are far from the background value. Alleviation of forecast bias in the middle atmosphere for a global atmospheric prediction system is attempted via improvement of the quality control and bias correction of the satellite radiance data; in particular, the sensitivity of the analysis to the satellite radiance outlier check parameters for the Naval Research Laboratory’s three-dimensional variational data assimilation system [Naval Research Laboratory Atmospheric Variational Data Assimilation System (NAVDAS)] is investigated. A series of forecast experiments are performed with an extended-top (0.04 hPa or ∼65 km) version of the U.S. Navy’s Operational Global Atmospheric Prediction System (NOGAPS) for the month of January 2007. The experiments vary the prescribed radiance observation error variance for the Advanced Microwave Sounding Unit-A (AMSU-A) and the tolerance factors for the AMSU-A and NAVDAS quality control processes. The biases of geopotential height, temperature, and wind in the middle atmosphere are significantly reduced when the observation error limit for the highest-altitude AMSU-A channel (i.e., 14) is relaxed from 0.95 to 3 K and the tolerance factors for the AMSU-A and NAVDAS quality control processes are relaxed from 3 to 4. The improvement is due to assimilation of more high quality AMSU-A radiance data from the highest-peaking channel.
Post Hoc Evaluation of Hazardous Weather: Snowstorms in the Montréal, Québec, Area in March 2008
Authors: Descurieux Jacques
Published: November 2009

The post hoc evaluation of meteorological events that have severe consequences for individuals, property, economic activities, and the environment is a powerful analytical tool. The paper provides a factual and evidence-based analytical framework for the study of hazardous weather events that have major social, economic, and environmental effects. It is a process that seeks to improve and to determine the relevance of services. The analysis of the winter storms that hit the Montréal area in early March 2008 examines the relationship between the storms, the collapse of 18 roofs, the death of 3 persons, and the closure of more than 200 schools. It highlights the limited perception of the risks associated with unusual and severe winter weather. It reveals the lack of attention given in meteorology to the important paradigmatic relationship that exists between the weather elements, the associated risk factors, and the ensuing impacts. This study reveals the need for improvements in meteorological services related to risk communication and knowledge management.