bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II, Randomized Trial to Compare Anastrozole Combined with Gefitinib or Placebo in Postmenopausal Women with Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Cristofanilli Massimo , Valero Vicente , Mangalik Aroop , Royce Melanie , Rabinowitz Ian , Arena Francis P. , Kroener Joan F. , Curcio Elizabeth , Watkins Claire , Bacus Sarah , Cora Elsa M. , Anderson Elizabeth , Magill Patrick J. 
Published: March 2010

Abstract
Purpose: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor–positive metastatic breast cancer (MBC).
Experimental Design: Postmenopausal women with hormone receptor–positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective.
Results: Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed.
Conclusion: This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor–positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted. Clin Cancer Res; 16(6); 1904–14
GermlineBRCAMutations Denote a Clinicopathologic Subset of Prostate Cancer
Authors: Gallagher David J. , Gaudet Mia M. , Pal Prodipto , Kirchhoff Tomas , Balistreri Lisa , Vora Kinjal , Bhatia Jasmine , Stadler Zsofia , Fine Samson W. , Reuter Victor , Zelefsky Michael , Morris Michael J. , Scher Howard I. , Klein Robert J. , Norton Larry , Eastham James A. , Scardino Peter T. , Robson Mark E. , Offit Kenneth 
Published: March 2010

AbstractPurpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined.Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models.Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers.Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.
The Oncogene DEK Promotes Leukemic Cell Survival and Is Downregulated by both Nutlin-3 and Chlorambucil in B-Chronic Lymphocytic Leukemic Cells
Authors: Secchiero Paola , Voltan Rebecca , di Iasio Maria Grazia , Melloni Elisabetta , Tiribelli Mario , Zauli Giorgio 
Published: March 2010

Abstract
Purpose: To characterize the role of the oncogene DEK in modulating the response to either Nutlin-3, a small-molecule inhibitor of the MDM2/p53 interaction, or chlorambucil in primary B-chronic lymphocytic leukemia (B-CLL) cells.
Experimental Design: DEK mRNA and protein levels were evaluated in primary B-CLL samples (n = 21), p53wild-type SKW6.4, p53mutated BJAB lymphoblastoid cell lines, and normal CD19+ B lymphocytes–treated Nutlin-3 or chlorambucil (10 μmol/L, each). Knocking down experiments with either p53 or DEK small interfering RNA (siRNA) were done to investigate the potential role of p53 in controlling the expression of DEK and the role of DEK in leukemic cell survival/apoptosis.
Results: Both Nutlin-3 and chlorambucil downregulated DEK in primary B-CLL samples (n = 21) and SKW6.4 but not in BJAB cells. Knocking down p53 attenuated the effect of Nutlin-3 on DEK expression, whereas knocking down DEK significantly increased both spontaneous and Nutlin-3–induced apoptosis. Conversely, counteracting DEK downmodulation by using p53 small interfering RNA reduced Nutlin-3–mediated apoptosis. On the other hand, Nutlin-3 potently induced p53 accumulation, but it did not affect DEK levels in normal CD19+ B lymphocytes.
Conclusions: These data show that the downregulation of DEK in response to either Nutlin-3 or chlorambucil represents an important molecular determinant in the cytotoxic response of leukemic cells, and suggest that strategies aimed to downregulate DEK might improve the therapeutic potential of these drugs. Clin Cancer Res; 16(6); 1824–33
Targeted Inhibition of Inducible Nitric Oxide Synthase Inhibits Growth of Human Melanoma In vivo and Synergizes with Chemotherapy
Authors: Sikora Andrew G. , Gelbard Alexander , Davies Michael A. , Sano Daisuke , Ekmekcioglu Suhendan , Kwon John , Hailemichael Yared , Jayaraman Padmini , Myers Jeffrey N. , Grimm Elizabeth A. , Overwijk Willem W. 
Published: March 2010

Abstract
Purpose: Aberrant expression of inflammatory molecules, such as inducible nitric oxide (NO) synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. Whereas iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and NO can have both protumor and antitumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model.
Experimental Design: We used an immunodeficient non-obese diabetic/severe combined immunodeficient xenograft model to test the susceptibility of two different human melanoma lines to the orally-given iNOS-selective small molecule antagonist N6-(1-iminoethyl)-l-lysine-dihydrochloride (L-nil) with and without cytotoxic cisplatin chemotherapy.
Results: L-nil significantly inhibited melanoma growth and extended the survival of tumor-bearing mice. L-nil treatment decreased the density of CD31+ microvessels and increased the number of apoptotic cells in tumor xenografts. Proteomic analysis of melanoma xenografts with reverse-phase protein array identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical antiapoptotic protein Bcl-2 was downregulated in vivo and in vitro after L-nil treatment, which was associated with increased susceptibility to cisplatin-mediated tumor death. Consistent with this observation, combination therapy with L-nil plus cisplatin in vivo was more effective than either drug alone, without increased toxicity.
Conclusions: These data support the hypothesis that iNOS and iNOS-derived NO support tumor growth in vivo and provide convincing preclinical validation of targeted iNOS inhibition as therapy for solid tumors. Clin Cancer Res; 16(6); 1834–44
The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee
Authors: Seymour Lesley , Ivy S. Percy , Sargent Daniel , Spriggs David , Baker Laurence , Rubinstein Larry , Ratain Mark J. , Le Blanc Michael , Stewart David , Crowley John , Groshen Susan , Humphrey Jeffrey S. , West Pamela , Berry Donald 
Published: March 2010

Abstract
The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics “fail” in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e.g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation. Clin Cancer Res; 16(6); 1764–9
Activation of Wnt Signaling Pathway by Human Papillomavirus E6 and E7 Oncogenes in HPV16-Positive Oropharyngeal Squamous Carcinoma Cells
Authors: Rampias Theodore , Boutati Eleni , Pectasides Eirini , Sasaki Clarence , Kountourakis Panteleimon , Weinberger Paul , Psyrri Amanda 
Published: March 2010

Abstract
We sought to determine the role of human papillomavirus (HPV) E6 and E7 oncogenes in nuclear β-catenin accumulation, a hallmark of activated canonical Wnt signaling pathway. We used HPV16-positive oropharyngeal cancer cell lines 147T and 090, HPV-negative cell line 040T, and cervical cell lines SiHa (bearing integrated HPV16) and HeLa (bearing integrated HPV18) to measure the cytoplasmic and nuclear β-catenin levels and the β-catenin/Tcf transcriptional activity before and after E6/E7 gene silencing. Repression of HPV E6 and E7 genes induced a substantial reduction in nuclear β-catenin levels. Luciferase assay showed that transcriptional activation of Tcf promoter by β-catenin was lower after silencing. The protein levels of β-catenin are tightly regulated by the ubiquitin/proteasome system. We therefore performed expression analysis of regulators of β-catenin degradation and nuclear transport and showed that seven in absentia homologue (Siah-1) mRNA and protein levels were substantially upregulated after E6/E7 repression. Siah-1 protein promotes the degradation of β-catenin through the ubiquitin/proteasome system. To determine whether Siah-1 is important for the proteasomal degradation of β-catenin in HPV16-positive oropharyngeal cancer cells, we introduced a Siah-1 expression vector into 147T and 090 cells and found substantial reduction of endogenous β-catenin in these cells. Thus, E6 and E7 are involved in β-catenin nuclear accumulation and activation of Wnt signaling in HPV-induced cancers. In addition, we show the significance of the endogenous Siah-1–dependent ubiquitin/proteasome pathway for β-catenin degradation and its regulation by E6/E7 viral oncoproteins in HPV16-positive oropharyngeal cancer cells. Mol Cancer Res; 8(3); 433–43
The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency
Authors: Lahkim Bennani-Belhaj Kenza , Rouzeau Sébastien , Buhagiar-Labarchède Géraldine , Chabosseau Pauline , Onclercq-Delic Rosine , Bayart Emilie , Cordelières Fabrice , Couturier Jérôme , Amor-Guéret Mounira 
Published: March 2010

Abstract
Little is known about the functional interaction between the Bloom's syndrome protein (BLM) and the recombinase RAD51 within cells. Using RNA interference technology, we provide the first demonstration that RAD51 acts upstream from BLM to prevent anaphase bridge formation. RAD51 downregulation was associated with an increase in the frequency of BLM-positive anaphase bridges, but not of BLM-associated ultrafine bridges. Time-lapse live microscopy analysis of anaphase bridge cells revealed that BLM promoted cell survival in the absence of Rad51. Our results directly implicate BLM in limiting the lethality associated with RAD51 deficiency through the processing of anaphase bridges resulting from the RAD51 defect. These findings provide insight into the molecular basis of some cancers possibly associated with variants of the RAD51 gene family. Mol Cancer Res; 8(3); 385–94
Homocysteine induces caspase activation by endoplasmic reticulum stress in platelets from type 2 diabetics and healthy donors
Authors: Zbidi Hanene , Redondo Pedro , López Jose , Bartegi Aghleb , Salido Gines , Rosado Juan 
Published: March 2010

SummaryDiabetes mellitus is a disease characterised by hyperglycaemia and associated with several cardiovascular disorders, including angiopathy and platelet hyperactivity, which are major causes of morbidity and mortality in type 2 diabetes mellitus. In type 2 diabetic patients, homo-cysteine levels are significantly increased compared with healthy subjects. Hyperhomocysteinaemia is an independent risk factor for macro-and microangiopathy and mortality. The present study is aimed to investigate the effect of homocysteine on platelet apoptosis. Changes in cytosolic or intraluminal free Ca2+ concentration were determined by fluorimetry. Caspase activity and phosphorylation of the eukaryotic initiation factor 2α (eIF2α) were explored by Western blot. Our results indicate that homocysteine releases Ca2+ from agonist sensitive stores, enhances eIF2α phosphorylation at Ser51 and activates caspase-3 and -9 independently of extracellular Ca2+. Homocysteine induced activation of caspase-3 and -9 was abolished by salubrinal, an agent that prevents endoplasmic reticulum (ER) stress-induced apoptosis. Homo-cysteine-induced platelet effects were significantly greater in type 2 diabetics than in healthy subjects. These findings demonstrate that homocysteine induces ER stress-mediated apoptosis in human platelets, an event that is enhanced in type 2 diabetic patients, which might be involved in the pathogenesis of cardiovascular complications associated with type 2 diabetes mellitus.
Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3
Authors: Jurk Kerstin , Schulz Ansgar , Kehrel Beate , Räpple Daniel , Schulze Harald , Möbest Dieter , Friedrich Wilhelm , Omran Heymut , Deak Erika , Henschler Reinhard , Scheele Jürgen , Zieger Barbara 
Published: March 2010

SummaryLeukocyte adhesion deficiency-III (LAD-III) also called leukocyte adhesion deficiency-1/variant (LAD1v) is a rare congenital disease caused by defective integrin activation of leukocytes and platelets. Patients with LAD-III present with non-purulent infections and increased bleeding symptoms. We report on a novel integrin-dependent platelet dys-function in two brothers with LAD-III syndrome caused by a homozygous mutation 1717C>T in the FERMT3 gene leading to a premature stop codon R573X in the focal adhesion protein kindlin-3. Stimulation of patients´ platelets with all used agonists resulted in a severely decreased binding of soluble fibrinogen indicating a defect in inside-out activation of the integrin αIIbβ3 (GPIIb/IIIa). Patients´ platelets did not respond to the α2β1-integrin agonist aggretin-A at all. Our data on granula secretion indicate for the first time that the thrombin receptor PAR-4 but not PAR-1 may be important in integrin-triggered granule secretion in response to thrombin. In contrast, collagen mediated platelet granule secretion was not affected in LAD-III-patients. Thus, integrin-signalling may be not essential in collagen-induced granule secretion. The patients’ peripheral blood mononuclear cells showed a severe loss of adhesion capacity to VCAM-1 and to endothelial cells compared to cells from healthy donors. Rap-1 activation after PMA stimulation could be observed in controls´ but not in patients´ cells. After haematogenesis stem cell transplantation (HSCT) the brothers showed no symptoms of bleeding or immunodeficiency and the integrin-dependent platelet and leukocyte functions normalised.
Heparins from porcine and bovine intestinal mucosa: Are they similar drugs?
Authors: Vairo Bruno , Cinelli Leonardo , Santos Gustavo , Fonseca Roberto , Aquino Rafael , Pereira Mariana , Mourão Paulo 
Published: March 2010

SummaryIncreasing reports of bleeding and peri- or post-operative blood dyscrasias in Brazil were possibly associated with the use of heparin from bovine instead of porcine intestine. These two pharmaceutical grade heparins were analysed for potential differences. NMR analyses confirmed that porcine heparin is composed of mainly trisulfated disaccharides →4-α-IdoA2S-1→4-α-GlcNS6S-1→. Heparin from bovine intestine is also composed of highly 2-sulfated α-iduronic acid residues, but the sulfation of the α-glucosamine units vary significantly: ~50% are 6-and N-disulfated, as in porcine heparin, while ~36% are 6-desulfated and ~14% N-acetylated. These heparins differ significantly in their effects on coagulation, thrombosis and bleeding. Bovine heparin acts mostly through factor Xa. Compared to porcine heparin on a weight basis, bovine heparin exhibited approximately half of the anticoagulant and antithrombotic effects, but similar effect on bleeding. These two heparins also differ in their protamine neutralisation curves. The doses of heparin from bovine intestine required for effective antithrombotic protection and the production of adverse bleeding effects are closer than those for porcine heparin. This observation may explain the increasing bleeding observed among Brazilian patients. Our results suggest that these two types of heparin are not equivalent drugs.
Arctic Oscillation during the Mid-Holocene and Last Glacial Maximum from PMIP2 Coupled Model Simulations
Authors: Lü Jun-Mei , Kim Seong-Joong , Abe-Ouchi Ayako , Yu Yongqiang , Ohgaito Rumi 
Published: March 2010

Abstract
Changes in the Arctic Oscillation (AO) during the mid-Holocene and the Last Glacial Maximum were compared to preindustrial (PI) simulations using four coupled ocean–atmosphere models [i.e., Community Climate System Model (CCSM), third climate configuration of the Met Office Unified Model (HadCM3) Met Office Surface Exchanges Scheme, version 2 (MOSES2), L’Institut Pierre-Simon Laplace (IPSL), and Model for Interdisciplinary Research on Climate 3.2 (MIROC3.2)] from the second phase of the Paleoclimate Modeling Intercomparison Project. Results show that the amplitude of the simulated AO during the mid-Holocene is a little smaller than that of the preindustrial simulation. Although the AO pattern and vertical structures are similar to those in the preindustrial simulation, the polar westerlies are slightly weakened and displaced downward to the lower stratosphere, accompanied by weakening of the polar vortex and warming of the cold polar cap region. During the Last Glacial Maximum, when the Northern Hemisphere experiences severe cooling, the intensity of the AO decreases substantially compared to the mid-Holocene, with smaller standard deviations of the AO indices in all models. Furthermore, the magnitude of positive and negative centers of the AO spatial pattern decreases and the strength of the polar vortex and westerlies weakens further with the center of westerlies displaced into the midlatitude upper troposphere. The polar cap region becomes anomalously warm in the stratosphere, whereas it remains cold in the troposphere. The AO appears to be sensitive to background climate state.
Upward-propagating stationary Rossby waves are found to be stronger during the mid-Holocene and Last Glacial Maximum than in the preindustrial simulation. This increase in planetary wave activity might be responsible for the simulated weakening of the AO during the mid-Holocene and Last Glacial Maximum. Recent studies have shown that there is a significant correlation between Eurasian fall snow cover and the winter AO. The upward propagation of Rossby waves was further proposed to explain the physical process linking the AO with the snow depth. It is suggested that a large increase in fall snow depth during the Last Glacial Maximum strengthens the upward-propagating stationary Rossby waves relative to the PI.