Nori 1-motives

Let EHM be Nori's category of effective homological mixed motives. In this paper, we consider the thick abelian subcategory EHM_1 generated by the i-th relative homology of pairs of varieties for i = 0,1. We show that EHM_1 is naturally equivalent to the abelian category M_1 of Deligne 1-motives with torsion; this is our main theorem. Along the way, we obtain several interesting results. Firstly, we realize M_1 as the universal abelian category obtained, using Nori's formalism, from the Betti representation of an explicit diagram of curves. Secondly, we obtain a conceptual proof of a theorem of Vologodsky on realizations of 1-motives. Thirdly, we verify a conjecture of Deligne on extensions of 1-motives in the category of mixed realizations for those extensions that are effective in Nori's sense

Seasonal moisture sources and the isotopic composition of precipitation, rivers, and carbonates across the Andes at 32º-35.5°S

Constraining the influence of different moisture sources across the flanks of mountain ranges is important for understanding tectonic, geomorphic, and paleoclimate problems at geologic timescales, as well as evaluating climate change and water resources on human time scales. The stable isotope compositions of stream waters and precipitation are an ideal tool for this task. This study reports the results of a 2 year monthly precipitation sampling campaign on the eastern flank of the Andes in the Mendoza Province of Argentina, which began in September 2008. A total of 104 precipitation samples spanning some 2500 m of relief from nine sites were analyzed for δD and δ18O. In addition, 81 samples from Andean rivers collected on both sides of the range in 2002 and 2007 were analyzed. We employ a Rayleigh isotope fractionation modeling approach to explore spatial and temporal variations in precipitation and river water compositions. The results indicate that precipitation on the eastern slopes of the Andes at ~33°S, at elevations above 2 km, is largely derived from a westerly, Pacific-source component and a mixture of easterly and westerly sources below 2 km. Further south at ~35°S, river water compositions exhibit a strong winter influence. At 33°S, rivers have an isotopic minimum of ~ −18? across the core of the range, which has an average elevation of 4000 m, and are topographically offset from similar isotopic values of precipitation by +1000 m. Comparison of precipitation and river water data with temperature-corrected δ18O estimates from pedogenic carbonates illustrates that carbonates capture the range of variability observed in modern precipitation and Rayleigh fractionation models.Fil: Hoke, Gregory D.. Syracuse University. Department of Earth Sciences; Estados UnidosFil: Aranibar, Julieta Nelida. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Viale, Maximiliano. Universidad de Chile. Departamento de Geofísica. Facultad de Ciencias Físicas y Matemáticas; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Araneo, Diego Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Llano, Carina. Museo de Historia Natural de San Rafael. Departamento de Antropología; Argentin

Master-equations for the study of decoherence

Different structures of master-equation used for the description of decoherence of a microsystem interacting through collisions with a surrounding environment are considered and compared. These results are connected to the general expression of the generator of a quantum dynamical semigroup in presence of translation invariance recently found by Holevo.Comment: 10 pages, latex, no figures, to appear in Int. J. Theor. Phy

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up

Background: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. Patients and methods: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m2 plus cyclophosphamide 4 mg/m2 with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. Results: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). Conclusions: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encourage

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

Background: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. Patients and methods: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. Results: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. Conclusion: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherap

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer

Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. Patients and methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). Results: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. Conclusion: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therap

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer

Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. Patients and methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). Results: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. Conclusion: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therap

A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice

Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15-40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression.Fil: Lopez, Maria Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Rivera, Angel A.. University Of Alabama At Birmingahm; Estados UnidosFil: Viale, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Benedetti, Lorena Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Cuneo, Nicasio. Hospital Municipal de Oncología Marie Curie; ArgentinaFil: Kimball, Kristopher J.. University Of Alabama At Birmingahm; Estados UnidosFil: Wang, Minghui. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Douglas, Joanne T.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Zhu, Zeng B.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Bravo, Alicia I.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "eva Peron"; ArgentinaFil: Gidekel, Manuel. Universidad de la Frontera; ChileFil: Alvarez, Ronald D.. University Of Alabama At Birmingahm; Estados UnidosFil: Curiel, David T.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados Unidos. University of Washington; Estados UnidosFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentin

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer

Background: The International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. Patients and methods: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of ‘classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF→ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. Results: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF→ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). Conclusions: For pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhe