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SUMMARY The surface heat flow of southern South America was examined based on an updated database containing 1113 locations. Accordingly, this study presents the most accurate heat flow map of the southern portion of the continent (south of 16°30′S latitude), covering areas that previously presented limited information. The main anomalies show a strong spatial correlation with geothermal zones and with the most up-to-date lithospheric thickness maps. The blanketing effect produced by the sedimentary basins reduce the surface heat flow up to 27 mW m–2 over the thickest basins. The study region was separated into four large areas and their connection to tectonic processes analysed. The Central Andes present high heat flow zones related to a thick radiogenic crust, volcanic activity, and a hot asthenospheric wedge. In the Pampean flat-slab region, the low heat flow coincides mostly with the horizontal projection of the Juan Fernández aseismic ridge and not with a wide region as previously thought. Furthermore, a close relationship between the subduction of the ridges at different angles and a cold upper-plate lithosphere is suggested. Besides active regions of arc magmatism and a thin lithosphere, we propose that a hot upper-plate upwelling beneath the Patagonian Platform is also contributing to the high heat flow in the area. The foreland region exhibits a low heat flow coinciding with a thick cratonic lithosphere, and local high heat flow values in suture zones possibly triggered by ancient delamination beneath these regions.

Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression.Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal–regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents.Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK- and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors.Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. Clin Cancer Res; 18(12); 3316–27. ©2012 AACR.

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Supplementary Figure 1. Represents CD30 serum levels at various time during the therapy in 22 patients

Supplementary Tables. Includes 4 tables: a) Supplementary Table 1 describing clinical characteristics of all HL patients b) Supplementary Table 2 describing disease characteristics of HL responding patients c) Supplementary Table 3 describing adverse events observed during the month of therapy with perifosine alone d) Supplementary Table 4 describing association of serum soluble cytokine levels with therapy response

Legend of Supplementary Figure 1

Purpose: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.Experimental Design: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.Results: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4–21). The most common drug-related toxicities were grade 1–2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand–foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.Conclusions: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort. Clin Cancer Res; 20(22); 5641–51. ©2014 AACR.

Supplementary Figure 4 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Figure 1 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Figure 5 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Figure 2C from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Figure 3 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Figure 6 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Supplementary Table 1, Figure Legends 1-6 from Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Geological settings characterized by multiple coeval tectonic regimes provide a unique opportunity to understand complex interactions among different geodynamic processes. However, they remain comparatively less studied from an experimental point of view than areas with more simple patterns of deformation resulting from primary plate–boundary interactions. Here, we carried out analog experiments involving simultaneous shortening and orthogonal extension under different rheological conditions, including the effect of crustal inheritance. We performed brittle experiments and brittle–ductile experiments to simulate cases of “strong” and “weak” crusts, respectively. We present two types of experiments: (i) one-stage experiments with either shortening only or synchronous orthogonal shortening and stretching and (ii) two-stage experiments with a first stage of stretching and a second stage with either shortening only or synchronous orthogonal shortening and stretching. In our models, deformation is accommodated by a combination of normal, thrust, and strike-slip faults with structure location depending on boundary conditions and crustal inheritance. For brittle models, we show that the three types of structures can develop at the same time for intermediate ratios of stretching (extension) over shortening rates (1.40). For larger ratios and for the same amount of stretching, deformation is accommodated by normal faults at edges and in the center of the model as well as by conjugate strike-slip faults at the edges of the model. For brittle–ductile models, we always observe strike-slip faults that crosscut the entire model. They are associated with shortening-orthogonal thrust faults for models with low Ve/Vs and no initial extensional stage or stretching-orthogonal normal faults for models with high Ve/Vs and an initial extensional stage. Whatever the crustal strength, the past deformation history, and the stretching / shortening ratio, both normal and thrust faults remain with similar orientations, i.e., stretching-orthogonal and shortening-orthogonal, respectively. Instead, strike-slip faults exhibit orientations with respect to the shortening direction that vary between ∼0 and ∼65∘. Strike-slip faults parallel to the shortening direction develop in previously extended portions of models with a brittle–ductile crust, while strike-slip faults with a high angle form at the boundaries of the brittle model, their orientation being to some extent influenced by pre-existing or newly forming graben in the center of the model. We also show that extensional structures formed during a first stage of deformation are never inverted under orthogonal shortening but can be reactivated as normal or strike-slip faults depending on Ve/Vs. Our experiments reproduce V-shaped conjugate strike-slip systems and normal faulting during compression similar to structures observed in the Tibetan Plateau, the eastern Alps, western Anatolia, and the Central Asia orogen. Models with two-stage deformation show variable extensional to strike-slip reactivation of former extensional basins during basin-parallel shortening, which resembles synorogenic foreland transtensional reactivations documented in the Baikal and Golfo de San Jorge basins.

Purpose We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression‐free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results About 1227 patients were included. The 7‐year OS was 84.3% (95% CI 80.8‐87.2) for ABVD vs 87.7% (95% CI 84.5‐90.2) for BEACOPP. Two follow‐up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09‐2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7‐year PFS was 71.1% (95% CI 67.1‐74.6) for ABVD vs 81.1% (95% CI 77.5‐84.2) for BEACOPP (P, Advanced Hodgkin lymphoma (HL) are treated with two different chemotherapy regimens (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine [ABVD] or bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone [BEACOPP]) that have two different toxicity profiles. In this pooled analysis of four randomized trials comparing these two regimens, and with a median follow‐up of 7 years, progression‐free survival is significantly superior with the BEACOPP regimen. The 7 years overall survival was 84.3% for ABVD and 87.7% for BEACOPP. The main cause of death after ABVD is HL, but second malignancy including 10 myeloid malignancies after BEACOPP.

Vertical slab-tearing has been widely reported in modern convergent settings profoundly influencing subduction and mantle dynamics. However, evaluating a similar impact in ancient convergent settings, where oceanic plates have been subducted and the geological record is limited, remains challenging. In this study, we correlate the lower mantle structure, which retained the past subduction configuration, with the upper-plate geological record to show a deep slab rupture interpreted as a large-scale tearing event in the early Mesozoic beneath southwestern Gondwana. For this purpose, we integrated geochronological and geological datasets with P-wave global seismic tomography and plate-kinematic reconstructions. The development of a Late Triassic-Early Jurassic slab-tearing episode supports (i) a slab gap at lower mantle depths, (ii) a contrasting spatiotemporal magmatic evolution, (iii) a lull in arc activity, and (iv) intraplate extension and magmatism in the Neuquén and Colorado basins. This finding not only has implications for identifying past examples of a fundamental process that shapes subduction zones, but also illustrates an additional mechanism to trigger slab-tearing in which plate rupture is caused by opposite rotation of slab segments. Fil: Gianni, Guido Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto Geofísico Sismológico Volponi; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro. Departamento de Geología; Argentina Fil: Navarrete Granzotto, César Rodrigo. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro. Departamento de Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Spagnotto, Silvana Liz. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Departamento de Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina

A novel geodynamic evolution model of the southwestern region of Gondwana from the late Triassic to the middle Jurassic period is proposed in this contribution, based on new data collected in the Patagonian region and an exhaustive bibliographic review. New geochemical data of La Leona Fm. (Deseado Massif) and a new zircon U/Pb age (207.6 + 4.1/−2.3 Ma), added to a compilation of previous geochronological and geochemical data, allow confirming the existence of an Upper Triassic magmatic arc in central Patagonia, with typical adakitic features. This volcanic arc developed about ~1000?1100 km away from the hypothetical paleo-trench (at its most distal portion) in and intraplate position. New geological mapping carried out in the surrounding areas of these arc-related products allowed recognizing an important and previously underestimated late Triassic contractional episode that affected the south-central Patagonian region, which can be correlated with multiple events of deformation in southwestern Gondwana as far as in the Cape and Sierra de la Ventana fold belts. After this contractional episode, the Jurassic Chon Aike Silicic Large Igneous Province (SLIP - Deseado Massif and North Patagonian Massif) outbursts from a crustal source linked to a mantle thermal anomaly, as new geochemical data and previous data indicate. New and previous structural, geochemical, and geochronological data allow us to propose the existence of a late Triassic-earliest early Jurassic flat-slab episode (~227?190? Ma), here referred to as the South Gondwanian flat-slab, comparable in size with the largest present and previously documented flat-slab configurations on Earth. This event would have been responsible for the inland arc migration, from a western position on the Antarctic Peninsula to central Patagonia (Central Patagonian Batholith), as well as the widespread contractional pulse registered in southwestern Gondwana. The existence of this late Triassic shallow subduction episode is reinforced by a combination of P-wave seismic tomographic data and a recent plate kinematic reconstruction that reveal an anomalous inland location for the subducted slab, presently at the base of the lower mantle. In Lower Jurassic times, a slab-detachment episode developed simultaneously with the impingement and southwestward displacement of the Karoo mantle plume, would have favored the destabilization of the flat-subduction configuration. A re-establishment of the subduction in southwestern Gondwana, associated with the Lower Jurassic magmatic arc retraction (Subcordilleran Patagonian Batholith), occurred under extensional conditions most likely associated with slab rollback and a southwestward asthenospheric return flow. This upper mantle flow may have exerted a suction effect on the Karoo mantle plume towards Patagonia, expanding its lifespan with a continuous southwestward rejuvenation of the synextensional SLIP Chon Aike´s magmatism. Fil: Navarrete, Cesar. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina Fil: Gianni, Guido Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina Fil: Encinas, A.. Universidad de Concepción; Chile Fil: Marquez, Marcelo Jose. Secretaría de Industria y Minería. Servicio Geológico Minero Argentino; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina Fil: Kamerbeek, Constanza Belén. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Valle, Mauro Nicolás. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Folguera, A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina