A prospective evaluation of treatment with Selective Internal Radiation Therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy

BACKGROUND: To prospectively evaluate the efficacy and safety of selective internal radiation (SIR) spheres in patients with inoperable liver metastases from colorectal cancer who have failed 5FU based chemotherapy. METHODS: Patients were prospectively enrolled at three Australian centres. All patients had previously received 5-FU based chemotherapy for metastatic colorectal cancer. Patients were ECOG 0–2 and had liver dominant or liver only disease. Concurrent 5-FU was given at investigator discretion. RESULTS: Thirty patients were treated between January 2002 and March 2004. As of July 2004 the median follow-up is 18.3 months. Median patient age was 61.7 years (range 36 – 77). Twenty-nine patients are evaluable for toxicity and response. There were 10 partial responses (33%), with the median duration of response being 8.3 months (range 2–18) and median time to progression of 5.3 mths. Response rates were lower (21%) and progression free survival shorter (3.9 mths) in patients that had received all standard chemotherapy options (n = 14). No responses were seen in patients with a poor performance status (n = 3) or extrahepatic disease (n = 6). Overall treatment related toxicity was acceptable, however significant late toxicity included 4 cases of gastric ulceration. CONCLUSION: In patients with metastatic colorectal cancer that have previously received treatment with 5-FU based chemotherapy, treatment with SIR-spheres has demonstrated encouraging activity. Further studies are required to better define the subsets of patients most likely to respond

Ocean warming, not acidification, controlled coccolithophore response during past greenhouse climate change

Current carbon dioxide emissions are an assumed threat to oceanic calcifying plankton (coccolithophores) not just due to rising sea-surface temperatures, but also because of ocean acidification (OA). This assessment is based on single species culture experiments that are now revealing complex, synergistic, and adaptive responses to such environmental change. Despite this complexity, there is still a widespread perception that coccolithophore calcification will be inhibited by OA. These plankton have an excellent fossil record, and so we can test for the impact of OA during geological carbon cycle events, providing the added advantages of exploring entire communities across real-world major climate perturbation and recovery. Here we target fossil coccolithophore groups (holococcoliths and braarudosphaerids) expected to exhibit greatest sensitivity to acidification because of their reliance on extracellular calcification. Across the Paleocene-Eocene Thermal Maximum (56 Ma) rapid warming event, the biogeography and abundance of these extracellular calcifiers shifted dramatically, disappearing entirely from low latitudes to become limited to cooler, lower saturation-state areas. By comparing these range shift data with the environmental parameters from an Earth system model, we show that the principal control on these range retractions was temperature, with survival maintained in high-latitude refugia, despite more adverse ocean chemistry conditions. Deleterious effects of OA were only evidenced when twinned with elevated temperatures

QES-Fire: A dynamically coupled fast-response wildfire model

A microscale wildfire model, QES-Fire, that dynamically couples the fire front to microscale winds was developed using a simplified physics rate of spread (ROS) model, a kinematic plume-rise model and a mass-consistent wind solver. The model is three-dimensional and couples fire heat fluxes to the wind field while being more computationally efficient than other coupled models. The plume-rise model calculates a potential velocity field scaled by the ROS model\u27s fire heat flux. Distinct plumes are merged using a multiscale plume-merging methodology that can efficiently represent complex fire fronts. The plume velocity is then superimposed on the ambient winds and the wind solver enforces conservation of mass on the combined field, which is then fed into the ROS model and iterated on until convergence. QES-Fire\u27s ability to represent plume rise is evaluated by comparing its results with those from an atmospheric large-eddy simulation (LES) model. Additionally, the model is compared with data from the FireFlux II field experiment. QES-Fire agrees well with both the LES and field experiment data, with domain-integrated buoyancy fluxes differing by less than 17% between LES and QES-Fire and less than a 10% difference in the ROS between QES-Fire and FireFlux II data

Coccolithophore calcification response to past ocean acidification and climate change

Anthropogenic carbon dioxide emissions are forcing rapid ocean chemistry changes and causing ocean acidification (OA), which is of particular significance for calcifying organisms, including planktonic coccolithophores. Detailed analysis of coccolithophore skeletons enables comparison of calcite production in modern and fossil cells in order to investigate biomineralization response of ancient coccolithophores to climate change. Here we show that the two dominant coccolithophore taxa across the Paleocene–Eocene Thermal Maximum (PETM) OA global warming event (~56 million years ago) exhibited morphological response to environmental change and both showed reduced calcification rates. However, only Coccolithus pelagicus exhibits a transient thinning of coccoliths, immediately before the PETM, that may have been OA-induced. Changing coccolith thickness may affect calcite production more significantly in the dominant modern species Emiliania huxleyi, but, overall, these PETM records indicate that the environmental factors that govern taxonomic composition and growth rate will most strongly influence coccolithophore calcification response to anthropogenic change

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4–based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism

Prior bevacizumab and efficacy of later anti-epidermal growth factor receptor antibodies in metastatic colorectal cancer: results from a large international registry

The sequencing of biologic agents used in metastatic colorectal cancer can affect the outcomes. We analyzed a multicenter registry to address a question that could not be answered using current clinical trial data. We found that whether or not patients had received previous bevacizumab, the effect of epidermal growth factor receptor antibodies in later lines of therapy was maintained. Background: The FIRE-3 [5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment colorectal cancer (CRC)] study reported that first-line FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab resulted in similar progression-free survival (PFS) but improved overall survival (OS). A potential explanation is that the initial biologic agent administered in metastatic CRC (mCRC) affects later line efficacy of the other treatments. We sought to test this hypothesis. Materials and Methods: We interrogated our mCRC registry (Treatment of Recurrent and Advanced Colorectal Cancer) regarding treatment and outcome data for RAS wild-type patients receiving epidermal growth factor receptor inhibitors (EGFRIs) in second and subsequent lines. Survival outcomes from the beginning of EGFRI use were determined as a function of previous bevacizumab use and the interval between ceasing bevacizumab and beginning EGFRI use. Results: Of 2061 patients, 222 eligible patients were identified, of whom 170 (77%) had received previous bevacizumab and 52 (23%) had not. PFS and OS from the start of EGFRIs did not differ by previous bevacizumab use (3.8 vs. 4.2 months; hazard ratio [HR], 1.12; P =.81; 9.0 vs. 9.2 months; HR, 1.19; P =.48, respectively) for the whole cohort or when analyzed by the primary tumor side (HR for left side, 1.07; P =.57; HR for right side, 1.2; P =.52). PFS was significantly shorter with right-sided primary tumors when the interval between bevacizumab and EGFRI use was 6 months (median, 2.2 vs. 6 months; HR, 2.23; P =.01) but not with left-sided tumors (median, 4.2 vs. 5.5 months; HR, 1.12; P =.26). Conclusion: Previous bevacizumab use had no effect on the activity of subsequent EGFRIs. The apparent effect of time between biologic agents in right-sided tumors might reflect patient selection

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin