Direct Evidence that Bevacizumab, an Anti-VEGF Antibody, Up-regulates SDF1 , CXCR4, CXCL6, and Neuropilin 1 in Tumors from Patients with Rectal Cancer

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy

Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer

This study was designed to assess the safety and efficacy of capecitabine and mitomycin C (MMC) in previously untreated patients with advanced colorectal cancer (CRC). Patients received capecitabine 2500 mg m2 day 1, orally divided in two doses of 1250 mg m-2 in the morning and evening for 14 days every 21 days and MMC 7 mg m-2 (maximum total dose 14 mg) as an intravenous bolus every 6 weeks for a total of four courses. The median age was 70 years (range 24–85) and the majority of patients (86.9%) were of performance status 1/2. The most common metastatic site was liver. In all, 84 patients were assessable for response. The overall response rate was 38% (95% CI: 27.7–49.3) and a further 33.3% of patients achieved stable disease over 12 weeks. There was good symptom resolution ranging from 64 to 86%. Grade 3/4 toxicity was as follows: hand–foot syndrome 19.7%; diarrhoea 10%; neutropenia 2.4%; infection 2.3%. Capecitabine and MMC have shown encouraging activity with a favourable toxicity profile, a convenient administration schedule, and could be considered for patients deemed unsuitable for oxaliplatin and irinotecan combinations.S Rao, D Cunningham, T Price, M E Hill, P J Ross, N Tebbutt, A R Norman, J Oates and P Shellit

Students as ecologists: Strategies for successful mentorship of undergraduate researchers

Guiding undergraduates through the ecological research process can be incredibly rewarding and present opportunities to break down barriers to inclusion and diversity in scientific disciplines. At the same time, mentoring undergraduate researchers is a complicated process that requires time and flexibility. While many academics receive extensive guidance on how to be successful in research endeavors, we pay much less attention to training in mentorship and working collaboratively with undergraduate students. This paper seeks to provide a framework for successfully collaborating with undergraduates including initial recruitment, development of a contract, fostering student ownership of research projects, and submission of a polished manuscript.While institutions worldwide encourage undergraduate research and publication, little training and professional development are provided to potential mentors. Our paper fills a critical gap in knowledge and provides a framework for academic mentors of all career stages to successfully guide students from question to publication.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149365/1/ece35090_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149365/2/ece35090.pd

Mu2e Technical Design Report

The Mu2e experiment at Fermilab will search for charged lepton flavor violation via the coherent conversion process mu- N --> e- N with a sensitivity approximately four orders of magnitude better than the current world's best limits for this process. The experiment's sensitivity offers discovery potential over a wide array of new physics models and probes mass scales well beyond the reach of the LHC. We describe herein the preliminary design of the proposed Mu2e experiment. This document was created in partial fulfillment of the requirements necessary to obtain DOE CD-2 approval.Comment: compressed file, 888 pages, 621 figures, 126 tables; full resolution available at http://mu2e.fnal.gov; corrected typo in background summary, Table 3.

Controls on surface soil drying rates observed by SMAP and simulated by the Noah land surface model

Drydown periods that follow precipitation events provide an opportunity to assess controls on soil evaporation on a continental scale. We use SMAP (Soil Moisture Active Passive) observations and Noah simulations from drydown periods to quantify the role of soil moisture, potential evaporation, vegetation cover, and soil texture on soil drying rates. Rates are determined using finite differences over intervals of 1 to 3 days. In the Noah model, the drying rates are a good approximation of direct soil evaporation rates, and our work suggests that SMAP-observed drying is also predominantly affected by direct soil evaporation. Data cover the domain of the North American Land Data Assimilation System Phase 2 and span the first 1.8 years of SMAP's operation. Drying of surface soil moisture observed by SMAP is faster than that simulated by Noah. SMAP drying is fastest when surface soil moisture levels are high, potential evaporation is high, and when vegetation cover is low. Soil texture plays a minor role in SMAP drying rates. Noah simulations show similar responses to soil moisture and potential evaporation, but vegetation has a minimal effect and soil texture has a much larger effect compared to SMAP. When drying rates are normalized by potential evaporation, SMAP observations and Noah simulations both show that increases in vegetation cover lead to decreases in evaporative efficiency from the surface soil. However, the magnitude of this effect simulated by Noah is much weaker than that determined from SMAP observations

Controls on surface soil drying rates observed by SMAP and simulated by the Noah land surface model

Drydown periods that follow precipitation events provide an opportunity to assess controls on soil evaporation on a continental scale. We use SMAP (Soil Moisture Active Passive) observations and Noah simulations from drydown periods to quantify the role of soil moisture, potential evaporation, vegetation cover, and soil texture on soil drying rates. Rates are determined using finite differences over intervals of 1 to 3 days. In the Noah model, the drying rates are a good approximation of direct soil evaporation rates, and our work suggests that SMAP-observed drying is also predominantly affected by direct soil evaporation. Data cover the domain of the North American Land Data Assimilation System Phase 2 and span the first 1.8 years of SMAP's operation. Drying of surface soil moisture observed by SMAP is faster than that simulated by Noah. SMAP drying is fastest when surface soil moisture levels are high, potential evaporation is high, and when vegetation cover is low. Soil texture plays a minor role in SMAP drying rates. Noah simulations show similar responses to soil moisture and potential evaporation, but vegetation has a minimal effect and soil texture has a much larger effect compared to SMAP. When drying rates are normalized by potential evaporation, SMAP observations and Noah simulations both show that increases in vegetation cover lead to decreases in evaporative efficiency from the surface soil. However, the magnitude of this effect simulated by Noah is much weaker than that determined from SMAP observations