Edward J. Kim

Quantifying Uncertainty in Modeling Snow Microwave Radiance for a Mountain Snowpack at the Point-Scale, Including Stratigraphic Effects

Merging microwave radiances and modeled estimates of snowpack states in a data assimilation scheme is a potential method for snowpack characterization. A radiance assimilation scheme for snow requires a land surface model (LSM) coupled to a radiative transfer model (RTM). In this paper, we explore the degree of model fidelity required in order for radiance assimilation to yield benefits for snowpack characterization. Specifically, we characterize the uncertainty of Microwave Emission Model for Layered Snowpacks (MEMLS) radiance predictions by quantifying model accuracy and sensitivity to the following: (1) the LSM snowpack layering scheme and (2) the properties of the snow layers, including melt-refreeze ice layers. MEMLS was consistent with the measured brightness temperatures at 18.7 and 36.5 GHz with a bias (mean absolute error) of 0.1 K (3.1 K) for the vertical polarization and 3.4 K (9.3 K) for the horizontal polarization. An error in the predictions at horizontal polarization is due to uncertainty in ice-layer properties. It was found that in order for predicted brightness temperatures from the coupled LSM and RTM to be adequate for radiance assimilation purposes, the following must be satisfied: (1) the LSM snowpack layering scheme must accurately represent the stratigraphic snowpack layers; (2) dynamics of melt-refreeze ice layers must be modeled explicitly, and the predicted density of melt-refreeze layers must be accurate within ; and (3) the MEMLS correlation length must be predicted within 0.016 mm, or effective optical grain diameter must be predicted within 0.045 mm. Recommendations for future field measurements are made.

A Multi-Institutional Phase 2 Study of Neoadjuvant Gemcitabine and Oxaliplatin With Radiation Therapy in Patients With Pancreatic Cancer

The purpose of this study was to evaluate preoperative treatment with full‐dose gemcitabine, oxaliplatin, and radiation therapy (RT) in patients with localized pancreatic cancer.

A blended global snow product using visible, passive microwave and scatterometer satellite data

A joint US Air Force/National Aeronautics and Space Administration (NASA) blended global snow product that uses Earth Observation System Moderate Resolution Imaging Spectroradiometer (MODIS), Advanced Microwave Scanning Radiometer for the Earth Observing System (AMSR-E) and Quick Scatterometer (QuikSCAT or QSCAT) data has been developed. Existing snow products derived from these sensors have been blended into a single, global, daily, user-friendly product by using a newly developed Air Force Weather Agency (AFWA)/NASA Snow Algorithm (ANSA). This initial blended snow product uses minimal modelling to expeditiously yield improved snow products, which include, or will include, snow-cover extent, fractional snow cover, snow water equivalent (SWE), onset of snowmelt and identification of actively melting snow cover. The blended snow products are currently 25-km resolution. These products are validated with data from the lower Great Lakes region of the USA, from Colorado obtained during the Cold Land Processes Experiment (CLPX), and from Finland. The AMSR-E product is especially useful in detecting snow through clouds; however, passive microwave data miss snow in those regions where the snow cover is thin, along the margins of the continental snowline, and on the lee side of the Rocky Mountains, for instance. In these regions, the MODIS product can map shallow snow cover under cloud-free conditions. The confidence for mapping snow-cover extent is greater with the MODIS product than with the microwave product when cloud-free MODIS observations are available. Therefore, the MODIS product is used as the default for detecting snow cover. The passive microwave product is used as the default only in those areas where MODIS data are not applicable due to the presence of clouds and darkness. The AMSR-E snow product is used in association with the difference between ascending and descending satellite passes or diurnal-amplitude variations (DAV) to detect the onset of melt, and a QSCAT product will be used to map areas of snow that are actively melting.

Intercomparison of Electromagnetic Models for Passive Microwave Remote Sensing of Snow

Electromagnetic models can be used for understanding the interaction between electromagnetic waves and matter, interpreting experimental data, and retrieving geophysical parameters. Comparing the results of different snow models, when driven with the same set of input parameters, can benefit remote sensing of snow. Microwave brightness temperatures of snow at 19 and 37 GHz for six different classes of snow (prairie, tundra, taiga, alpine, maritime, and ephemeral) are simulated by means of four different electromagnetic models: the Helsinki University of Technology snow emission model, the microwave emission model of layered snowpacks, a dense-medium radiative-transfer theory model, and a strong fluctuation theory model. The frequency behavior of the extinction coefficients obtained with the different models between 5 and 90 GHz is also studied. The four models are also driven with inputs derived from snow-pit data, and the outputs are compared with ground-based measurements of brightness temperatures at 18.7 and 36.5 GHz. Significant differences among the brightness temperatures and the extinction coefficients simulated with the four models in the cases of the six classes of snow are observed. Moreover, no particular model is found to be able to systematically reproduce all of the experimental data. The results highlight the need to more closely examine the relationships relating mean grain size and correlation length, introduce multiple layers in each model, and to perform controlled laboratory measurements on materials with well-known electromagnetic properties in order to improve the understanding of the causes of the observed differences and to improve model performance

Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma

Purpose: The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449–mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma. Experimental Design: Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity. Results: On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade ≥3 adverse events were noted in 56% of patients. Conclusion: We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer. Clin Cancer Res; 20(23); 5937–45. ©2014 AACR.

ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.

Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.

The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer.

Background Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized. Methods Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth. Results Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population. Conclusion The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.

Anti-DLL4 Has Broad Spectrum Activity in Pancreatic Cancer Dependent on Targeting DLL4-Notch Signaling in Both Tumor and Vasculature Cells

Purpose: We previously showed that targeting Delta-like ligand 4 (DLL4) in colon and breast tumors inhibited tumor growth and reduced tumor initiating cell frequency. In this report, we have extended these studies to pancreatic cancer and probed the mechanism of action in tumor and stromal cells involved in antitumor efficacy. Experimental Design: Patient-derived pancreatic xenograft tumor models were used to evaluate the antitumor effect of anti-DLL4. To investigate the mechanism of action, we compared the activity of targeting DLL4 in tumor cells with an anti-human DLL4 antibody (anti-hDLL4) and in the host stroma/vasculature with an anti-mouse DLL4 antibody (anti-mDLL4). The effect of these antibodies on cancer stem cell frequency was examined by in vivo limiting dilution assays. Results: The combination of anti-hDLL4 and anti-mDLL4 was efficacious in a broad spectrum of pancreatic tumor xenografts and showed additive antitumor activity together with gemcitabine. Treatment with either anti-hDLL4 or anti-mDLL4 delayed pancreatic tumor recurrence following termination of gemcitabine treatment, and the two together produced an additive effect. Anti-hDLL4 had a pronounced effect in reducing the tumorigenicity of pancreatic cancer cells based on serial transplantation and tumorsphere assays. In contrast, disruption of tumor angiogenesis with anti-mDLL4 alone or with anti-VEGF had minimal effects on tumorigenicity. Gene expression analyses indicated that anti-DLL4 treatment regulated genes that participate in Notch signaling, pancreatic differentiation, and epithelial-to-mesenchymal transition. Conclusions: Our findings suggest a novel therapeutic approach for pancreatic cancer treatment through antagonism of DLL4/Notch signaling. Clin Cancer Res; 18(19); 5374–86. ©2012 AACR.

Measurement of Low Amounts of Precipitable Water Vapor Using Ground-Based Millimeterwave Radiometry

Abstract Extremely dry conditions characterized by amounts of precipitable water vapor (PWV) as low as 1–2 mm commonly occur in high-latitude regions during the winter months. While such dry atmospheres carry only a few percent of the latent heat energy compared to tropical atmospheres, the effects of low vapor amounts on the polar radiation budget—both directly through modulation of longwave radiation and indirectly through the formation of clouds—are considerable. Accurate measurements of PWV during such dry conditions are needed to improve polar radiation models for use in understanding and predicting change in the climatically sensitive polar regions. To this end, the strong water-vapor absorption line at 183.310 GHz provides a unique means of measuring low amounts of PWV. Weighting function analysis, forward model calculations based upon a 7-yr radiosonde dataset, and retrieval simulations consistently predict that radiometric measurements made using several millimeter-wavelength (MMW) channels near ...

Advances in pancreatic cancer.

Purpose of reviewThis review intends to describe recent studies on the interaction between pancreatic cancer cells and tumor stroma, and potential opportunities and limitations to therapeutically targeting the stroma. Recent findingsPancreatic cancer is characterized by densely desmoplastic stroma. It is becoming increasingly clear that there are complex and mutually supportive interactions between cancer cells and the stroma. Specific signaling pathways exist between cancer cells and cancer-associated fibroblasts that contribute to hypoxic desmoplasia. Recent developments in therapeutic approaches to targeting the stroma have demonstrated potential for enhancing efficacy of cytotoxic therapies. However, the heterogeneity and genomic complexity between tumors has also become more evident based on recent findings. There is increasing evidence for hierarchy of cancer cells with identification of a subpopulation of cancer stem cells that are inherently resistant to traditional therapies. SummaryTargeting pancreatic cancer stroma is a novel therapeutic strategy that appears justified based on recent studies; however, continued focus is needed to develop more effective therapies against cells resistant to standard chemotherapy.