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Background MCC is an aggressive cutaneous malignancy. Though checkpoint inhibitor therapy has dramatically improved the treatment landscape, outcome remains poor for those that are refractory to anti-PD1/PDL1 therapy. Combination checkpoint inhibition and the use of radiation therapy have been proposed as potentially synergistic interventions to improve immunotherapy (IT) response rates (RR). Methods In this multi-institutional trial, we enrolled patients (pts) with metastatic or recurrent MCC, ECOG PS 0-1, with at least 2 distinct metastatic lesions. Prior chemotherapy or immunotherapy was permitted. Primary endpoint was objective RR. In a randomized design of 2 experimental arms, pts received NIVO 240mg IV q2 wks plus IPI 1mg/kg IV q6 wks (arm A), or the same combination plus SBRT to 24Gy in 3 fractions between cycles 1 and 2 (arm B). Each arm uses a Simon Mini-Max two-stage design for futility, with total accrual of 50 assuming full accrual. Results To date, 16 pts have been enrolled, including 4 treatment-naive and 12 PD1/PDL1-refractory pts. 11 pts were male and 5 pts female. Median age at enrollment was 75.5. On Arm A, the RR was 80% (1 CR, 3 PR) in 4/5 evaluable pts. On Arm B, the RR was 17% (1 PR) among 6 evaluable pts. 4 pts are pending initial staging and 1 pt expired prior to first evaluation. Collectively, 2/8 (25%) PD1/PDL1refractory pts and 3/3 (100%) IT-naive pts have achieved CR/PR. 7 pts experienced > G2 immune toxicity (1 G3 myocarditis, 1 G3 colitis, 1 G2 arthritis, 1 G2 cough, 3 G2 dermatitis, 1 G2 neurotoxicity, 1 G2 blurred vision, 1 G2 abdominal pain, 2 G2 hypothyroidism, 1 G2 renal insufficiency). 1 pt was taken off the trial due to toxicity. Conclusions NIVO + IPI is safe and demonstrates promising initial efficacy in advanced MCC in both PD1/PDL1-naive and refractory cases. SBRT can be safely added to this and its contribution to efficacy is being explored pending futility analysis. Arm A of the trial has already met efficacy criteria to proceed to full accrual. Clinical trial identification NCT03071406. Legal entity responsible for the study H. Lee. Moffitt Cancer Center & Research Institute. Funding Bristol-Myers Squibb. Disclosure S. Kim: Research grant / Funding (institution), IIT funded through BMS rare malignancy program: BMS. N.I. Khushalani: Advisory / Consultancy: BMS. L. Harrison: Research grant / Funding (self): Viewray. All other authors have declared no conflicts of interest.

Background Opioid receptors are implicated in cancer progression and long-term patient outcomes. However, the prognostic significance, underlying mechanisms, and therapeutic value of mu-opioid receptor (MOP) in hepatocellular carcinoma (HCC) remain unclear. Methods MOP expression in human biopsy HCC samples was evaluated using RNA microarrays, quantitative real-time polymerase chain reaction (qRT-PCR), and immunochemical analyses. Molecular and cellular techniques, including siRNA-mediated depletion and lentiviral vector-mediated overexpression, were used to elucidate the functions and mechanisms of MOP. The effect of the MOP agonist morphine in HCC was evaluated both in vitro and in vivo. The therapeutic value of MOP inhibitors in HCC progression and metastasis was investigated with in vitro experiments and subcutaneous and orthotopic HCC mouse models in vivo. Results Through microarray analysis and qRT-PCR, we identified that MOP is highly expressed in human HCC tumours. High MOP expression in HCC tumours was confirmed by immunocytochemistry and correlated with aggressive clinicopathological features and a worse prognosis. Depletion of MOP suppressed cell proliferation, migration, and invasion, whereas overexpression of MOP promoted cell growth and metastasis in human HCC cell lines. Both clinical and biological evidence revealed that MOP-mediated epithelial-mesenchymal transition promotes HCC metastasis and poor prognosis. Morphine promotes cell proliferation, migration, and invasion in vitro and in vivo in mouse models. More importantly, MOP inhibitors suppressed cell growth, invasion, and metastasis in vitro and in the subcutaneous and orthotopic xenograft models. Conclusions MOP plays a key oncogenic function in hepatocarcinogenesis. Its overexpression is associated with poor prognosis in patients with HCC. Furthermore, MOP inhibitors may be a promising strategy for HCC therapy.

Researchers analyzed and presented volume data from the Visible Human Project (VHP) and data from high-resolution 3D ion-abrasion scanning electron microscopy (IA-SEM). They acquired the VHP data using cryosectioning, a destructive approach to 3D human anatomical imaging resulting in whole-body images with a field of view approaching 2 meters and a minimum resolvable feature size of 300 microns. IA-SEM is a type of block-face imaging microscopy, a destructive approach to microscopic 3D imaging of cells. The field of view of IA-SEM data is on the order of 10 microns (whole cell) with a minimum resolvable feature size of 15 nanometers (single-slice thickness). Despite the difference in subject and scale, the analysis and modeling methods were remarkably similar. They are derived from image processing, computer vision, and computer graphics techniques. Moreover, together we are employing medical illustration, visualization, and rapid prototyping to inform and inspire biomedical science. By combining graphics and biology, we are imaging across nine orders of magnitude of space to better promote public health through research.

Objective. The phosphorylation status of the BCL2 Antagonist of Cell Death (BAD) protein influences cell survival and apoptosis. BAD phosphorylation is determined by the relative activity of a series of kinases and phosphatases within the BAD pathway. We therefore sought to evaluate the influence that expression of the BAD apoptosis pathway has on breast cancer progression and on clinical outcome in a series of breast cancer patients. Methods. We used Principal components analysis to derive a BAD-pathway gene expression signature with a corresponding “pathway score” representing overall gene expression levels for BAD pathway genes. The BAD-pathway signature score was evaluated in clinical-genomic breast cancer datasets obtained from a total of 502 patients, including intra-ductal hyperplasia (n=8), ductal carcinoma in-situ (n=30), and three separate data sets of invasive ductal carcinoma patient samples (n=23, n=286, n=155). The influence of the BAD-pathway signature score on breast cancer progression and relapse-free survival was evaluated by student's t-test and Kaplan Meier/log-rank test, respectively. Results. We developed a 48-gene BAD-pathway signature, the expression score of which decreased with progression from intra-ductal hyperplasia through ductal carcinoma in-situ and invasive ductal carcinoma (p=0.0004). Furthermore, BAD-pathway signature score was associated with relapse free survival from breast cancer in two independent clinical-genomic datasets (n=286, p=0.01; n=155, p=0.02). Conclusions.BAD pathway gene expression is associated with breast cancer progression and disease-free survival. The pathway represents an appealing human cancer prognostic biomarker and therapeutic target. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-08-01.

The acceleration guidance concept is to plan an aerodynamic acceleration proe le that integrates to the desired e nal position and velocity and satise es all vehicleconstraints and to track theacceleration proe le. The longitudinal entryguidanceforthespaceshuttleisaccelerationguidance;adragdecelerationproe lethatintegratestothedesired downrange and satise es the vehicle constraints is planned and tracked primarily by bank-angle adjustments. The kinematics relating the drag proe le to the downrange assume that the entry trajectory is a great circle arc. In this paper we consider lateral as well as longitudinal motion in acceleration planning. Three differential equations that are the kinematic relations between the aerodynamic accelerations and the position and velocity variables with energy as the independent variable are used as the basis for two methods of planning the drag and lateral acceleration proe les. The e rst is simpler and produces a feasible trajectory for a given angle-of-attack proe le. The second requires more computation, but produces an optimal trajectory using both angle-of-attack and angleof-bank variations to control the entry trajectory and has greater capability to shape the entry trajectory. Both methods are demonstrated using an X-33 vehicle model. The optimal method is capable of achieving a specie ed e nal heading angle and adjusting the number of bank reversals.

Kinetic studies were performed over silica-alumina and acidic zeolites to determine the effects of temperature (from 600 to 700 K) and reactant pressures (

Microcalorimetry was used to determine the differential enthalpy changes of adsorption versus coverage on HZSM-5 and Hmordenite of reactants and products of methylamine synthesis. The enthalpy changes of adsorption of dimethylether, ammonia, monomethylamine, and dimethylamine on Bronsted acid sites vary linearly from −90 to −250 kJ/mol with the gaseous proton affinities of these basic molecules. The enthalpy changes of adsorption of water and methanol vary from −60 to −90 kJ/mol. In situ infrared spectroscopy indicates that methoxyl species are present on the catalyst in flowing methanol at temperatures near 600 K; however, adsorbed ammonia and methylamines are associated with the Bronsted acid sites in gas mixtures of methanol and ammonia typically used for methylamine synthesis at these temperatures. These results suggest that dimethylether formation from methanol may occur through surface methoxyl species, while methylamine synthesis most likely involves adsorbed ammonium cations.

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Microcalorimetric measurements and temperature-programmed desorption (TPD) experiments were conducted to study the acidic properties of H-mordenite and H-ZSM-5. Both zeolites possess a relatively homogeneous acid-strength distribution. The enthalpy changes of adsorption for ammonia on H-mordenite and H-ZSM-5 are −157 and −150 kJ mol−1, respectively. Analyses of the TPD spectra, constrained by the microcalorimetric results, indicate that the standard entropy changes of ammonia adsorption on H-mordenite and H-ZSM-5 are −159 and −171 J mol−1 K−1, respectively. Accordingly, ammonia retains a significant fraction of its local entropy on H-mordenite (i.e., rotation and vibration ), while ammonia adsorbed on H-ZSM-5 loses approximately a third of its local entropy. Pyridine desorption from these zeolites is limited by molecular diffusion in the zeolite particles and for this reason is a poor choice as a probe molecule for assessment of acid-site strength by TPD.

The combination of thermogravimetry, microcalorimetry and infrared spectroscopy studies of pyridine adsorption has been used to characterize the acidity of a ZSM-5 catalyst. The majority of the acid sites are Bronsted acid centers associated with framework Al species, with heats of pyridine adsorption equal to 140 kJ/mol. Non-framework Al species in the zeolite sample of this study eliminate an approximately equal number of Bronsted acid sites. These nonframework Al species also produce strong Lewis acid sites with pyridine adsorption heats greater than 140 kJ/mol, as well as weak adsorption sites (e.g., weak Bransted acid sites or hydrogen bonding sites) with heats equal to 90–140 kJ/mol.

The acidic properties of a USY-based fluid catalytic cracking catalyst steamed at various severities and amorphous silica-alumina were investigated by microcalorimetry and infrared spectroscopy using pyridine adsorption at 473 K. Microcalorimetric measurements of the differential heat of pyridine adsorption versus adsorbate coverage revealed a heterogeneous acid site distribution for the catalysts. Besides showing the expected progressive decrease in the number of acid sites for pyridine adsorption, our measurements showed that the strength of Bronsted acid sites decreased with increasing severity of steam treatment. Infrared spectra of adsorbed pyridine revealed a significant decrease in the ratio of Bronsted to Lewis acid sites upon steaming. Amorphous silica-alumina had a relatively large number of acid sites of which a large proportion were Bronsted acid sites. However, the strength of these Bronsted sites was lower than that of the mildly steamed USY catalysts. This lower Bronsted acid strength, we believe, is related to lower activity for gas-oil cracking over silica-alumina.

Solid-state deuterium NMR has been used to detect Bronsted acid sites and non-acidic silanols in D-exchanged zeolites. The quadrupolar coupling constant for Bronsted sites in DY zeolite is 234±2 kHz, and the sites are axially symmetric. This reduction by 1 4 from the water OD coupling constant is indicative of the acidic character of the OD bond. The acid deuterons are immobile at room temperature on a millisecond timescale. Effects of reversible adsorption of ammonia are readily monitored through changes in peaks corresponding to OD and O − NH 3 D + species.

The acidity characteristics of H-ZSM-5, H-Mordenite and H-Y zeolite have been studied by microcalorimetric and gravimetric measurements of pyridine adsorption. H-ZSM-5 and H-Mordenite have Bronsted acid sites of primarily homogenous strength, with H-Mordenite having the stronger sites, whereas H-Y zeolite had Bronsted sites of varying strength. The effects of Na exchange level in H-Y zeolite and high temperature calcination for H-Mordenite have also been examined.

CEACAM1 is a cell-cell adhesion molecule that mediates homophilic cell adhesion. In addition, CEACAM1 was also shown to suppress the growth of prostate, breast, and colon tumors. Structural and functional analyses showed that the adhesion activity of CEACAM1 is mediated by its extracellular domain while its cytoplasmic domain is necessary and sufficient for growth-inhibitory activity. The signal pathways leading to CEACAM1-mediated growth suppression are not known. We studied the importance of phosphorylation of serine 503 in this growth-inhibitory signaling pathway. Full-length CEACAM1 was found to be phosphorylated in vivo in both tyrosine and serine residues. Mutation of tyrosine 488 to phenylalanine did not abolish the tumor-suppressive activity of CEACAM1, suggesting that phosphorylation at tyrosine 488 is not critical for CEACAM1's tumor-suppressive activity. Although expression of CEACAM1's cytoplasmic domain inhibited the growth of DU145 prostate cancer cells in vivo, mutation of serine 503 to alanine abolished the growth-inhibitory activity. In addition, the change of serine 503 to aspartic acid produced tumor-suppressive activity similar to that of the wild-type CEACAM1. These results suggested that phosphorylation at serine 503 is essential for CEACAM1's growth-inhibitory function in vivo.

Drug absorption in the human body depends on the dissolution rate of the drug. Suitable dissolution characteristics are important to ensure that the drug will achieve the desired therapeutic effects. To assess the similarity of dissolution rates of several drug lots, we apply a general growth curve model with different covariance structures. The Box-Cox power transformation and the naive log transformation are applied to a function of the dissolution rate. The predictive sample-reuse, or cross-validation, method is employed in selecting an appropriate model with best predictive accuracy. A testing procedure for examining the similarity among the drug lots is also conducted. A partially Bayesian approach is used for the assessment of dissolution equivalence.

The reversible monoamine oxidase-A (MAO-A) inhibitors were developed by researchers in response to safety concerns about the old irreversible MAO inhibitors. Scientists devised this new class of MAO-A inhibitors with the hope that selectivity for the MAO-A receptor and reversibility of the inhibition would result in efficacy in depression with improved safety. Moclobemide is the first reversible MAO-A inhibitor to be widely marketed and is currently approved for marketing in approximately 50 countries. In determining the safety profile of a drug, the following strategy is generally employed by a manufacturer: (a) comparison of the drug to placebo in clinical trials to identify the more commonly occurring adverse reactions; (b) comparison of the drug to other known drugs in clinical trials to determine relative frequencies of adverse reactions; (c) examination of reports from practitioners, the so-called spontaneously reported adverse event reports to confirm that what is seen under the experimental conditions of clinical trials is also seen in "real life" and to generate hypotheses about rare adverse reactions to the drug; (d) identification of further adverse reactions from overdose reports; and (e) the conduct of postmarketing studies to further determine drug-drug interactions. Such a strategy was employed by the manufacturer for moclobemide, and this article reviews the results of data accumulated concerning moclobemide safety.

The reversible monoamine oxidase-A (MAO-A) inhibitors were developed by researchers in response to safety concerns about the old irreversible MAO inhibitors. Scientists devised this new class of MAO-A inhibitors with the hope that selectivity for the MAO-A receptor and reversibility of the inhibition would result in efficacy in depression with improved safety. Moclobemide is the first reversible MAO-A inhibitor to be widely marketed and is currently approved for marketing in approximately 50 countries. In determining the safety profile of a drug, the following strategy is generally employed by a manufacturer: (a) comparison of the drug to placebo in clinical trials to identify the more commonly occurring adverse reactions; (b) comparison of the drug to other known drugs in clinical trials to determine relative frequencies of adverse reactions; (c) examination of reports from practitioners, the so-called spontaneously reported adverse event reports to confirm that what is seen under the experimental conditions of clinical trials is also seen in "real life" and to generate hypotheses about rare adverse reactions to the drug; (d) identification of further adverse reactions from overdose reports; and (e) the conduct of postmarketing studies to further determine drug-drug interactions. Such a strategy was employed by the manufacturer for moclobemide, and this article reviews the results of data accumulated concerning moclobemide safety.

Radar imagery of shallow coastal waters (usually

This report surveys the oceanic subsurface dynamic processes which have signatures on the ocean surface. These surface effects can appear in the form of changes in both surface current distributions and local wave structures (or profiles). Based upon their physical scales, these effects are classified into phenomena produced by mechanisms associated with weak and strong interactions. Two types of phenomena are distinct among surface wave weak interactions: (1) broad band phenomena--includes wave-wave energy transfer and general wave train instability; and (2) narrow band phenomena--includes Benjamin-Feir instability, recurrence, and envelope solitons. All these phenomena share the following physical characteristics: (1) they may be manifested only by the long dominant waves in a wave field and yet the behavior of short waves is determined by the strong interactions with the long waves rather than by these processes; and (2) they are evolutionary phenomena with a time scale of 1/(ak) sq times the wave period where a is the wave amplitude and k is the wave number of the dominant wave. The strong interactions are those phenomena whose time scale is of the order of the wave period and space scale is of the order of the wavelength. Detailed wave structures (or profiles) are the prime sources of information. Strong interactions include the strong Longuet- Higgins instability, wave-current interactions, long wave-short wave interactions, and the processes of parasitic capillary formation and microscale breaking induced by surface and drift.

Numerical models, utilizing field data taken during the Naval Research Laboratory (NRL) Phelps Bank Experiment of July 1982, are used for the evaluation of two-dimensional oceanic current velocity field, swell characteristics, modulation of Bragg resonant wavelet spectral wave energy density, and microwave radar cross-section over Phelps Bank for the simulation of radar imagery (SAR/SLAR) intensity. The objective of this work is to delineate the physical processes responsible for patterns in radar imagery (SAR/SLAR) that correlate with complex bottom topography. The analyses are still in progress and the general methodology being pursued is given here.

Coordinated microwave and in situ measurements were performed during the 1982 Naval Research Laboratory Phelps Bank experiment (Nantucket Shoals). The measurements including airborne X band APD-10 synthetic aperture radar imagery and airborne X and shipboard L band coherent radars together with extensive hydrographic, oceanographic, and meteorological information are reported. The microwave measurements show large variations of backscatter power (over 20 dB at both L and X band) for winds less than 7 m/s. Generally, regions of strong backscatter cluster near large bottom slopes, suggesting their generation by the bottom topography. However, for winds greater than 7 m/s (7–12 m/s in this experiment) the variations of microwave backscatter power decrease to 2–3 dB for both frequency bands and become decorrelated from the bottom topography. An explanation for this may be that wind drift near the surface layer tends to mask the ocean surface features relating to the bottom topography when its magnitude is comparable to the rotary tide and the residual circulation due to tidal stress. A current gradient (front) seemingly not related to bottom topography also produced 20-dB variations in the power backscattered to the L band radar.

Seasat synthetic aperture radar (SAR) images of the ocean contain a wealth of ocean features ranging in size from 100 km mesoscale eddies to internal waves and dekameter surface waves [Beal et al, 1981]. In particular SAR and SLAR (side-looking airborne, or real-aperture, radar) images of shallow water (usually less than 40 m deep) near coastal areas (e.g., Nantucket Shoals, English Channel, German Bight, etc.) contain features that relate almost one to one with the bottom topography (see cover figure as an example). Also evident in the cover figure are tide-induced internal waves (top and middle right in the image), a number of current rips, a current shear front near the bottom edge of the image, and the dark region covering a great part of the middle portion indicating small microwave backscatter power, the result of very stable atmospheric conditions owing to cold upwelling water underneath warm air.