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Algorithms for discrete optimization of proteins play a central role in recent advances in protein structure prediction and design. We wish to improve the resources available for computational biologists to rapidly prototype such algorithms and to easily scale these algorithms to many processors. To that end, we describe the implementation and use of two new open source resources, citing potential benefits over existing software. We discuss CHOMP, a new object-oriented library for macromolecular optimization, and SHARPEN, a framework for scaling CHOMP scripts to many computers. These tools allow users to develop new algorithms for a variety of applications including protein repacking, protein-protein docking, loop rebuilding, or homology model remediation. Particular care was taken to allow modular energy function design; protein conformations may currently be scored using either the OPLSaa molecular mechanical energy function or an all-atom semiempirical energy function employed by Rosetta.

Indium nitride (InN) is a promising yet technologically challenging material with a high defect density and unusual material properties. Its high electron mobility may be utilized in high power electronic devices, and its high absorbance and low energy optical response make it a promising candidate for multi-junction, high-efficient solar cell technology. Studies of absorption and photoluminescence optical response of epitaxial InN resulted in a large correction of the fundamental bandgap from the originally proposed 1.9 eV to now below 0.7 eV. Yet, it is still debated if the commonly measured optical transitions below the original high bandgap values are actually caused by a large concentration of defects, on the order of 1020/cm3, rather than reflecting a low fundamental bandgap. Many applications of this material, e.g. in high-efficient solar cell technology, are primarily dependent on the successful production of a contacted p-n junction, which has not yet been achieved. This contribution addresses the controversy in the bandgap discussion of InN. Valence electron energy loss spectroscopy (VEELS) of InN allows spatially resolved analysis of the density of states in the transmission electron microscope (TEM). Standard optical characterization is compared with results from TEM characterization.

We evaluated the performance of multiparametric prostate magnetic resonance imaging (mp-MRI) and MRI/transrectal ultrasound (TRUS) fusion-guided biopsy (FB) for monitoring patients with prostate cancer on active surveillance (AS).Patients undergoing mp-MRI and FB of target lesions identified on mp-MRI between August 2007 and August 2014 were reviewed. Patients meeting AS criteria (Clinical stage T1c, Gleason grade ≤ 6, prostate-specific antigen density ≤ 0.15, tumor involving ≤ 2 cores, and ≤ 50% involvement of any single core) based on extended sextant 12-core TRUS biopsy (systematic biopsy [SB]) were included. They were followed with subsequent 12-core biopsy as well as mp-MRI and MRI/TRUS fusion biopsy at follow-up visits until Gleason score progression (Gleason ≥ 7 in either 12-core or MRI/TRUS fusion biopsy). We evaluated whether progression seen on mp-MRI (defined as an increase in suspicion level, largest lesion diameter, or number of lesions) was predictive of Gleason score progression.Of 152 patients meeting AS criteria on initial SB (mean age of 61.4 years and mean prostate-specific antigen level of 5.26 ng/ml), 34 (22.4%) had Gleason score ≥ 7 on confirmatory SB/FB. Of the 118 remaining patients, 58 chose AS and had at least 1 subsequent mp-MRI with SB/FB (median follow-up = 16.1 months). Gleason progression was subsequently documented in 17 (29%) of these men, in all cases to Gleason 3+4. The positive predictive value and negative predictive value of mp-MRI for Gleason progression was 53% (95% CI: 28%-77%) and 80% (95% CI: 65%-91%), respectively. The sensitivity and specificity of mp-MRI for increase in Gleason were also 53% and 80%, respectively. The number needed to biopsy to detect 1 Gleason progression was 8.74 for SB vs. 2.9 for FB.Stable findings on mp-MRI are associated with Gleason score stability. mp-MRI appears promising as a useful aid for reducing the number of biopsies in the management of patients on AS. A prospective evaluation of mp-MRI as a screen to reduce biopsies in the follow-up of men on AS appears warranted.

Dr. Little and his colleagues report successful results for lung tumor microwave ablation. [1] One underappreciated technical pitfall which can be seen with microwave ablation in the lung is needle slippage and stabilization. This may become more relevant with the emergence of microwave and cryoablation needles which often have heavy hubs, hardware and cords exerting forces on the needle, which can change the depth or angle of insertion of the needle when not stabilized by the operator’s hand. This may pull the needle off-angle or deeper than desired, and may be more common in compliant lung tissue. In one patient, while performing microwave ablation of a lung cancer, the microwave needle advanced 2cm further towards the heart, due to the weight of the device and gravity towards the table (Figure 1). A similar phenomenon can also be seen with steep cranio-caudal access for ablations in the liver dome during respiration, with the liver moving along the needle insertion axis (ie- subcostal skin to liver dome). A common simple technique for needle stabilization is propping the needle's handle in position by rolling sterile towels around its hub, however the needle is not absolutely fixed in place. The “stick” feature in cryoablation may also mitigate this pitfall and prevent migration. Figure 1 Cone beam CT before (A) and after (B) needle slippage. Planned needle path and planned treatment volume (C) in navigation and ablation planner software (Allura Xper FD20, Phillips Healthcare, Best, Netherlands) Disposable needle guidance and stabilization devices, such as the SeeStar® (AprioMed, Uppsala, Sweden) [2,3] and the SimpliFY™ (NeoRad, Oslo, Norway), may help address this challenge. These sterile devices are placed on the skin, and the needle is placed into the clamp of the device allowing fixation of the microwave needle in the insertion angle. (Figure 2) Figure 2 SimpliFY™ (A) stabilizing an radio-frequency ablation needle (Covidien, Boulder, CO, USA) and SeeStar® (B) stabilizing a cryo-ablation needle (Endocare , HealthTronics Inc, Austin, TX, USA) Note bending of needle shaft caused by tension ... However, not all guiding devices secure the depth of insertion. The SimpliFY™ has a mobile needle gripper with an adjustable screw/clamp that can subsequently be used to hold the needle in place at the pre-determined depth. (Figure 2a) In contrast, note the similar SeeStar® allows for simultaneous alignment of the needle along both angular axes (Figure 2b), but does not have a mechanism to secure the depth of the needle insertion. Physicians performing percutaneous interventions should be aware of the possibility of needle slippage and theoretical risks posed to surrounding tissue and organs, as well as potential solutions.

The Missile Defense Agency (MDA) tasked IDA to study and assess management methods and organizational structures that have proved successful in the development of technologies with an emphasis on the roles of longer-term science and technology (S&T) work and radical innovation in support of ongoing systems development To do so this report reviews and analyzes the experiences of several (1) public organizations that undertook large-scale systems developments and (2) large private companies that have been consistently technically innovative This provides the groundwork for consideration of specific management and organizational options for MDA.

63 Background: Active surveillance (AS) is an option for patients with low risk prostate cancer (PCa); however, determining disease progression is challenging. At the NCI, multiparametric MRI (MP-MRI) with our biopsy protocol (MR-US fusion-guided plus 12 core extended sextant biopsy) has been used to confirm eligibility for AS. We evaluated the utility of these modalities in monitoring patients on AS. Methods: Patients who underwent MP-MRI of the prostate with biopsy per our protocol between 2007-2012 were reviewed. We selected a subset who met Johns Hopkins criteria for AS (Gleason score≤6, PSA density≤0.15, tumor involvement of ≤2 cores, and ≤50% of any single core) by outside 12−core TRUS biopsy. Patients with Gleason score≤6 confirmed at first NCI biopsy session were followed with annual MP-MRI and biopsy. MRI progression was defined as an increase in MP-MRI suspicion level, lesion diameter, or number of lesions. Pathologic progression was defined as an increase to Gleason score≥7 in either 12-core or MR-fusion biopsy. We determined the association between MRI and pathologic progression. Results: 129 patients met JHU criteria for AS by outside biopsy. Mean age was 61.6 years and mean PSA 5.16ng/mL. 28/129 (21.7%) patients had Gleason score ≥7 at first NCI biopsy session.31 patients had at least two biopsy sessions (mean follow up 18 months, range 12-54 months) of which 9/31 (29%) increased in Gleason score, all to 3+4=7. Fusion biopsy detected more pathologic progression than did standard biopsy (Table). The positive predictive value of MP-MRI for pathologic progression was 50%, while the negative predictive value was 84%. The sensitivity and specificity of MP-MRI for increase in Gleason score was 67% and 73%, respectively. Conclusions: Stable findings on MP-MRI are associated with Gleason score stability in patients with low-risk PCa choosing AS. The majority of patients who had pathologic progression were detected on fusion biopsy, which may suggest that random biopsies are unnecessary in this population. Larger studies are needed to validate these findings. [Table: see text]

84 Background: Historically, pathologic findings from standard 12-core prostate biopsies are upgraded in 25 to 33% of patients after radical prostatectomy (RP). MRI/US fusion prostate biopsy has been shown to upgrade prostate cancer compared to standard 12-core biopsy in 32% of patients. MRI/US fusion biopsy may offer a more accurate representation of whole gland pathology. We evaluate the rate of pathologic upgrade in standard 12-core biopsy and MRI/US fusion biopsy when compared with whole gland pathology from RP. Methods: Patients who underwent random prostate biopsy, fusion biopsy and subsequently RP for prostate cancer from 2012 to 2013 were included. Pathology was reviewed by a single pathologist. The cohort was divided into clinically significant high-grade (Gleason score 4+3 or higher) and clinically insignificant low-grade (Gleason score 3+4 or lower) sub cohorts. Pathological upgrade was defined as any increase in Gleason sum or primary Gleason score. McNemar’s test was used to compare the proportion of patients who were upgraded from random biopsy to RP versus the proportion that were upgraded from fusion biopsy to RP. Results: Sixty eight patients underwent 12-core and fusion prostate biopsy then subsequently RP. Mean prostate-specific antigen was 9.2ng/ml. There are total of 43 patients with clinically insignificant low-grade and 25 patients with clinically significant high-grade. Fusion biopsy upgraded 19 patients (28%) compared to 12-core biopsy, eight of these patients had negative 12-core biopsy. Pathology on the RP specimen upgraded 18 of the 12-core results (26%) compare to only eight fusion biopsy results (11%). (p =0.0095) 14 patients (20%) who had clinically insignificant low-grade disease on 12-core biopsy were upgraded to clinically significant high-grade on RP. Only two patients (3%) with clinically insignificant low-grade from fusion biopsy were upgraded on RP. (p< 0.0005) Conclusions: Prostate cancer detected on MRI/US fusion prostate biopsy has significantly lower rates of pathologic upgrade than standard 12-core biopsy when both were compared to prostatectomy specimens. MRI/US fusion biopsy may represent whole gland pathology more accurately compared to 12-core biopsy.

It is commonly believed that antibodies are too large (∼150kDa) to access the intracellular compartment. Therefore, therapeutic antibodies have been traditionally used to target cell surface receptors or soluble proteins in the circulation, leaving a large intracellular treasure of potential cancer-specific targets untapped. This review offers new perspectives on our recently proposed concept that antibodies can be used to target intracellular tumor antigens for anti-cancer therapy. We propose to vastly expand the repertoire of potential targets for cancer immunotherapy since many excellent cancer targets are inside cells.