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The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis. Significance: Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains. This article is highlighted in the In This Issue feature, p. 171

Multiwavelength variability studies of active galactic nuclei (AGN) can be used to probe their inner regions which are not directly resolvable. Dust reverberation mapping (DRM) estimates the size of the dust emitting region by measuring the delays between the infrared (IR) response to variability in the optical light curves. We measure DRM lags of Zw229-015 between optical ground-based and Kepler light curves and concurrent IR Spitzer 3.6 and 4.5 $\mu$m light curves from 2010-2015, finding an overall mean rest-frame lag of 18.3 $\pm$ 4.5 days. Each combination of optical and IR light curve returns lags that are consistent with each other within 1$\sigma$, which implies that the different wavelengths are dominated by the same hot dust emission. The lags measured for Zw229-015 are found to be consistently smaller than predictions using the lag-luminosity relationship. Also, the overall IR response to the optical emission actually depends on the geometry and structure of the dust emitting region as well, so we use Markov chain Monte Carlo (MCMC) modelling to simulate the dust distribution to further estimate these structural and geometrical properties. We find that a large increase in flux between the 2011-2012 observation seasons, which is more dramatic in the IR light curve, is not well simulated by a single dust component. When excluding this increase in flux, the modelling consistently suggests that the dust is distributed in an extended flat disk, and finds a mean inclination angle of 49$^{+3}_{-13}$ degrees., Comment: 32 pages, 32 Figures, 7 Tables; Accepted for publication in MNRAS

R code of our analysis clock like mutational signatures in Hodgkin lymphoma WGS and WES.

The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis.Significance:Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains.This article is highlighted in the In This Issue feature, p. 171

All supplementary figures S1-S17

R code of our analysis for driver mutation discovery in Hodgkin lymphoma WGS and WES.

Supplementary Tables S1-S20

VAF concordance

Supplemental Figure Legends

Supplementary Data file including supplementary methods and clinical case vignettes.

Reasons for not using recommended targeted therapy.

PU-H71 suppresses tumor growth in a Ramos xenograft Model.

IPA analysis of Hps90 client protein networks

Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.

Hsp90 client proteins identified by PU-H71 high affinity capture

BL tumors undergo growth suppression without apoptosis upon treatment with PU-H71 in-vivo.

BL tumors overexpress Hsp90

Patient sequencing data, by patient number and diagnosis.

BL cells but not normal GC B-cells are sensitive to inhibition by PU-H71.

Chemical Structure of PU-H71 and BEZ-235

CCR Translation for This Article from Scatter Spectroscopic Imaging Distinguishes between Breast Pathologies in Tissues Relevant to Surgical Margin Assessment

supplemental legend

Response prediction scores for 22 rounds of leave-one-out cross-validation are presented. The test set individual in each round is denoted by a black asterisk, while training set responders and non-responders are denoted by blue dots and red dots, respectively. Test set individuals with scores above/below the dashed line were predicted to be vaccine responders/non-responders. Of the variants found to be associated with vaccine response among training set individuals (P < 0.005), up-weighting in the prediction model was applied to those within genes that participate in the following pathways: (A) no pathway, (B) KEGG: Extracellular matrix receptor interactions, (C) KEGG: Natural killer cell mediated cytotoxicity, (D) PID: αVβ3 integrin pathway, (E) PID: Caspase pathway, (F) PID: SHP2 pathway, (G) REACTOME: Cell surface interactions at the vascular wall, (H) REACTOME: PPARα activates gene expression, (I) PID: αMβ2 integrin pathway, (J) PID: Integrin 1 pathway, and (K) REACTOME: Metabolism of amino acids and derivatives.

Genes in colorectal cancer liver metastases that were sequenced.

Purpose: We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine.Experimental Design: Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane–related functions.Results: There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%).Conclusions: Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399–406. ©2016 AACR.

Vaccine response-associated genes identified by the Combined Multivariate and Collapsing method.

PDF file, 133K, Diagnostic distribution of tissue population and mean+/-standard deviation for spectrally derived scattering parameters per diagnostic category.

We present reverberation mapping measurements for the prominent ultraviolet broad emission lines of the active galactic nucleus Mrk817 using 165 spectra obtained with the Cosmic Origins Spectrograph on the Hubble Space Telescope. Our ultraviolet observations are accompanied by X-ray, optical, and near-infrared observations as part of the AGN Space Telescope and Optical Reverberation Mapping Program 2 (AGN STORM 2). Using the cross-correlation lag analysis method, we find significant correlated variations in the continuum and emission-line light curves. We measure rest-frame delayed responses between the far-ultraviolet continuum at 1180 A and Ly$\alpha$ $\lambda1215$ A ($10.4_{-1.4}^{+1.6}$ days), N V $\lambda1240$ A ($15.5_{-4.8}^{+1.0}$days), SiIV + OIV] $\lambda1397$ A ($8.2_{-1.4}^{+1.4}$ days), CIV $\lambda1549$ A ($11.8_{-2.8}^{+3.0}$ days), and HeII $\lambda1640$ A ($9.0_{-1.9}^{+4.5}$ days) using segments of the emission-line profile that are unaffected by absorption and blending, which results in sampling different velocity ranges for each line. However, we find that the emission-line responses to continuum variations are more complex than a simple smoothed, shifted, and scaled version of the continuum light curve. We also measure velocity-resolved lags for the Ly$\alpha$, and CIV emission lines. The lag profile in the blue wing of Ly$\alpha$ is consistent with virial motion, with longer lags dominating at lower velocities, and shorter lags at higher velocities. The CIV lag profile shows the signature of a thick rotating disk, with the shortest lags in the wings, local peaks at $\pm$ 1500 $\rm km\,s^{-1}$, and a local minimum at line center. The other emission lines are dominated by broad absorption lines and blending with adjacent emission lines. These require detailed models, and will be presented in future work., Comment: Submitted to ApJ. 25 pages, 8 figures, and 6 tables

We evaluated long range antennae and associated solar-powered global positioning system (GPS) ear tags designed for use with domestic cattle, as a novel system for monitoring ranging behaviour of the koala (Phascolarctos cinereus). The mean location error of our GPS tags was 33.9 m (s.e. = 0.46). The tags were relatively light (30 g), reported eight locations per day when attached to koala radio-collars and had an operating life that exceeded our study period (8 months). Deployed as a stand-alone, solar powered, remote system, this technology can provide a viable option for wildlife tracking projects.

Here, we present a multimodal, lamprey-inspired, 3D printed soft fluidic robot/actuator based on an antagonistic pneunet architecture. The Pacific Lamprey is a unique fish which is able to climb wetted vertical surfaces using its suction-cup mouth and snake-like morphology. The continuum structure of these fish lends itself to soft robots, given their ability to form continuous bends. Additionally, the high gravimetric and volumetric power density attainable by soft actuators make them good candidates for climbing robots. Fluidic soft robots are often limited in the forces they can exert due to limitations on their actuation pressure. This actuator is able to operate at relatively high pressures (for soft robots) of 756 kPa (95 psig) with a −3 dB bandwidth of 2.23 Hz to climb at rates exceeding 18 cm/s. The robot is capable of progression on a vertical surface using a compliant microspine attachment as the functional equivalent of the lamprey’s more complex suction-cup mouth. The paper also presents the details of the 3D-printed manufacturing of this actuator/robot.

Soft robots offer an alternative approach to manipulate within a constrained space while maintaining a safe interaction with the external environment. Owing to its adaptable compliance characteristic, external contact force can easily deform the robot shapes and lead to undesired robot kinematic and dynamic properties. Accurate contact detection and contact location estimation are of critical importance for soft robot modeling, control, trajectory planning, and eventually affect the success of task completion. In this article, we focus on the investigation of a one degree of freedom (1-DoF) soft pneumatic bending robot, which is regarded as one of the fundamental components to construct complex, multi-DoFs soft robots. This 1-DoF soft robot is modeled through the integral representation of the spatial curve, where direct and instantaneous kinematics are calculated explicitly through a modal method. The fixed centrode deviation method is used to detect the external contact and estimate the contact location. Simulation results and experimental studies indicate that the contact location can be accurately estimated by solving a nonlinear least-square optimization problem. Experimental validation shows that the proposed algorithm is able to successfully estimate the contact location with the estimation error of 1.46 mm.

Background Objectives: We performed a randomized, double-blind, placebo-controlled trial to determine if using Secretin intra-operatively to identify leaks and subsequently target operative intervention would decrease the frequency of clinically significant post-operative pancreatic fistula formation. Methods Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to receive intra-operative Secretin or placebo intra-operatively following the completed pancreaticojejunostomy or closure of the cut remnant stump. If a potential leak was identified, targeted therapy with directed suture placement was performed. Results 170 patients were randomized; 83 receiving placebo and 87 receiving Secretin. The rate of clinically significant fistula formation was 3% (3/87) in the Secretin group and 6% (5/83) in the placebo group (p = 0.489). The rate of biochemical leak was 29% (25/87) in the Secretin group and 19% (16/83) in the placebo group (p = 0.157). There were no Grade C post-operative fistula in either group. Of the 9% of patients in the Secretin group who had a targeted intra-operative intervention, none developed a clinically significant fistula. Adverse events were similar between groups. Conclusions Compared to placebo, intra-operative Secretin administration was not associated with an overall reduction in clinically significant pancreatic fistula formation. However, patients with an intra-operative leak identified by Secretin may benefit from intervention (clinicaltrials.gov: NCT02160808 ).

We combine our dynamical modeling black-hole mass measurements from the Lick AGN Monitoring Project 2016 sample with measured cross-correlation time lags and line widths to recover individual scale factors, f, used in traditional reverberation-mapping analyses. We extend our sample by including prior results from Code for AGN Reverberation and Modeling of Emission Lines (caramel) studies that have utilized our methods. Aiming to improve the precision of black-hole mass estimates, as well as uncover any regularities in the behavior of the broad-line region (BLR), we search for correlations between f and other AGN/BLR parameters. We find (i) evidence for a correlation between the virial coefficient log 10 ( f mean , σ ) and black-hole mass, (ii) marginal evidence for a similar correlation between log 10 ( f rms , σ ) and black-hole mass, (iii) marginal evidence for an anticorrelation of BLR disk thickness with log 10 ( f mean , FWHM ) and log 10 ( f rms , FWHM ) , and (iv) marginal evidence for an anticorrelation of inclination angle with log 10 ( f mean , FWHM ) , log 10 ( f rms , σ ) , and log 10 ( f mean , σ ) . Last, we find marginal evidence for a correlation between line-profile shape, when using the root-mean-square spectrum, log 10 ( FWHM / σ ) rms , and the virial coefficient, log 10 ( f rms , σ ) , and investigate how BLR properties might be related to line-profile shape using caramel models.

The coronavirus disease (COVID-19) crisis has placed enormous strain on global health care due to the sudden and exorbitant caseload burdens, compounded by insufficient access to the requisite supplies and equipment necessary to treat patients. Most notably, critical shortages of mechanical ventilators, which are essential for oxygenating patients who cannot breathe on their own, have forced physicians to make difficult decisions between who will and will not receive treatment, especially in resource-limited communities. In this article, we describe the efforts undertaken by a consortium of engineers, roboticists, and clinicians from Vanderbilt University to develop an easily reproducible mechanical ventilator out of core components that can be sourced locally, inexpensively, and en masse.

Aim: Image-guided surgery (IGS) allows for accurate, real-time localization of subsurface critical structures during surgery. No prior IGS systems have described a feasible method of intraoperative reregistration after manipulation of the kidney during robotic partial nephrectomy (PN). We present a method for seamless reregistration during IGS and evaluate accuracy before and after tumor resection in two validated kidney phantoms. Materials and Methods: We performed robotic PN on two validated kidney phantoms—one with an endophytic tumor and one with an exophytic tumor—with our IGS system utilizing the da Vinci Xi robot. Intraoperatively, the kidney phantoms' surfaces were digitized with the da Vinci robotic manipulator via a touch-based method and registered to a three-dimensional segmented model created from cross-sectional CT imaging of the phantoms. Fiducial points were marked with a surgical marking pen and identified after the initial registration using the robotic manipulator. Segmented images were displayed via picture-in-picture in the surgeon console as tumor resection was performed. After resection, reregistration was performed by reidentifying the fiducial points. The accuracy of the initial registration and reregistration was compared. Results: The root mean square (RMS) averages of target registration error (TRE) were 2.53 and 4.88 mm for the endophytic and exophytic phantoms, respectively. IGS enabled resection along preplanned contours. Specifically, the RMS averages of the normal TRE over the entire resection surface were 0.75 and 2.15 mm for the endophytic and exophytic phantoms, respectively. Both tumors were resected with grossly negative margins. Point-based reregistration enabled instantaneous reregistration with minimal impact on RMS TRE compared with the initial registration (from 1.34 to 1.70 mm preresection and from 1.60 to 2.10 mm postresection). Conclusions: We present a novel and accurate registration and reregistration framework for use during IGS for PN with the da Vinci Xi surgical system. The technology is easily integrated into the surgical workflow and does not require additional hardware.