Publications by authors named "Daniel Berger"

132 Publications

Two Stream Active Query Suggestion for Active Learning in Connectomics.

Comput Vis ECCV 2020 Aug 4;12363:103-120. Epub 2020 Dec 4.

Harvard University.

For large-scale vision tasks in biomedical images, the labeled data is often limited to train effective deep models. Active learning is a common solution, where a query suggestion method selects representative unlabeled samples for annotation, and the new labels are used to improve the base model. However, most query suggestion models optimize their learnable parameters only on the limited labeled data and consequently become less effective for the more challenging unlabeled data. To tackle this, we propose a query suggestion approach. In addition to the supervised feature extractor, we introduce an unsupervised one optimized on all raw images to capture diverse image features, which can later be improved by fine-tuning on new labels. As a use case, we build an end-to-end active learning framework with our query suggestion method for 3D synapse detection and mitochondria segmentation in connectomics. With the framework, we curate, to our best knowledge, the largest connectomics dataset with dense synapses and mitochondria annotation. On this new dataset, our method outperforms previous state-of-the-art methods by 3.1% for synapse and 3.8% for mitochondria in terms of region-of-interest proposal accuracy. We also apply our method to image classification, where it outperforms previous approaches on CIFAR-10 under the same limited annotation budget. The project page is https://zudi-lin.github.io/projects/#two_stream_active.
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http://dx.doi.org/10.1007/978-3-030-58523-5_7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746018PMC
August 2020

A high-throughput alpha particle irradiation system for monitoring DNA damage repair, genome instability and screening in human cell and yeast model systems.

Nucleic Acids Res 2020 11;48(19):e111

Robson DNA Science Centre, Departments of Biochemistry and Molecular Biology and Oncology, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 1N4, Canada.

Ionizing radiation (IR) is environmentally prevalent and, depending on dose and linear energy transfer (LET), can elicit serious health effects by damaging DNA. Relative to low LET photon radiation (X-rays, gamma rays), higher LET particle radiation produces more disease causing, complex DNA damage that is substantially more challenging to resolve quickly or accurately. Despite the majority of human lifetime IR exposure involving long-term, repetitive, low doses of high LET alpha particles (e.g. radon gas inhalation), technological limitations to deliver alpha particles in the laboratory conveniently, repeatedly, over a prolonged period, in low doses and in an affordable, high-throughput manner have constrained DNA damage and repair research on this topic. To resolve this, we developed an inexpensive, high capacity, 96-well plate-compatible alpha particle irradiator capable of delivering adjustable, low mGy/s particle radiation doses in multiple model systems and on the benchtop of a standard laboratory. The system enables monitoring alpha particle effects on DNA damage repair and signalling, genome stability pathways, oxidative stress, cell cycle phase distribution, cell viability and clonogenic survival using numerous microscopy-based and physical techniques. Most importantly, this method is foundational for high-throughput genetic screening and small molecule testing in mammalian and yeast cells.
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http://dx.doi.org/10.1093/nar/gkaa782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641727PMC
November 2020

Education and training for image-guided adaptive brachytherapy for cervix cancer-The (GEC)-ESTRO/EMBRACE perspective.

Brachytherapy 2020 Nov - Dec;19(6):827-836. Epub 2020 Aug 16.

Department of Radiation Oncology, Medical University of Vienna, Wien, Austria.

Image-guided adaptive brachytherapy (IGABT) has been shown to improve local/regional control and survival for cervix cancer patients while reducing morbidity. However, the technique is complex involving several conceptual, methodological, and technical innovations compared to conventional brachytherapy. The delivery of high-quality IGABT which will translate into improved outcomes is therefore critically dependent on effective education and training of all health professionals involved in the brachytherapy treatment process. This paper reviews the (GEC)-ESTRO/EMBRACE initiatives for education and training to promote the dissemination and implementation of IGABT for cervix cancer worldwide. The new skills required in different health professionals for successful implementation of IGABT are described. The achievements and challenges of current educational strategies for disseminating IGABT are discussed. Innovations to improve the effectiveness of current and future educational strategies are explored.
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http://dx.doi.org/10.1016/j.brachy.2020.06.012DOI Listing
August 2020

Structural characterization of an ionic liquid in bulk and in nano-confined environment using data from MD simulations.

Data Brief 2020 Feb 23;28:104794. Epub 2019 Nov 23.

Group for Computational Life Sciences, Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia.

This article contains data on structural characterization of the [C2Mim][NTf2] in bulk and in nano-confined environment obtained using MD simulations. These data supplement those presented in the paper "Insights from Molecular Dynamics Simulations on Structural Organization and Diffusive Dynamics of an Ionic Liquid at Solid and Vacuum Interfaces" [1], where force fields with three different charge methods and three charge scaling factors were used for the analysis of the IL in the bulk, at the interface with the vacuum and the IL film in the contact with a hydroxylated alumina surface. Here, we present details on the construction of the model systems in an extended detailed methods section. Furthermore, for best parametrization, structural and dynamic properties of IL in different environment are studied with certain features presented herein.
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http://dx.doi.org/10.1016/j.dib.2019.104794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909096PMC
February 2020

Vienna-II ring applicator for distal parametrial/pelvic wall disease in cervical cancer brachytherapy: An experience from two institutions: Clinical feasibility and outcome.

Radiother Oncol 2019 12 5;141:123-129. Epub 2019 Sep 5.

Department of Radiotherapy, Comprehensive Cancer Center, Medical University of Vienna (MUV), Austria; Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.

Purpose: Recent evidence from EMBRACE shows that around 16% patients with locally advanced cervical cancer (LACC) have residual tumor in distal parametrium (DP) and pelvic wall disease (LPW) after concurrent radio-chemotherapy (CCRT). Adequate target coverage with standard brachytherapy approaches represents a challenge. Therefore, we modified the Vienna I applicator with an add-on cap allowing for additional oblique needles into the DP/LPW (Vienna II). We report here the feasibility and clinical outcomes using Vienna II applicator in LACC patients treated in 2 institutions.

Methods And Materials: 69 patients with residual disease in DP/LPW after CCRT were accrued. FIGO (2009) stage was 26% IIB, 52% III, 15% IVA, 7% IVB (para-aortic nodes). At diagnosis 91% had disease involving DP/LPW. After CCRT, patients underwent image guided adaptive brachytherapy (IGABT) using Vienna II applicator. IGABT details, acute complications, dose volume parameters and clinical outcome variables were compiled and analyzed.

Results: Residual DP/LPW disease at BT was found in 90% patients. Median total number of needles were 7 [3-15], oblique 4 [1-7]. Manageable intraoperative utero-vaginal complications occurred in 8 patients and manageable arterial bleeding in 6 patients during removal. Mean distance between tandem and outer contour of CTV was 38 mm and mean CTV (±SD) volume was 69 ± 32 cm. The mean D CTV was 86 ± 7 Gy (EQD2) and mean (±SD) D (Gy, EQD2) 86 ± 12, 68 ± 7, 68 ± 9 for bladder, rectum and sigmoid respectively. Actuarial LC, PFS, OS at 3/5 years was 76/72%, 56/50%, 62/54% and G3-4 late toxicities (n = 23) were observed in 14 patients (20%).

Conclusions: IGABT using Vienna II applicator allows for appropriate target coverage in tumors extending into DP/LPW at the time of BT. Clinical use is feasible and results in good local control, DFS and OS with moderate rate of acute and late ≥G3 toxicity.
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http://dx.doi.org/10.1016/j.radonc.2019.08.004DOI Listing
December 2019

Isotope systematics and chemical composition of tin ingots from Mochlos (Crete) and other Late Bronze Age sites in the eastern Mediterranean Sea: An ultimate key to tin provenance?

PLoS One 2019 26;14(6):e0218326. Epub 2019 Jun 26.

Curt-Engelhorn-Zentrum Archäometrie gGmbH, Mannheim, Germany.

The origin of the tin used for the production of bronze in the Eurasian Bronze Age is still one of the mysteries in prehistoric archaeology. In the past, numerous studies were carried out on archaeological bronze and tin objects with the aim of determining the sources of tin, but all failed to find suitable fingerprints. In this paper we investigate a set of 27 tin ingots from well-known sites in the eastern Mediterranean Sea (Mochlos, Uluburun, Hishuley Carmel, Kfar Samir south, Haifa) that had been the subject of previous archaeological and archaeometallurgical research. By using a combined approach of tin and lead isotopes together with trace elements it is possible to narrow down the potential sources of tin for the first time. The strongly radiogenic composition of lead in the tin ingots from Israel allows the calculation of a geological model age of the parental tin ores of 291 ± 17 Ma. This theoretical formation age excludes Anatolian, central Asian and Egyptian tin deposits as tin sources since they formed either much earlier or later. On the other hand, European tin deposits of the Variscan orogeny agree well with this time span so that an origin from European deposits is suggested. With the help of the tin isotope composition and the trace elements of the objects it is further possible to exclude many tin resources from the European continent and, considering the current state of knowledge and the available data, to conclude that Cornish tin mines are the most likely suppliers for the 13th-12th centuries tin ingots from Israel. Even though a different provenance seems to be suggested for the tin from Mochlos and Uluburun by the actual data, these findings are of great importance for the archaeological interpretation of the trade routes and the circulation of tin during the Late Bronze Age. They demonstrate that the trade networks between the eastern Mediterranean and some place in the east that are assumed for the first half of the 2nd millennium BCE (as indicated by textual evidence from Kültepe/Kaneš and Mari) did not exist in the same way towards the last quarter of the millennium.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594607PMC
February 2020

Insights from molecular dynamics simulations on structural organization and diffusive dynamics of an ionic liquid at solid and vacuum interfaces.

J Colloid Interface Sci 2019 Oct 6;553:350-363. Epub 2019 Jun 6.

Group of Computational Life Sciences, Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia; PULS Group, Center for Nanostructured Films, Department of Physics, FAU Erlangen-Nürnberg, Cauerstraße 3, 91058, Erlangen, Germany. Electronic address:

Hypothesis: A reliable modelling approach is required for simultaneous characterisation of static and dynamic properties of bulk and interfacial ionic liquids (ILs). This is a prerequisite for a successful investigation of experimentally inaccessible, yet important properties, including those that change significantly with the distance from both vacuum and solid interfaces.

Simulations: We perform molecular dynamics simulations of bulk [CMim][NTf], and thick IL films in contact with vacuum and hydroxylated sapphire surface, using the charge methods CHelpG, RESP-HF and RESP-B3LYP with charge scaling factors 1.0, 0.9 and 0.85.

Findings: By determining and employing appropriate system sizes and simulations lengths, and by benchmarking against self-diffusion coefficients, surface tension, X-ray reflectivity, and structural data, we identify RESP-HF/0.9 as the best non-polarizable force field for this IL. We use this optimal parametrisation to predict novel physical properties of confined IL films. First we fully characterise the internal configurations and orientations of IL molecules relative to, and as a function of the distance from the solid and vacuum interfaces. Second, we evaluate densities together with mobilities in-plane and normal to the interfaces and find that strong correlations between the IL's stratification and diffusive transport in the interfacial layers persist for several nanometres deep into IL films.
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http://dx.doi.org/10.1016/j.jcis.2019.06.017DOI Listing
October 2019

Individual Oligodendrocytes Show Bias for Inhibitory Axons in the Neocortex.

Cell Rep 2019 06;27(10):2799-2808.e3

Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Reciprocal communication between neurons and oligodendrocytes is essential for the generation and localization of myelin, a critical feature of the CNS. In the neocortex, individual oligodendrocytes can myelinate multiple axons; however, the neuronal origin of the myelinated axons has remained undefined and, while largely assumed to be from excitatory pyramidal neurons, it also includes inhibitory interneurons. This raises the question of whether individual oligodendrocytes display bias for the class of neurons that they myelinate. Here, we find that different classes of cortical interneurons show distinct patterns of myelin distribution starting from the onset of myelination, suggesting that oligodendrocytes can recognize the class identity of individual types of interneurons that they target. Notably, we show that some oligodendrocytes disproportionately myelinate the axons of inhibitory interneurons, whereas others primarily target excitatory axons or show no bias. These results point toward very specific interactions between oligodendrocytes and neurons and raise the interesting question of why myelination is differentially directed toward different neuron types.
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http://dx.doi.org/10.1016/j.celrep.2019.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968376PMC
June 2019

Structuring of Bioceramics by Micro-Grinding for Dental Implant Applications.

Micromachines (Basel) 2019 May 9;10(5). Epub 2019 May 9.

Laboratory for Precision Machining (LFM), Leibniz Institute for Materials Engineering (IWT), MAPEX Center for Materials and Processes, University of Bremen, 28359 Bremen, Germany.

Metallic implants were the only option for both medical and dental applications for decades. However, it has been reported that patients with metal implants can show allergic reactions. Consequently, technical ceramics have become an accessible material alternative due to their combination of biocompatibility and mechanical properties. Despite the recent developments in ductile mode machining, the micro-grinding of bioceramics can cause insufficient surface and subsurface integrity due to the inherent hardness and brittleness of these materials. This work aims to determine the influence on the surface and subsurface damage (SSD) of zirconia-based ceramics ground with diamond wheels of 10 mm diameter with a diamond grain size (d) of 75 μm within eight grinding operations using a variation of the machining parameters, i.e., peripheral speed (v), feed speed (v), and depth of cut (a). In this regard, dental thread structures were machined on fully sintered zirconia (ZrO), alumina toughened zirconia (ATZ), and zirconia toughened alumina (ZTA) bioceramics. The ground workpieces were analysed through a scanning electron microscope (SEM), X-ray diffraction (XRD), and white light interferometry (WLI) to evaluate the microstructure, residual stresses, and surface roughness, respectively. Moreover, the grinding processes were monitored through forces measurement. Based on the machining parameters tested, the results showed that low peripheral speed (v) and low depth of cut (a) were the main conditions investigated to achieve the optimum surface integrity and the desired low grinding forces. Finally, the methodology proposed to investigate the surface integrity of the ground workpieces was helpful to understand the zirconia-based ceramics response under micro-grinding processes, as well as to set further machining parameters for dental implant threads.
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http://dx.doi.org/10.3390/mi10050312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562720PMC
May 2019

Con: Liver Biopsy Remains the Gold Standard to Evaluate Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Clin Liver Dis (Hoboken) 2019 Apr 30;13(4):114-116. Epub 2019 Apr 30.

Rush University Medical Center, Section of Hepatology Chicago IL.

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http://dx.doi.org/10.1002/cld.740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491029PMC
April 2019

Liver Diseases During Pregnancy.

Clin Liver Dis 2019 05 26;23(2):345-361. Epub 2019 Feb 26.

Section of Hepatology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 319, Chicago, IL 60612, USA. Electronic address:

Liver diseases during pregnancy pose a unique clinical challenge because they can affect the lives of both the mother and unborn child. Although severe liver disease is rare, pregnancy-related liver disease affects approximately 3% of pregnancies and can be fatal. Timely recognition and diagnosis are essential in order to institute appropriate management strategies. This article provides an overview of liver diseases during pregnancy and is divided into 2 sections: (1) liver diseases specific to pregnancy, and (2) preexisting or coincident liver diseases during pregnancy.
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http://dx.doi.org/10.1016/j.cld.2018.12.013DOI Listing
May 2019

The CHD6 chromatin remodeler is an oxidative DNA damage response factor.

Nat Commun 2019 01 16;10(1):241. Epub 2019 Jan 16.

Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes. Here, we show that Chromodomain Helicase DNA-binding protein 6 (CHD6), distinct to other CHD enzymes, is stabilized during oxidative stress via reduced degradation. CHD6 relocates rapidly to DNA damage in a manner dependent upon oxidative lesions and a conserved N-terminal poly(ADP-ribose)-dependent recruitment motif, with later retention requiring the double chromodomain and central core. CHD6 ablation increases reactive oxygen species persistence and impairs anti-oxidant transcriptional responses, leading to elevated DNA breakage and poly(ADP-ribose) induction that cannot be rescued by catalytic or double chromodomain mutants. Despite no overt epigenetic or DNA repair abnormalities, CHD6 loss leads to impaired cell survival after chronic oxidative stress, abnormal chromatin relaxation, amplified DNA damage signaling and checkpoint hypersensitivity. We suggest that CHD6 is a key regulator of the oxidative DNA damage response.
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http://dx.doi.org/10.1038/s41467-018-08111-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335469PMC
January 2019

North American survey on the post-neuroimaging management of children with mild head injuries.

J Neurosurg Pediatr 2018 10;23(2):227-235

Departments of1Neurological Surgery.

OBJECTIVEThere remains uncertainty regarding the appropriate level of care and need for repeating neuroimaging among children with mild traumatic brain injury (mTBI) complicated by intracranial injury (ICI). This study's objective was to investigate physician practice patterns and decision-making processes for these patients in order to identify knowledge gaps and highlight avenues for future investigation.METHODSThe authors surveyed residents, fellows, and attending physicians from the following pediatric specialties: emergency medicine; general surgery; neurosurgery; and critical care. Participants came from 10 institutions in the United States and an email list maintained by the Canadian Neurosurgical Society. The survey asked respondents to indicate management preferences for and experiences with children with mTBI complicated by ICI, focusing on an exemplar clinical vignette of a 7-year-old girl with a Glasgow Coma Scale score of 15 and a 5-mm subdural hematoma without midline shift after a fall down stairs.RESULTSThe response rate was 52% (n = 536). Overall, 326 (61%) respondents indicated they would recommend ICU admission for the child in the vignette. However, only 62 (12%) agreed/strongly agreed that this child was at high risk of neurological decline. Half of respondents (45%; n = 243) indicated they would order a planned follow-up CT (29%; n = 155) or MRI scan (19%; n = 102), though only 64 (12%) agreed/strongly agreed that repeat neuroimaging would influence their management. Common factors that increased the likelihood of ICU admission included presence of a focal neurological deficit (95%; n = 508 endorsed), midline shift (90%; n = 480) or an epidural hematoma (88%; n = 471). However, 42% (n = 225) indicated they would admit all children with mTBI and ICI to the ICU. Notably, 27% (n = 143) of respondents indicated they had seen one or more children with mTBI and intracranial hemorrhage demonstrate a rapid neurological decline when admitted to a general ward in the last year, and 13% (n = 71) had witnessed this outcome at least twice in the past year.CONCLUSIONSMany physicians endorse ICU admission and repeat neuroimaging for pediatric mTBI with ICI, despite uncertainty regarding the clinical utility of those decisions. These results, combined with evidence that existing practice may provide insufficient monitoring to some high-risk children, emphasize the need for validated decision tools to aid the management of these patients.
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http://dx.doi.org/10.3171/2018.7.PEDS18263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717430PMC
October 2018

Mechanism of the Water-Gas Shift Reaction Catalyzed by Efficient Ruthenium-Based Catalysts: A Computational and Experimental Study.

Angew Chem Int Ed Engl 2019 Jan 12;58(3):741-745. Epub 2018 Dec 12.

Group of Computational Life Sciences, Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia.

Supported ionic liquid phase (SILP) catalysis enables a highly efficient, Ru-based, homogeneously catalyzed water-gas shift reaction (WGSR) between 100 °C and 150 °C. The active Ru-complexes have been found to exist in imidazolium chloride melts under operating conditions in a dynamic equilibrium, which is dominated by the [Ru(CO) Cl ] complex. Herein we present state-of-the-art theoretical calculations to elucidate the reaction mechanism in more detail. We show that the mechanism includes the intermediate formation and degradation of hydrogen chloride, which effectively reduces the high barrier for the formation of the requisite dihydrogen complex. The hypothesis that the rate-limiting step involves water is supported by using D O in continuous catalytic WGSR experiments. The resulting mechanism constitutes a highly competitive alternative to earlier reported generic routes involving nucleophilic addition of hydroxide in the gas phase and in solution.
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http://dx.doi.org/10.1002/anie.201811627DOI Listing
January 2019

Deciphering the molecular effects of romidepsin on germ cell tumours: DHRS2 is involved in cell cycle arrest but not apoptosis or induction of romidepsin effectors.

J Cell Mol Med 2019 01 20;23(1):670-679. Epub 2018 Nov 20.

Department of Developmental Pathology, Institute of Pathology, University Medical School Bonn, Bonn, Germany.

Testicular germ cell tumours (GCTs) mostly affect young men at age 17-40. Although high cure rates can be achieved by orchiectomy and chemotherapy, GCTs can still be a lethal threat to young patients with metastases or therapy resistance. Thus, alternative treatment options are needed. Based on studies utilising GCT cell lines, the histone deacetylase inhibitor romidepsin is a promising therapeutic option, showing high toxicity at very low doses towards cisplatin-resistant GCT cells, but not fibroblasts or Sertoli cells. In this study, we extended our analysis of the molecular effects of romidepsin to deepen our understanding of the underlying mechanisms. Patients will benefit from these analyses, since detailed knowledge of the romidepsin effects allows for a better risk and side-effect assessment. We screened for changes in histone acetylation of specific lysine residues and analysed changes in the DNA methylation landscape after romidepsin treatment of the GCT cell lines TCam-2, 2102EP, NCCIT and JAR, while human fibroblasts were used as controls. In addition, we focused on the role of the dehydrogenase/reductase DHRS2, which was strongly up-regulated in romidepsin treated cells, by generating DHRS2-deficient TCam-2 cells using CRISPR/Cas9 gene editing. We show that DHRS2 is dispensable for up-regulation of romidepsin effectors (GADD45B, DUSP1, ZFP36, ATF3, FOS, CDKN1A, ID2) but contributes to induction of cell cycle arrest. Finally, we show that a combinatory treatment of romidepsin plus the gluccocorticoid dexamethasone further boosts expression of the romidepsin effectors and reduces viability of GCT cells more strongly than under single agent treatment. Thus, romidepsin and dexamethasone might represent a new combinatorial approach for treatment of GCT.
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http://dx.doi.org/10.1111/jcmm.13971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307807PMC
January 2019

3-Stage Miller Cross-Coupled Load based Photodiode Readout for Glucose Monitoring.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:3918-3921

An innovative 3-stage miller compensted, cross-coupled load, based photodiode front end readout is designed for glucose monitoring. The Near Infrared Spectroscopy (NIRS) technique is used for the optical sensing of glucose non-invasively. The stable 3-stage open loop amplifier is designed for a gain of 68.3 dB, phase margin of 65°, GBW of 12.6 MHz and has a power consumption of 0.26 mW. The transimpedance amplifier achieves a gain of 84.46 dB, phase margin of 65°, has an input referred noise of 20.4 pAHz and consumes 0.55 mW of power from a 3.3 V supply using a 0.18 $\mu \mathrm{m}$ CMOS technology node.
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http://dx.doi.org/10.1109/EMBC.2018.8513335DOI Listing
July 2018

Nanobody immunostaining for correlated light and electron microscopy with preservation of ultrastructure.

Nat Methods 2018 12 5;15(12):1029-1032. Epub 2018 Nov 5.

Department of Molecular and Cellular Biology and The Center for Brain Science, Harvard University, Cambridge, MA, USA.

Morphological and molecular characteristics determine the function of biological tissues. Attempts to combine immunofluorescence and electron microscopy invariably compromise the quality of the ultrastructure of tissue sections. We developed NATIVE, a correlated light and electron microscopy approach that preserves ultrastructure while showing the locations of multiple molecular moieties, even deep within tissues. This technique allowed the large-scale 3D reconstruction of a volume of mouse hippocampal CA3 tissue at nanometer resolution.
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http://dx.doi.org/10.1038/s41592-018-0177-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405223PMC
December 2018

VAST (Volume Annotation and Segmentation Tool): Efficient Manual and Semi-Automatic Labeling of Large 3D Image Stacks.

Front Neural Circuits 2018 16;12:88. Epub 2018 Oct 16.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States.

Recent developments in serial-section electron microscopy allow the efficient generation of very large image data sets but analyzing such data poses challenges for software tools. Here we introduce Volume Annotation and Segmentation Tool (VAST), a freely available utility program for generating and editing annotations and segmentations of large volumetric image (voxel) data sets. It provides a simple yet powerful user interface for real-time exploration and analysis of large data sets even in the Petabyte range.
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http://dx.doi.org/10.3389/fncir.2018.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198149PMC
March 2019

The Role of Brachytherapy in the Treatment of Breast Cancer.

Breast Care (Basel) 2018 Jul 29;13(3):157-161. Epub 2018 May 29.

Department of Radiotherapy, Medical University of Vienna, Vienna, Austria.

Radiotherapy plays an important part in the management of breast cancer. Especially after breast-conserving surgery, external whole breast irradiation, occasionally with an additional local boost, is an integral part of breast conservation. Besides external radiation techniques, brachytherapy (BT) has long been among the treatment options, especially with regard to local boost application. With the emerging implementation of accelerated partial breast irradiation (APBI), BT in general and interstitial multi-catheter BT in particular, are gaining an increasing role in the management of a selected group of early breast cancer patients. APBI is an approach to reduce the irradiated area to the former tumor bed rather than treating the whole breast tissue in patients with a low baseline local recurrence risk. After a variety of phase I-III clinical studies, it is clearly evident that APBI will play a role in the treatment of this selected patient group. In this review, we focus on the clinical development and different available techniques of breast BT and provide a preview of prospects for its use.
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http://dx.doi.org/10.1159/000489638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062670PMC
July 2018

Adenoma detection rate metrics in colorectal cancer surveillance colonoscopy.

Surg Endosc 2018 07 16;32(7):3108-3113. Epub 2018 Jan 16.

Department of Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.

Background: A target goal for screening adenoma detection rate (S-ADR) of ≥ 25% has been set to define high-quality colonoscopy performance. However, there is no current accepted target goal for ADR in colorectal cancer (CRC) surveillance. This makes quality assessment challenging when physicians perform cancer surveillance colonoscopy but minimal screening procedures.

Methods: In this cohort study, consecutive colonoscopies performed at either Rush University Medical Center or Rush Oak Park Hospital by a gastroenterologist or colorectal surgeon in average risk screening population and CRC surveillance population were reviewed retrospectively from 2006 to 2012 and prospectively from 2013 to 2016. ADR in first surveillance colonoscopy following surgical resection of CRC (CRC-ADR) was reported in high-quality detectors (HQD) or low-quality detectors (LQD) based on achievement of 25% ADR in consecutive screening colonoscopy in average risk patients. Pearson's correlation was used to describe the association between individual S-ADR and CRC-ADR for colonoscopists.

Results: There was a very strong positive correlation (r = 0.88, p = 0.002) between ADR in average risk screening and first time CRC surveillance. For HQD as defined by S-ADR ≥ 25% (n = 10 colonoscopists), the CRC-ADR was 37.7% (78/207, SD 8%) which was very similar to their respective S-ADR of 33.4% (816/2440, p = 0.22). For LQD (n = 5 colonoscopists), the CRC-ADR was 20.2% (40/198) which was similar to their respective S-ADR of 20.1% (119/591, p = 0.99). The CRC-ADR was significantly higher for HQD than for LQD (37.7 vs. 20.2%, p < 0.0001).

Conclusions: The major finding of this study is a defined CRC-ADR for HQD based on the ability to achieve S-ADR ≥ 25%. S-ADR strongly correlates with CRC-ADR. CRC-ADR is quite similar to the colonoscopists' respective S-ADR for both HQD and LQD. For colonoscopists who perform limited screening colonoscopies but do perform CRC surveillance colonoscopies, ADR metrics similar to S-ADR to assess quality in colonoscopy could be considered.
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http://dx.doi.org/10.1007/s00464-018-6025-3DOI Listing
July 2018

Patients with small and diminutive proximal hyperplastic polyps have higher rates of synchronous advanced neoplasia compared with patients without serrated lesions.

Gastrointest Endosc 2018 Jun 11;87(6):1518-1526. Epub 2018 Jan 11.

Department of Gastroenterology, Rush University Medical Center, Chicago, Illinois, USA.

Background And Aims: The association of proximal small and diminutive hyperplastic polyps (HPs) with synchronous advanced neoplasia is not well-defined. However, sessile serrated polyps (SSPs), even when small, are known to portend a risk of synchronous neoplasia. Currently, the U.S. Multi-Society Task Force on Colorectal Cancer does not recommend a change in the surveillance interval when proximal small HPs are detected. We aimed to compare the rates of synchronous advanced neoplasia in a screening colonoscopy cohort of patients with small and then diminutive proximal HPs in comparison, first to a cohort absent any serrated or proximal HPs and then in comparison with a cohort with small proximal SSPs.

Methods: Consecutive screening colonoscopies were recorded between 2005 and 2010 at an academic medical center. Patients were divided into 3 mutually exclusive groups. Group 1 consisted of patients with at least 1 HP that was proximal to the sigmoid colon, <1 cm in endoscopic size, and up to 3 total HPs in number. Group 2 included patients without any proximal HPs or SSPs. Group 3 consisted of patients with 1 to 2 SSPs, with at least 1 being proximal to the sigmoid colon, that were <1 cm in endoscopic size and without dysplasia. Rates of synchronous advanced neoplasia in patients with small (<1 cm) and diminutive (≤5 mm) proximal HPs were compared with the rates for the other 2 groups.

Results: There were 482 of 2569 patients (18.8%) with a small proximal HP who met the criteria for Group 1. The rate of synchronous advanced neoplasia in patients with a small proximal HP (61/482, 12.7%) was significantly greater compared with the average risk in the non-serrated cohort (Group 2, 133/1878, 7.1%; P < .001). There was no significant difference in the rate of synchronous advanced neoplasia when the small proximal HP group was subdivided by size (≤5 mm, 51/404, 12.6% vs 6-9 mm, 10/78, 12.8%; P = 1.00). The rate of synchronous advanced neoplasia in patients with diminutive (≤5 mm) proximal HPs (51/404, 12.6%) was not significantly different from the rate observed with proximal SSPs of similar size (17/113, 15.0%; P = .529).

Conclusion: Patients with small and diminutive proximal HPs tend to harbor higher rates of synchronous advanced neoplasia compared with those without any serrated lesions detected on screening colonoscopy. Surveillance outcomes for metachronous advanced neoplasia for patients with small proximal HPs deserves further study. The synchronous advanced neoplasia rate in patients with proximal diminutive HPs is similar to that of proximal diminutive SSPs and could have implications in a resect and discard strategy.
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http://dx.doi.org/10.1016/j.gie.2017.12.028DOI Listing
June 2018

Inflatable multichannel rectal applicator for adaptive image-guided endoluminal high-dose-rate rectal brachytherapy: design, dosimetric characteristics, and first clinical experiences.

J Contemp Brachytherapy 2017 Aug 27;9(4):359-363. Epub 2017 Jul 27.

Department of Radiation Oncology, Comprehensive Cancer Center.

Purpose: To investigate the dosimetric results and first clinical experiences with a new designed balloon applicator with adjustable catheters for endoluminal brachytherapy for patients with locally advanced rectal cancer not undergoing surgery.

Material And Methods: The applicator consists of an inflatable rectal balloon with six attached Foley catheters used as guidance for the inserted brachytherapy plastic needles. The construction of the applicator and the dosimetric profile in terms of representative dose points in 0, 2, 5, 10 mm ipsilaterally and in 0 mm contralaterally are described. The first clinical outcomes in three patients are reported.

Results: For all three patients, a reproducible dose gradient was achieved. The surface dose on the target side was 204 ± 19% of the normalized dose in 5 mm (100%) tissue depth, and 143 ± 8% in 2 mm and 64 ± 3% in 10 mm tissue depth, while the surface dose on the contra-lateral side was 20 ± 8%. After radiochemotherapy with 50 Gy external beam radiotherapy and concomitant administration of capecitabine, a HDR brachytherapy boost in 2-3 fractions of 7-10 Gy each was delivered. All patients achieved a clinical complete response 3 month after the treatment, and no major toxicity was observed.

Conclusion: The use of the applicator was clinically feasible, and resulted in a stable and reproducible dose distribution. First clinical results are promising.
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http://dx.doi.org/10.5114/jcb.2017.69335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611456PMC
August 2017

Time-to-event analysis of surgically treated posthemorrhagic hydrocephalus in preterm infants: a single-institution retrospective study.

Childs Nerv Syst 2017 Nov 7;33(11):1917-1926. Epub 2017 Sep 7.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis Children's Hospital, One Children's Place, Suite 4S20, St. Louis, MO, 63110, USA.

Purpose: The purpose of this study is to report time points relevant to the neurosurgical management of posthemorrhagic hydrocephalus (PHH).

Methods: Data were collected retrospectively on 104 preterm infants with intraventricular hemorrhage (IVH) who received neurosurgical intervention for PHH at St. Louis Children's Hospital from 1994 to 2016. Kaplan-Meier curves were constructed for various endpoints.

Results: IVH grade on head ultrasound obtained through routine clinical care was II, III, and IV in 5 (4.8%), 33 (31.7%), and 66 (63.5%) of the patients, respectively. Neither IVH size nor location appeared to affect development of PHH. Days from birth to IVH, ventriculomegaly, temporizing neurosurgical procedure (TNP), and permanent neurosurgical intervention were 2.0 (95% CI 1.7-2.3), 3.0 (2.5-3.5), 24.0 (22.2-25.8), and 101.0 (90.4-111.6), respectively. Grades III and IV IVH did not differ in age at IVH diagnosis (Χ (1 d.f.) = 1.32, p = 0.25), ventriculomegaly (Χ  = 0.73, p = 0.40), TNP (Χ  = 0.61, p = 0.43), or permanent intervention (Χ  = 2.48, p = 0.17). Ventricular reservoirs and ventriculosubgaleal shunts were used in 71 (68.3%) and 30 (28.8%), respectively. Eighty (76.9%) of the patients ultimately received a VPS. Five (4.8%) underwent a primary endoscopic third ventriculostomy (ETV), and two (1.9%) had ETV for a revision procedure. Four of the seven ETVs had choroid plexus cauterization.

Conclusions: Although most infants who develop IVH and ventriculomegaly will do so within a few days of birth, at-risk infants should be observed for at least 4 weeks with serial head ultrasounds to monitor for PHH requiring surgery.
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http://dx.doi.org/10.1007/s00381-017-3588-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647248PMC
November 2017

ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses.

Philos Trans R Soc Lond B Biol Sci 2017 Oct;372(1731)

Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
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http://dx.doi.org/10.1098/rstb.2016.0283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577461PMC
October 2017

Endoscopic Third Ventriculostomy in Patients with Neurofibromatosis Type 1: A Multicenter International Experience.

World Neurosurg 2017 Nov 24;107:623-629. Epub 2017 Aug 24.

Department of Pediatric Neurosurgery, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel.

Background: Hydrocephalus in patients with neurofibromatosis (NF) type 1 is usually obstructive and may arise secondary to tumoral or nontumoral causes. Treatment of hydrocephalus in these patients is often challenging owing to combined pathologies and unique anatomic changes. The use of endoscopic third ventriculostomy (ETV) as treatment has rarely been described in this group. We aimed to characterize indications, considerations, and outcome of ETV in patients with NF 1 gathered in a multicenter international cohort.

Methods: Five centers participated in this retrospective study. Following institutional review board approval, data and images were collected. Patients of all ages with NF 1 who underwent ETV for treatment of obstructive hydrocephalus were included. Patients who had no postoperative radiologic or clinical follow-up were excluded. ETV failure was defined as recurrent clinical or radiologic signs of hydrocephalus.

Results: The study included 42 patients. Common etiologies for hydrocephalus were aqueductal/tectal tumor (31%), aqueductal web (26%), and aqueductal stenosis owing to NF-related changes (14%). Ten patients had a preoperative diagnosis of optic pathway glioma. ETV failures were identified in 6 patients within 1 month, in 3 patients within 9 months, and in 1 patient within 4 years. ETV was successful in 32 patients (76%) with a mean follow up of 59.4 months ± 50.9 (range, 4 months to 15 years).

Conclusions: ETV is a safe treatment for selected patients with NF 1 and obstructive hydrocephalus. Individual anatomic and pathologic aspects should be taken into consideration.
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http://dx.doi.org/10.1016/j.wneu.2017.08.053DOI Listing
November 2017

Cerebrospinal Fluid Biomarkers of Pediatric Hydrocephalus.

Pediatr Neurosurg 2017 11;52(6):426-435. Epub 2017 Aug 11.

Division of Pediatric Neurosurgery, Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.

Hydrocephalus (HC) is a common, debilitating neurological condition that requires urgent clinical decision-making. At present, neurosurgeons rely heavily on a patient's history, physical examination findings, neuroimaging, and clinical judgment to make the diagnosis of HC or treatment failure (e.g., shunt malfunction). Unfortunately, these tools, even in combination, do not eliminate subjectivity in clinical decisions. In order to improve the management of infants and children with HC, there is an urgent need for new biomarkers to complement currently available tools and enable clinicians to confidently establish the diagnosis of HC, assess therapeutic efficacy/treatment failure, and evaluate current and future developmental challenges, so that every child has access to the resources they need to optimize their outcome and quality of life.
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http://dx.doi.org/10.1159/000477175DOI Listing
August 2018

Cell diversity and network dynamics in photosensitive human brain organoids.

Nature 2017 05 26;545(7652):48-53. Epub 2017 Apr 26.

Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
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http://dx.doi.org/10.1038/nature22047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659341PMC
May 2017

Surface Adsorption Energetics Studied with "Gold Standard" Wave-Function-Based Ab Initio Methods: Small-Molecule Binding to TiO(110).

J Phys Chem Lett 2016 Oct 10;7(20):4207-4212. Epub 2016 Oct 10.

Max Planck Institute for Chemical Energy Conversion , Stiftstr. 34-36, 45470 Mülheim an der Ruhr, Germany.

Coupled-cluster theory with single, double, and perturbative triple excitations (CCSD(T)) is widely considered to be the "gold standard" of ab initio quantum chemistry. Using the domain-based pair natural orbital local correlation concept (DLPNO-CCSD(T)), these calculations can be performed on systems with hundreds of atoms at an accuracy of ∼99.9% of the canonical CCSD(T) method. This allows for ab initio calculations providing reference adsorption energetics at solid surfaces with an accuracy approaching 1 kcal/mol. This is an invaluable asset, not least for the assessment of density functional theory (DFT) as the prevalent approach for large-scale production calculations in energy or catalysis applications. Here we use DLPNO-CCSD(T) with embedded cluster models to compute entire adsorbate potential energy surfaces for the binding of a set of prototypical closed-shell molecules (HO, NH, CH, CHOH, CO) to the rutile TiO(110) surface. The DLPNO-CCSD(T) calculations show excellent agreement with available experimental data, even for the "infamous" challenge of correctly predicting the CO adsorption geometry. The numerical efficiency of the approach is within 1 order of magnitude of hybrid-level DFT calculations, hence blurring the borders between reference and production technique.
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http://dx.doi.org/10.1021/acs.jpclett.6b01845DOI Listing
October 2016

Maintaining low non-neoplastic polypectomy rates in high-quality screening colonoscopy.

Gastrointest Endosc 2017 Mar 3;85(3):581-587. Epub 2016 Sep 3.

Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA.

Background And Aims: Non-neoplastic polypectomies (NNPs) add pathology and procedural costs but do not reduce cancer risk and should be minimized. We sought to define the minimal non-neoplastic polypectomy rate (NNPR) for those colonoscopists achieving high-quality colorectal cancer screening based on adenoma detection rates (ADRs).

Methods: NNPRs for colonoscopists achieving high-quality adenoma detection rates were reported to determine minimal NNPR goals. Two approaches to tracking NNPR monitoring were compared: (1) total NNPR, an NNPR inclusive of all non-neoplastic specimens with exclusion of only hyperplastic polyp, sessile serrated polyp, and adenoma; and (2) normal tissue-only NNPR, an NNPR inclusive of those specimens with only normal colonic mucosa or lymphoid follicles.

Results: For those performing colonoscopy with high-quality ADRs (≥25%), half (6/12) of the colonoscopists had a total NNPR of ≤8.5% and 2 gastroenterologists had a total NNPR of ≤3.4%. The mean total NNPR of the cohort was 8.7% versus the normal tissue only NNPR, which was 7.5% (mean difference of 1.2%, standard deviation ± 0.97). The widest variation between total NNPR versus normal tissue only NNPR for any colonoscopist was 2.9%. The total NNPR ranged between 2.6% and 21.3% among 14 colonoscopists.

Conclusions: Colonoscopy with a high-quality ADR can be achieved while maintaining a low total NNPR. A total NNPR, inclusive of all non-neoplastic specimens as an alternative to an approach in which all specimens require individual review in order to select out only normal tissue can be considered for monitoring of NNPR.
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http://dx.doi.org/10.1016/j.gie.2016.08.029DOI Listing
March 2017