PTGL: extension to graph-based topologies of cryo-EM data for large protein structures.

SUMMARY: We provide a software to describe the topology of large protein complexes based mainly on cryo-EM data and stored as macromolecular Crystallographic Information Files (mmCIFs) in the PDB. The software extends the Protein Topology Graph Library and implements an efficient file parser to analyze mmCIFs. The extended Protein Topology Graph Library includes a graph-based representation of the topology of protein complexes on the supersecondary and quaternary structure level. The library holds topology graphs of 151 837 PDB files; 921 of them are large structures. The abstraction of protein structure complexes to undirected labeled graphs enables classification and comparison of large protein complexes on quaternary structure level. AVAILABILITY AND IMPLEMENTATION: Online access at http://ptgl.uni-frankfurt.de. Source code in Java under GNU public license 2.0 at https://github.com/MolBIFFM/vplg. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Prediction and analysis of redox-sensitive cysteines using machine learning and statistical methods.

Reactive oxygen species are produced by a number of stimuli and can lead both to irreversible intracellular damage and signaling through reversible post-translational modification. It is unclear which factors contribute to the sensitivity of cysteines to redox modification. Here, we used statistical and machine learning methods to investigate the influence of different structural and sequence features on the modifiability of cysteines. We found several strong structural predictors for redox modification. Sensitive cysteines tend to be characterized by higher exposure, a lack of secondary structure elements, and a high number of positively charged amino acids in their close environment. Our results indicate that modified cysteines tend to occur close to other post-translational modifications, such as phosphorylated serines. We used these features to create models and predict the presence of redox-modifiable cysteines in human mitochondrial complex I as well as make novel predictions regarding redox-sensitive cysteines in proteins.

Automated classification of radiology reports to facilitate retrospective study in radiology.

Retrospective research is an import tool in radiology. Identifying imaging examinations appropriate for a given research question from the unstructured radiology reports is extremely useful, but labor-intensive. Using the machine learning text-mining methods implemented in LingPipe [1], we evaluated the performance of the dynamic language model (DLM) and the Naïve Bayesian (NB) classifiers in classifying radiology reports to facilitate identification of radiological examinations for research projects. The training dataset consisted of 14,325 sentences from 11,432 radiology reports randomly selected from a database of 5,104,594 reports in all disciplines of radiology. The training sentences were categorized manually into six categories (Positive, Differential, Post Treatment, Negative, Normal, and History). A 10-fold cross-validation [2] was used to evaluate the performance of the models, which were tested in classification of radiology reports for cases of sellar or suprasellar masses and colloid cysts. The average accuracies for the DLM and NB classifiers were 88.5% with 95% confidence interval (CI) of 1.9% and 85.9% with 95% CI of 2.0%, respectively. The DLM performed slightly better and was used to classify 1,397 radiology reports containing the keywords "sellar or suprasellar mass", or "colloid cyst". The DLM model produced an accuracy of 88.2% with 95% CI of 2.1% for 959 reports that contain "sellar or suprasellar mass" and an accuracy of 86.3% with 95% CI of 2.5% for 437 reports of "colloid cyst". We conclude that automated classification of radiology reports using machine learning techniques can effectively facilitate the identification of cases suitable for retrospective research.

Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum.

The endoplasmic reticulum (ER) forms a complex endomembrane network that reaches into the cellular compartments of a neuron, including dendritic spines. Recent work discloses that the spine ER is a dynamic structure that enters and leaves spines. While evidence exists that ER Ca2+ release is involved in synaptic plasticity, the role of spine ER morphology remains unknown. Combining a new 3D spine generator with 3D Ca2+ modeling, we addressed the relevance of ER positioning on spine-to-dendrite Ca2+ signaling. Our simulations, which account for Ca2+ exchange on the plasma membrane and ER, show that spine ER needs to be present in distinct morphological conformations in order to overcome a barrier between the spine and dendritic shaft. We demonstrate that RyR-carrying spine ER promotes spine-to-dendrite Ca2+ signals in a position-dependent manner. Our simulations indicate that RyR-carrying ER can initiate time-delayed Ca2+ reverberation, depending on the precise position of the spine ER. Upon spine growth, structural reorganization of the ER restores spine-to-dendrite Ca2+ communication, while maintaining aspects of Ca2+ homeostasis in the spine head. Our work emphasizes the relevance of precise positioning of RyR-containing spine ER in regulating the strength and timing of spine Ca2+ signaling, which could play an important role in tuning spine-to-dendrite Ca2+ communication and homeostasis.

Percutaneous Transsternal Cryoablation of Ectopic Parathyroid Adenoma in the Anterior Mediastinum.

Ectopic parathyroid adenomas are common in the context of hyperparathyroidism and represent a unique challenge in terms of localization and treatment. Often they are related to higher serum calcium levels than those associated with parathyroid adenomas in typical locations. Additionally, ectopic adenomas often lead to higher morbidity due to failed parathyroid exploration and multiple attempts at surgical removal. We present two cases of computed tomography-guided percutaneous transsternal cryoablation of ectopic parathyroid adenomas in the anterior mediastinum, one after failed surgical resection and the other after failed transarterial embolization. Cryoablation may represent a safe and effective alternative to surgery or embolization and should be included in the therapeutic algorithm in patients with percutaneously accessible lesions.

ACR Appropriateness Criteria® Tinnitus.

Tinnitus is the perception of sound in the absence of an external source. It is a common symptom that can be related to hearing loss and other benign causes. However, tinnitus may be disabling and can be the only symptom in a patient with a central nervous system process disorder. History and physical examination are crucial first steps to determine the need for imaging. CT and MRI are useful in the setting of pulsatile tinnitus to evaluate for an underlying vascular anomaly or abnormality. If there is concomitant asymmetric hearing loss, neurologic deficit, or head trauma, imaging should be guided by those respective ACR Appropriateness Criteria® documents, rather than the presence of tinnitus. Imaging is not usually appropriate in the evaluation of subjective, nonpulsatile tinnitus that does not localize to one ear. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma.

Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk.Experimental Design: 192 patients underwent whole body PET/CT in the Total Therapy 3A (TT3A) trial and were evaluated using three-dimensional region-of-interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal.Results: In multivariate analysis, baseline TLG > 620 g and MTV > 210 cm3 remained a significant factor of poor PFS and OS after adjusting for baseline myeloma variables. Combined with the GEP70 risk score, TLG > 205 g identifies a high-risk-behaving subgroup with poor expected survival. In addition, TLG > 205 g accurately divides ISS stage II patients into two subgroups with similar outcomes to ISS stage I and ISS stage III, respectively.Conclusions: TLG and MTV have significant survival implications at baseline and offer a more precise quantitation of the glycolytic phenotype of active disease. These measures can be assessed more readily than before using FDA-approved software and should be standardized and incorporated into clinical trials moving forward. Clin Cancer Res; 23(8); 1981-7. ©2016 AACR.

ACR Appropriateness Criteria Head Trauma.

Neuroimaging plays an important role in the management of head trauma. Several guidelines have been published for identifying which patients can avoid neuroimaging. Noncontrast head CT is the most appropriate initial examination in patients with minor or mild acute closed head injury who require neuroimaging as well as patients with moderate to severe acute closed head injury. In short-term follow-up neuroimaging of acute traumatic brain injury, CT and MRI may have complementary roles. In subacute to chronic traumatic brain injury, MRI is the most appropriate initial examination, though CT may have a complementary role in select circumstances. Advanced neuroimaging techniques are areas of active research but are not considered routine clinical practice at this time. In suspected intracranial vascular injury, CT angiography or venography or MR angiography or venography is the most appropriate imaging study. In suspected posttraumatic cerebrospinal fluid leak, high-resolution noncontrast skull base CT is the most appropriate initial imaging study to identify the source, with cisternography reserved for problem solving. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria Myelopathy.

Patients presenting with myelopathic symptoms may have a number of causative intradural and extradural etiologies, including disc degenerative diseases, spinal masses, infectious or inflammatory processes, vascular compromise, and vertebral fracture. Patients may present acutely or insidiously and may progress toward long-term paralysis if not treated promptly and effectively. Noncontrast CT is the most appropriate first examination in acute trauma cases to diagnose vertebral fracture as the cause of acute myelopathy. In most nontraumatic cases, MRI is the modality of choice to evaluate the location, severity, and causative etiology of spinal cord myelopathy, and predicts which patients may benefit from surgery. Myelopathy from spinal stenosis and spinal osteoarthritis is best confirmed without MRI intravenous contrast. Many other myelopathic conditions are more easily visualized after contrast administration. Imaging performed should be limited to the appropriate spinal levels, based on history, physical examination, and clinical judgment. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals, and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management.

The disease spectrum currently known as the proteasome-associated autoinflammatory syndromes (PRAAS) was first described in 1939 in patients who presented with recurrent fevers beginning in infancy or early childhood, which were accompanied by nodular erythema, a pernio-like rash, and joint contractures. Since then, several syndromes, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Nakajo-Nishimura syndrome (NNS), joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy (JMP) syndrome, and Japanese autoinflammatory syndrome with lipodystrophy (JASL), have been used to categorize patients with diseases within the same spectrum. Recently, independent studies have identified mutations in the human proteasome subunit ß type 8 (PSMB8) gene, which result in a sustained inflammatory response in all syndromes. Further functional studies not only suggest a causative role of PSMB8 mutations but also imply that they represent one disease spectrum, referred to as PRAAS. In this paper, we review the clinical presentations and laboratory findings of PRAAS, as well as the most recent advances in pathogeneses, diagnosis, and treatment options for patients with diseases in this spectrum.

Server-based enterprise collaboration software improves safety and quality in high-volume PET/CT practice.

With increasing volumes of complex imaging cases and rising economic pressure on physician staffing, timely reporting will become progressively challenging. Current and planned iterations of PACS and electronic medical record systems do not offer workflow management tools to coordinate delivery of imaging interpretations with the needs of the patient and ordering physician. The adoption of a server-based enterprise collaboration software system by our Division of Nuclear Medicine has significantly improved our efficiency and quality of service.