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1.  Dual Inversion Recovery Ultrashort Echo Time (DIR-UTE) Imaging and Quantification of the Zone of Calcified Cartilage (ZCC) 
OBJECTIVE
To develop ultrashort echo time (UTE) magnetic resonance imaging (MRI) techniques to image the zone of calcified cartilage (ZCC), and quantify its T2*, T1 and T1ρ.
DESIGN
In this feasibility study a dual inversion recovery ultrashort echo time (DIR-UTE) sequence was developed for high contrast imaging of the ZCC. T2* of the ZCC was measured with DIR-UTE acquisitions at progressively increasing TEs. T1 of the ZCC was measured with saturation recovery UTE acquisitions at progressively increasing saturation recovery times. T1ρ of the ZCC was measured with spin-locking prepared DIR-UTE acquisitions at progressively increasing spin-locking times.
RESULTS
The feasibility of the qualitative and quantitative DIR-UTE techniques was demonstrated on phantoms and in six cadaveric patellae using a clinical 3T scanner. On average the ZCC has a short T2* ranging from 1.0 to 3.3 ms (mean ± standard deviation = 2.0 ± 1.2 ms), a short T1 ranging from 256 to 389 ms (mean ± standard deviation = 305 ± 45 ms), and a short T1ρ ranging from 2.2 to 4.6 ms (mean ± standard deviation = 3.6 ± 1.2 ms).
CONCLUSION
UTE MR based techniques have been developed for high resolution imaging of the ZCC and quantitative evaluation of its T2*, T1 and T1ρ relaxation times, providing noninvasive assessment of collagen orientation and proteoglycan content at the zone of calcified cartilage and the bone cartilage interface. These measurements may be useful for non-invasive assessment of the ZCC, including understanding the involvement of this tissue component in osteoarthritis.
doi:10.1016/j.joca.2012.09.009
PMCID: PMC4051156  PMID: 23025927
Ultrashort echo time; adiabatic inversion recovery; dual inversion recovery; T1ρ; ZCC
2.  Whole Abdominopelvic Intensity-Modulated Radiation Therapy for Desmoplastic Small Round Cell Tumor after Surgery 
Purpose
Desmoplastic small round cell tumor (DSCRT) is an uncommon pediatric tumor with a poor prognosis. Aggressive multimodality therapy is the current treatment approach, however treatment toxicity is of concern. We report our results with whole abdominopelvic intensity-modulated radiation therapy (WAP-IMRT) as a component of multimodality therapy for DSCRT at a single institution.
Materials/Methods
Medical records of all patients with DSCRT who received WAP-IMRT as part of definitive treatment at MD Anderson (2006-2010) were identified and reviewed.
Results
Eight patients with DSRCT received WAP-IMRT with a median follow-up of 15.2 months. All patients received multiple courses of chemotherapy followed by surgical debulking of intra-abdominal disease; seven also had intraoperative hyperthermic cisplatin. WAP-IMRT was delivered to a total dose of 30 Gy post-operatively; four patients received a simultaneous boost (6-10 Gy) to sites of gross residual disease. Seven patients received concurrent chemotherapy during WAP-IMRT. No RTOG grade 4 nausea, vomiting, or diarrhea occurred during RT. Red cell transfusions were given to two patients to maintain hemoglobin levels of greater than 10 g/dL. Grade 4 cytopenia requiring growth factor support occurred in only one patient; no other significant cytopenias were noted. WAP-IMRT resulted in 25% lower radiation doses to the lumbosacral vertebral bodies and pelvic bones than conventional RT plans. The median time to local or distant failure after WAP-IMRT was 8.73 months in seven patients. One patient who had completed RT 20 months before the last follow-up remains alive without evidence of disease. Five patients (63%) experienced treatment failure in the abdomen. Distant failure occurred in three patients (37.5%).
Conclusions
WAP-IMRT with concurrent radiosensitizing chemotherapy was well tolerated after aggressive surgery for DSCRT. Enhanced bone sparing with IMRT probably accounts for the low hematologic toxicity (vs. conventional WAP RT). This modality should be considered as an additional local-regional control option for DSRCT.
doi:10.1016/j.ijrobp.2011.06.1985
PMCID: PMC4005898  PMID: 22104361
Desmoplastic small round-cell tumor (DSRCT); whole abdominopelvic radiotherapy; pediatric cancer; sarcoma; peritoneal sarcomatosis; IMRT
3.  Spinal 5-HT3 receptors facilitate behavioral hypersensitivity induced by elevated calcium channel alpha-2-deltal-1 protein 
Background
Peripheral nerve injury induces upregulation of the calcium channel alpha-2-delta-1 proteins in the dorsal root ganglia and dorsal spinal cord that correlates with neuropathic pain development. Similar behavioral hypersensitivity was also observed in injury-free transgenic mice (TG) over-expressing the alpha-2-delta-1 proteins in neuronal tissues. To investigate pathways regulating alpha-2-delta-1 protein-mediated behavioral hypersensitivity, we examined whether spinal serotonergic 5-HT3 receptors are involved similarly in the modulation of behavioral hypersensitivity induced by either peripheral nerve injury in a nerve injury model or neuronal alpha-2-delta-1 over-expression in the TG model.
Methods
The effects of blocking behavioral hypersensitivity in these two models by intrathecal or systemic injections of 5-HT3 receptor antagonist, ondansetron, were compared.
Results
Our data indicated that the TG mice displayed similar behavioral hypersensitivities to non-painful mechanical stimulation (tactile allodynia) and painful thermal stimulation (thermal hyperalgesia) as that observed in the nerve injury model. Interestingly, tactile allodynia and thermal hyperalgesia in both models can be blocked similarly by intrathecal, but not systemic, injection of ondansetron.
Conclusions
Our data suggest that spinal 5-HT3 receptors are likely play a role in alpha-2-delta-1-mediated behavioral hypersensitivities through a descending serotonergic facilitation.
doi:10.1002/j.1532-2149.2012.00221.x
PMCID: PMC3548964  PMID: 23065867
4.  Validation of Recursive Partitioning Analysis and Diagnosis-Specific Graded Prognostic Assessment in patients treated initially with radiosurgery alone 
Journal of neurosurgery  2012;117(0):38-44.
Object
Brain metastases present a therapeutic challenge because patients with metastatic cancers live longer now than in the recent past due to systemic therapies that, while effective, may not penetrate the blood-brain barrier. In the present study the authors sought to validate the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), a new prognostic index that takes into account the histological characteristics of the primary tumor, and the Radiation Therapy Ontology Group Recursive Partitioning Analysis (RPA) system by using a single-institution database of patients who were treated initially with stereotactic radiosurgery (SRS) alone for brain metastases.
Methods
Investigators retrospectively identified adult patients who had undergone SRS at a single institution, MD Anderson Cancer Center, for initial treatment of brain metastases between 2003 and 2010 but excluded those who had undergone craniotomy and/or whole-brain radiation therapy at an earlier time; the final number was 251. The Leksell Gamma Knife was used to treat 223 patients, and a linear accelerator was used to treat 28 patients. The patient population was grouped according to DS-GPA scores as follows: 0–0.5 (7 patients), 1 (33 patients), 1.5 (25 patients), 2 (63 patients), 2.5 (14 patients), 3 (68 patients), and 3.5–4 (41 patients). The same patients were also grouped according to RPA classes: 1 (24 patients), 2 (216 patients), and 3 (11 patients). The most common histological diagnoses were non–small cell lung cancer (34%), melanoma (29%), and breast carcinoma (16%). The median number of lesions was 2 (range 1–9) and the median total tumor volume was 0.9 cm3 (range 0.3–22.9 cm3). The median radiation dose was 20 Gy (range 14–24 Gy). Stereotactic radiosurgery was performed as the sole treatment (62% of patients) or combined with a salvage treatment consisting of SRS (22%), whole-brain radiation therapy (12%), or resection (4%). The median duration of follow-up was 9.4 months.
Results
In this patient group the median overall survival was 11.1 months. The DS-GPA prognostic index divided patients into prognostically significant groups. Median survival times were 2.8 months for DS-GPA Scores 0–0.5, 3.9 months for Score 1, 6.6 months for Score 1.5, 12.9 months for Score 2, 11.9 months for Score 2.5, 12.2 months for Score 3, and 31.4 months for Scores 3.5–4 (p < 0.0001). In the RPA groups, the median overall survival times were 38.8 months for Class 1, 9.4 months for Class 2, and 2.8 months for Class 3 (p < 0.0001). Neither the RPA class nor the DS-GPA score was prognostic for local tumor control or new lesion–free survival. A multivariate analysis revealed that patient age > 60 years, Karnofsky Performance Scale score ≤ 80%, and total lesion volume > 2 cm3 were significant adverse prognostic factors for overall survival.
Conclusions
Application of the DS-GPA to a database of patients with brain metastases who were treated with SRS appears to be valid and offers additional prognostic refinement over that provided by the RPA. The DS-GPA may also allow for improved selection of patients to undergo initial SRS alone and should be studied further.
doi:10.3171/2012.3.GKS1289
PMCID: PMC3910154  PMID: 23205787
stereotactic radiosurgery; Gamma Knife surgery; brain metastasis; prognostic factor; Diagnosis-Specific Graded Prognostic Assessment; Recursive Partitioning Analysis
5.  Bipartite Medial Cuneiform: Case Report and Retrospective Review of 1000 Magnetic Resonance (MR) Imaging Studies 
Case Reports in Medicine  2014;2014:130979.
Objective. To present a unique case report of a Lisfranc fracture in a patient with a bipartite medial cuneiform and to evaluate the prevalence of the bipartite medial cuneiform in a retrospective review of 1000 magnetic resonance (MR) imaging studies of the foot. Materials and Methods. Case report followed by a retrospective review of 1000 MR imaging studies of the foot for the presence or absence of a bipartite medial cuneiform. Results. The incidence of the bipartite medial cuneiform is 0.1%. Conclusion. A bipartite medial cuneiform is a rare finding but one with both clinical and surgical implications.
doi:10.1155/2014/130979
PMCID: PMC3920919  PMID: 24587806
6.  Correction: Building Large Collections of Chinese and English Medical Terms from Semi-Structured and Encyclopedia Websites 
PLoS ONE  2013;8(12):10.1371/annotation/fab3bd89-3ae3-445f-a418-207bbd7d4377.
doi:10.1371/annotation/fab3bd89-3ae3-445f-a418-207bbd7d4377
PMCID: PMC3865328
7.  Phase I/II Trial of Single Session Stereotactic Body Radiotherapy for Previously Un-irradiated Spinal Metastases 
Cancer  2012;118(20):5069-5077.
Background
This Phase I/II study tests the hypothesis that single-fraction SBRT for previously un-irradiated spinal metastases is a safe, feasible, and efficacious treatment approach.
Methods
All patients were evaluated by a multidisciplinary team. Spinal MRI was performed before treatment and at regular intervals to both define target volume and response to treatment. SBRT was delivered to a peripheral dose of 16–24 Gy in 1 fraction while limiting dose to the spinal cord. Higher doses were used for renal cell histology. The NCI Common Toxicity Criteria 2.0 and McCormick neurological function score were used as toxicity assessment tools.
Results
A total of 61 patients harboring 63 tumors of the non-cervical spine were enrolled and treated with SBRT between 2005 and 2010 on a prospective Phase I/II trial at the University of Texas M. D. Anderson Cancer Center. Mean follow-up was 20 months. Actuarial 18-month imaging local control for all patients was 88%. Actuarial 18-month overall survival for all patients was 64%. Median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology and SBRT dose. Two patients experienced radiation adverse events (Grade 3 or higher). Actuarial 18-month freedom from neurologic deterioration from any cause as was 82%.
Conclusions
This Phase I/II data support an expanded indication for SBRT as first-line treatment of selected spinal metastases patients. Additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication.
doi:10.1002/cncr.27530
PMCID: PMC3635840  PMID: 22511344
radiation; stereotactic body radiotherapy; radiosurgery; spinal metastases
8.  An intraoperative multimodal neurophysiologic approach to successful resection of precentral gyrus epileptogenic lesions 
Epilepsia  2012;53(4):e75-e79.
Cortical dysplasias (CDs) are highly epileptogenic lesions with a good prognosis of seizure freedom, if totally resected. However, their accurate delineation and resection can be difficult, and depend on the extent of pathology and lesion location. Intraoperative neurophysiologic assessments are valuable in these situations. We present an illustrative case of intractable epilepsy where judicious use of intraoperative neurophysiologic–techniques guided resection of precentral CD, under general anesthesia and in the absence of preoperative electrophysiologic mapping data. Ictal onset was accurately delineated using electrocorticography (ECoG). Phase reversal of the median somatosensory-evoked potentials (MSSEPs) localized the central sulcus (CS). Motor evoked potentials (MEPs) triggered by high-frequency monopolar anodal electrical cortical stimulation at the primary motor cortex (PMC) threshold delineated the PMC. Using this technique, PMC and the corticospinal tract (CST) were continuously monitored during resection. No changes in MEPs from the pre-resection baseline were seen; no residual abnormal activity was present in the postresection ECoG. The patient emerged from surgery without deficits and has been seizure free during a 10-month follow-up. Staged multimodal intraoperative neurophysiology can be used successfully under general anesthesia to guide resection of epileptogenic lesions within the precentral gyrus, as an add-on or, in certain situations, as a viable alternative to preoperative electrophysiologic mapping.
doi:10.1111/j.1528-1167.2011.03400.x
PMCID: PMC3779883  PMID: 22309192
Electrocorticography; Motor mapping; Cortical dysplasia; Central sulcus
9.  A classification approach to coreference in discharge summaries: 2011 i2b2 challenge 
Objective
To create a highly accurate coreference system in discharge summaries for the 2011 i2b2 challenge. The coreference categories include Person, Problem, Treatment, and Test.
Design
An integrated coreference resolution system was developed by exploiting Person attributes, contextual semantic clues, and world knowledge. It includes three subsystems: Person coreference system based on three Person attributes, Problem/Treatment/Test system based on numerous contextual semantic extractors and world knowledge, and Pronoun system based on a multi-class support vector machine classifier. The three Person attributes are patient, relative and hospital personnel. Contextual semantic extractors include anatomy, position, medication, indicator, temporal, spatial, section, modifier, equipment, operation, and assertion. The world knowledge is extracted from external resources such as Wikipedia.
Measurements
Micro-averaged precision, recall and F-measure in MUC, BCubed and CEAF were used to evaluate results.
Results
The system achieved an overall micro-averaged precision, recall and F-measure of 0.906, 0.925, and 0.915, respectively, on test data (from four hospitals) released by the challenge organizers. It achieved a precision, recall and F-measure of 0.905, 0.920 and 0.913, respectively, on test data without Pittsburgh data. We ranked the first out of 20 competing teams. Among the four sub-tasks on Person, Problem, Treatment, and Test, the highest F-measure was seen for Person coreference.
Conclusions
This system achieved encouraging results. The Person system can determine whether personal pronouns and proper names are coreferent or not. The Problem/Treatment/Test system benefits from both world knowledge in evaluating the similarity of two mentions and contextual semantic extractors in identifying semantic clues. The Pronoun system can automatically detect whether a Pronoun mention is coreferent to that of the other four types. This study demonstrates that it is feasible to accomplish the coreference task in discharge summaries.
doi:10.1136/amiajnl-2011-000734
PMCID: PMC3422828  PMID: 22505762
Natural language processing; information retrieval; clinical decision support; biomedical informatics; text processing; medical records
10.  Feature engineering combined with machine learning and rule-based methods for structured information extraction from narrative clinical discharge summaries 
Objective
A system that translates narrative text in the medical domain into structured representation is in great demand. The system performs three sub-tasks: concept extraction, assertion classification, and relation identification.
Design
The overall system consists of five steps: (1) pre-processing sentences, (2) marking noun phrases (NPs) and adjective phrases (APs), (3) extracting concepts that use a dosage-unit dictionary to dynamically switch two models based on Conditional Random Fields (CRF), (4) classifying assertions based on voting of five classifiers, and (5) identifying relations using normalized sentences with a set of effective discriminating features.
Measurements
Macro-averaged and micro-averaged precision, recall and F-measure were used to evaluate results.
Results
The performance is competitive with the state-of-the-art systems with micro-averaged F-measure of 0.8489 for concept extraction, 0.9392 for assertion classification and 0.7326 for relation identification.
Conclusions
The system exploits an array of common features and achieves state-of-the-art performance. Prudent feature engineering sets the foundation of our systems. In concept extraction, we demonstrated that switching models, one of which is especially designed for telegraphic sentences, improved extraction of the treatment concept significantly. In assertion classification, a set of features derived from a rule-based classifier were proven to be effective for the classes such as conditional and possible. These classes would suffer from data scarcity in conventional machine-learning methods. In relation identification, we use two-staged architecture, the second of which applies pairwise classifiers to possible candidate classes. This architecture significantly improves performance.
doi:10.1136/amiajnl-2011-000776
PMCID: PMC3422834  PMID: 22586067
xy804280; thu; text processing; natural language processing; medical records
11.  Named entity recognition of follow-up and time information in 20 000 radiology reports 
Objective
To develop a system to extract follow-up information from radiology reports. The method may be used as a component in a system which automatically generates follow-up information in a timely fashion.
Methods
A novel method of combining an LSP (labeled sequential pattern) classifier with a CRF (conditional random field) recognizer was devised. The LSP classifier filters out irrelevant sentences, while the CRF recognizer extracts follow-up and time phrases from candidate sentences presented by the LSP classifier.
Measurements
The standard performance metrics of precision (P), recall (R), and F measure (F) in the exact and inexact matching settings were used for evaluation.
Results
Four experiments conducted using 20 000 radiology reports showed that the CRF recognizer achieved high performance without time-consuming feature engineering and that the LSP classifier further improved the performance of the CRF recognizer. The performance of the current system is P=0.90, R=0.86, F=0.88 in the exact matching setting and P=0.98, R=0.93, F=0.95 in the inexact matching setting.
Conclusion
The experiments demonstrate that the system performs far better than a baseline rule-based system and is worth considering for deployment trials in an alert generation system. The LSP classifier successfully compensated for the inherent weakness of CRF, that is, its inability to use global information.
doi:10.1136/amiajnl-2012-000812
PMCID: PMC3422839  PMID: 22771530
Text processing; natural language processing; medical records
12.  Building Large Collections of Chinese and English Medical Terms from Semi-Structured and Encyclopedia Websites 
PLoS ONE  2013;8(7):e67526.
To build large collections of medical terms from semi-structured information sources (e.g. tables, lists, etc.) and encyclopedia sites on the web. The terms are classified into the three semantic categories, Medical Problems, Medications, and Medical Tests, which were used in i2b2 challenge tasks. We developed two systems, one for Chinese and another for English terms. The two systems share the same methodology and use the same software with minimum language dependent parts. We produced large collections of terms by exploiting billions of semi-structured information sources and encyclopedia sites on the Web. The standard performance metric of recall (R) is extended to three different types of Recall to take the surface variability of terms into consideration. They are Surface Recall (), Object Recall (), and Surface Head recall (). We use two test sets for Chinese. For English, we use a collection of terms in the 2010 i2b2 text. Two collections of terms, one for English and the other for Chinese, have been created. The terms in these collections are classified as either of Medical Problems, Medications, or Medical Tests in the i2b2 challenge tasks. The English collection contains 49,249 (Problems), 89,591 (Medications) and 25,107 (Tests) terms, while the Chinese one contains 66,780 (Problems), 101,025 (Medications), and 15,032 (Tests) terms. The proposed method of constructing a large collection of medical terms is both efficient and effective, and, most of all, independent of language. The collections will be made publicly available.
doi:10.1371/journal.pone.0067526
PMCID: PMC3706590  PMID: 23874426
13.  The Embryonic Transcriptome of the Red-Eared Slider Turtle (Trachemys scripta) 
PLoS ONE  2013;8(6):e66357.
The bony shell of the turtle is an evolutionary novelty not found in any other group of animals, however, research into its formation has suggested that it has evolved through modification of conserved developmental mechanisms. Although these mechanisms have been extensively characterized in model organisms, the tools for characterizing them in non-model organisms such as turtles have been limited by a lack of genomic resources. We have used a next generation sequencing approach to generate and assemble a transcriptome from stage 14 and 17 Trachemys scripta embryos, stages during which important events in shell development are known to take place. The transcriptome consists of 231,876 sequences with an N50 of 1,166 bp. GO terms and EC codes were assigned to the 61,643 unique predicted proteins identified in the transcriptome sequences. All major GO categories and metabolic pathways are represented in the transcriptome. Transcriptome sequences were used to amplify several cDNA fragments designed for use as RNA in situ probes. One of these, BMP5, was hybridized to a T. scripta embryo and exhibits both conserved and novel expression patterns. The transcriptome sequences should be of broad use for understanding the evolution and development of the turtle shell and for annotating any future T. scripta genome sequences.
doi:10.1371/journal.pone.0066357
PMCID: PMC3686863  PMID: 23840449
14.  Aging phenotypes in cultured normal human mammary epithelial cells are correlated with decreased telomerase activity independent of telomere length 
Genome Integrity  2013;4:4.
Background
Shortening of telomeres, which are essential for maintenance of genomic integrity, is a mechanism commonly associated with the aging process. Here we ascertained whether changes in telomere lengths or telomerase activity correlated with age in normal human mammary epithelial cells (HMEC), or with phenotypes of aging in breast. Accordingly, flow cytometry fluorescence in situ hybridization (flowFISH) was used to determine relative telomere lengths (RTL), and telomerase activity was measured by the telomeric repeat amplification protocol (TRAP), in a collection of 41 primary HMEC strains established from women aged 16 to 91 years.
Results
RTL measurements of HMEC strains that were heterogeneous with respect to lineage composition revealed no significant associations between telomere length with age, maximum observed population doublings, or with lineage composition of the strains. However, within strains, luminal epithelial and cKit-expressing epithelial progenitor cells that were flow cytometry-enriched from individual HMEC strains exhibited significantly shorter telomeres relative to isogenic myoepithelial cells (P < 0.01). In unsorted strains, detectable telomerase activity did not correlate with RTL. Telomerase activity declined with age; the average age of strains that exhibited TRAP activity was 29.7 ± 3.9y, whereas the average age of strains with no detectable TRAP activity was 49.0 ± 4.9y (P < 0.01). Non-detectable TRAP activity also was correlated with phenotypes of aging previously described in HMEC strains; increased proportions of CD227-expressing luminal epithelial cells (P < 0.05) and cKit-expressing progenitor cells (P < 0.05).
Conclusions
Telomere shortening did not correlate with the chronological ages of HMEC strains, whereas decreased telomerase activity correlated with age and with lineage distribution phenotypes characteristic of aging.
doi:10.1186/2041-9414-4-4
PMCID: PMC3672013  PMID: 23718190
Aging; Human mammary epithelial cell; HMEC; Telomere; Telomerase
15.  CHMP6 and VPS4A mediate recycling of Ras to the plasma membrane to promote growth factor signaling 
Oncogene  2012;31(43):4630-4638.
While Ras is well-known to function on the plasma membrane (PM) to mediate growth factor signaling, increasing evidence suggests that Ras has complex roles in the cytoplasm. To uncover these roles, we screened a cDNA library and isolated H-Ras-binding proteins that also influence Ras functions. Many isolated proteins regulate trafficking involving endosomes; CHMP6/VPS20 and VPS4A, which interact with ESCRT-III, were chosen for further study. We showed that the binding is direct and occurs in endosomes. Furthermore, the binding is most efficient when H-Ras has a functional effector-binding-loop and is GTP-bound and ubiquitylated. CHMP6 and VPS4A also bound N-Ras, but not K-Ras. Repressing CHMP6 and VPS4A blocked Ras-induced transformation, which correlated with inefficient Ras localization to the PM as measured by cell fractionation and photobleaching. Moreover, silencing CHMP6 and VPS4A also blocked EGFR recycling. These data suggest that Ras interacts with key ESCRT-III components to promote recycling of itself and EGFR back to the PM to create a positive feedback loop to enhance growth factor signaling.
doi:10.1038/onc.2011.607
PMCID: PMC3326214  PMID: 22231449
signal transduction; oncogene; tumorigenesis; trafficking; ESCRT-III
16.  A prospective analysis of the clinical effects of stereotactic body radiation therapy in cancer patients with spinal metastases without spinal cord compression 
The lancet oncology  2012;13(4):395-402.
Summary
Background
This study investigated the clinical benefit of using hypofractionated stereotactic body radiotherapy (SBRT) to manage spinal metastases in patients with cancer and to reduce cancer-related symptoms.
Methods
Cancer patients (n=149) with mechanically stable, non–cord-compressing, spinal metastases (n=166) were treated by SBRT in a phase I/II study. Patients received a total dose of 27–30 Gy, typically in three fractions. Symptoms were measured repeatedly by the Brief Pain Inventory (BPI) and the M. D. Anderson Symptom Inventory (MDASI). The primary endpoint was to establish the safety, feasibility, and efficacy of using a CT-on-Rails or Trilogy Stereotactic Spine Radiation Therapy system to treat spinal and paraspinal tumors and to document pain relief and toxicity associated with such treatment. Symptom outcomes were estimated according to protocol using descriptive analysis and ordinal regression modeling. This is the final report for the completed enrollment and follow-up.
Findings
The median follow-up time was 15·9 (interquartile range 9·5–30·3) months and the mean was 20·9 (SD=17·1) months. The actuarial tumor progression-free survival rates at one year and two years post-SBRT were 80·5% and 72·4%, respectively. Patients reported significant MDASI pain reduction (p=0·00003) during the six months post-SBRT. Patients reporting no pain from bone metastases on the BPI increased from 39/149 (26·2%) before SBRT to 55/102 (53·9%) six months post-SBRT (p<0·0001). BPI pain reduction from baseline to four weeks post-SBRT was clinically meaningful (effect size=0·47, p<0·01). These improvements were accompanied by significant reduction in opioid use during the six months post-SBRT (p<0·05) and a significant reduction in MDASI symptom interference with daily life (p<0·01).. Only a few instances of nonneurological grade 3 toxicities occurred (one report each of nausea, vomiting, diarrhea, fatigue, dysphagia, neck pain, diaphoresis, two reports of pain associated with severe tongue edema and trismus, and 3 reports of noncardiac chest pain). No grade 4 toxicities occurred.
Interpretation
SBRT is an effective primary or salvage treatment of mechanically stable spinal metastasis. Significant reduction in patient-reported pain and other symptoms was evident six months post-SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities.
doi:10.1016/S1470-2045(11)70384-9
PMCID: PMC3605896  PMID: 22285199
SBRT; pain; symptoms; patient-reported outcomes (PROs); spine; metastasis
17.  Escorting Ras 
Small GTPases  2012;3(4):236-239.
Ras proteins are best known to function on the plasma membrane to mediate growth factor signaling. Controlling the length of time that Ras proteins stay on the plasma membrane is an effective way to properly modulate the intensity and duration of growth factor signaling. It has been shown previously that H- and N-Ras proteins in the GTP-bound state can be ubiquitylated via a K-63 linkage, which leads to endosome internalization and results in a negative-feedback loop for efficient signal attenuation. In a more recent study, two new Ras effectors have been isolated, CHMP6 and VPS4A, which are components of the ESCRT-III complex, best known for mediating protein sorting in the endosomes. Surprisingly, these molecules are required for efficient Ras-induced transformation. They apparently do so by controlling recycling of components of the Ras pathway back to the plasma membrane, thus creating a positive-feedback loop to enhance growth factor signaling. These results suggest the fates of endosomal Ras proteins are complex and dynamic — they can be either stored and/or destroyed or recycled. Further work is needed to decipher how the fate of these endosomal Ras proteins is determined.
doi:10.4161/sgtp.20460
PMCID: PMC3520888  PMID: 22735486
ubiquitination; trafficking; desensitization; G-protein; signal transduction; post-translational modfication; endocytosis; cancer; oncogene; tumorigenesis
18.  Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline 
Practical Radiation Oncology  2012;2(3):210-225.
Purpose
To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases.
Methods and Materials
Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management.
Results
The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation).
Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3).
Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3).
Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3).
It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful.
Conclusions
Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).
doi:10.1016/j.prro.2011.12.004
PMCID: PMC3808749  PMID: 24175001
19.  Schizosaccharomyces pombe Arc3 is a conserved subunit of the Arp2/3 complex required for polarity, actin organization, and endocytosis 
Yeast (Chichester, England)  2011;28(6):495-503.
We characterized the Schizosaccharomyces pombe arc3 gene, whose product shares sequence homology with that of the budding yeast ARC18 and human ARPC3/p21 subunits of the Arp2/3 complex. Our data showed that Arc3p co-localizes with F-actin patches at the cell ends, but not with F-actin cables or the equatorial actin ring, and binds other subunits of the Arp2/3 complex. Gene deletion analysis showed that arc3 is essential for viability. When arc3 expression was repressed, F-actin patches became dispersed throughout the cell with greatly reduced mobility. Furthermore in arc3-repressed cells, endocytosis was also inhibited. Human ARPC3 rescued the viability of the S. pombe arc3 null mutant; in addition, ARPC3 also localizes to F-actin patches in human cells. These data suggest that Arc3p is an evolutionarily conserved subunit of the Arp2/3 complex required for proper F-actin organization and efficient endocytosis.
doi:10.1002/yea.1853
PMCID: PMC3107344  PMID: 21449051
20.  Busy traveling Ras 
Cell Cycle  2011;10(8):1180-1181.
doi:10.4161/cc.10.8.15259
PMCID: PMC3117130  PMID: 21436618
21.  Use of a Deformable Atlas to Identify Cryptic Critical Structures in the Treatment of Glioblastoma Multiforme 
PLoS ONE  2012;7(3):e32098.
Dose constraints for traditional neural critical structures (e.g. optic chiasm, brain stem) are a standard component of planning radiation therapy to the central nervous system. Increasingly, investigators are becoming interested in accounting for the dose delivered to other non-target neural structures (e.g. hippocampi), which are not easily identified on axial imaging. In this pilot study, a commercially available digital atlas was used to identify cryptic neural structures (hippocampus, optic radiations, and visual cortices) in 6 patients who received intensity modulated radiation therapy (IMRT) as part of multimodal management of glioblastoma multiforme (GBM). The patient's original IMRT plans were re-optimized, with avoidance parameters for the newly identified critical structures. Re-optimization was able to reduce both mean and maximum dose to the volumes of interest, with a more pronounced effect for contralateral structures. Mean dose was reduced by 11% and 3% to contralateral and ipsilateral structures, respectively, with comparable reduction in maximum dose of 10% and 2%, respectively. Importantly, target coverage was not compromised, with an average change in coverage of 0.2%. Overall, our results demonstrate the feasibility of incorporating tools for cryptic critical structure identification into the treatment planning process for GBM.
doi:10.1371/journal.pone.0032098
PMCID: PMC3312881  PMID: 22461883
22.  Neurophysiological correlates of object recognition in the dorsal subiculum 
The medial temporal lobe (MTL) encompasses a network of interconnected cortical areas that is considered the neural substrate for some types of memory, such as spatial, episodic, recognition, and associative memory. Within the MTL, the subiculum has been well characterized in terms of its connectivity and structure, but its functional role remains elusive. A long-held view is that the subiculum is mainly involved in spatial encoding because it exhibits spatially selective firing and receives prominent projections from the CA1 field, which is an essential substrate for spatial memory. However, the dorsal subiculum (DS) is also reciprocally connected to the perirhinal and postrhinal cortices, which are critically involved in recognition memory. This connectivity pattern suggests that DS might encode not only spatial signals but also recognition signals. Here, we examined this hypothesis by recording with multi-electrodes in DS and CA1 of freely behaving mice, as they performed the novel object recognition (NOR) task. Analysis of network oscillations revealed that theta power was significantly higher in DS when mice explored novel objects as compared to familiar objects and that this theta modulation was absent in CA1. We also found significant differences in coherence between DS and CA1, in the theta and gamma bands, depending on whether mice examined objects or engaged in spatial exploration. Furthermore, single-unit recordings revealed that DS cells did not exhibit phase-locked firing to theta and differed from CA1 place cells in that they had multiple peaks of spatially selective firing. We also detected DS units that were responsive specifically to novel object exploration, indicating that a subset of DS neurons were tuned to novelty during the NOR task. We have thus identified clear neurophysiological correlates for recognition within the DS, at the network and single-unit levels, strongly suggesting that it participates in encoding recognition-related signals.
doi:10.3389/fnbeh.2012.00046
PMCID: PMC3400129  PMID: 22833721
novel object; theta; gamma; coherence; place cell; mouse
23.  The eIF3 interactome reveals the translasome, a supercomplex linking protein synthesis and degradation machineries 
Molecular cell  2009;36(1):141-152.
Summary
eIF3 promotes translation initiation, but relatively little is known about its full range of activities in the cell. Here, we employed affinity purification and highly sensitive LC-MS/MS to decipher the fission yeast eIF3 interactome, which was found to contain 230 proteins. eIF3 assembles into a large supercomplex, the translasome, which contains elongation factors, tRNA-synthetases, 40S and 60S ribosomal proteins, chaperones, and the proteasome. eIF3 also associates with ribosome biogenesis factors and the importins-β Kap123p and Sal3p. Our genetic data indicated that the binding to both importins-β is essential for cell growth, and photobleaching experiments revealed a critical role for Sal3p in the nuclear import of one of the translasome constituents, the proteasome. Our data reveal the breadth of the eIF3 interactome and suggest that factors involved in translation initiation, ribosome biogenesis, translation elongation, quality control, and transport are physically linked to facilitate efficient protein synthesis.
doi:10.1016/j.molcel.2009.09.026
PMCID: PMC2789680  PMID: 19818717
24.  Mesenchymal Stem Cells Can Participate in Ischemic Neovascularization 
Plastic and reconstructive surgery  2009;123(2 Suppl):45S-55S.
Background
Cells from the bone marrow contribute to ischemic neovascularization, but the identity of these cells remains unclear. The authors identify mesenchymal stem cells as a bone marrow–derived progenitor population that is able to engraft into peripheral tissue in response to ischemia.
Methods
A murine model of skin ischemia was used. Bone marrow, blood, and skin were harvested at different time points and subjected to flow cytometric analysis for mesenchymal and hematopoietic markers (n = 3 to 7 per time point). Using a parabiotic model pairing donor green fluorescent protein (GFP)–positive with recipient wild-type mice, progenitor cell engraftment was examined in ischemic tissue by fluorescence microscopy, and engrafted cells were analyzed by flow cytometry for endothelial and mesenchymal markers. In vitro, the ability of both bone marrow–and adipose-derived mesenchymal stem cells to adopt endothelial characteristics was examined by analyzing (1) the ability of mesenchymal stem cells to take up DiI-acetylated low-density lipoprotein and Alexa Fluor lectin, and (2) phenotypic changes of mesenchymal stem cells co-cultured with GFP-labeled endothelial cells or under hypoxic/vascular endothelial growth factor stimulation.
Results
In vivo, the bone marrow mesenchymal stem cell population decreased significantly immediately after surgery, with subsequent engraftment of these cells in ischemic tissue. Engrafted cells lacked the panhematopoietic antigen CD45, consistent with a mesenchymal origin. In vitro, bone marrow–and adipose-derived mesenchymal stem cells took up DiI-acetylated low-density lipoprotein and Alexa Fluor lectin, and expressed endothelial markers under hypoxic conditions.
Conclusions
The authors’ data suggest that mesenchymal precursor cells can give rise to endothelial progenitors. Consequently, cell-based therapies augmenting the mesenchymal stem cell population could represent powerful alternatives to current therapies for ischemic vascular disease.
doi:10.1097/PRS.0b013e318191be4a
PMCID: PMC2878772  PMID: 19182663
25.  Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition 
Neurobiology of aging  2007;30(3):407-419.
Dysregulated cholesterol metabolism is a major risk factor for atherosclerosis and other late-onset disorders, such as Alzheimer’s disease. The scavenger receptor, class B, type I (SR-BI) is critical in maintaining the homeostasis of cholesterol and α-tocopherol. SR-BI binds high density lipoproteins (HDL) and mediates the selective transfer of cholesteryl esters and α-tocopherol from circulating HDL to cells. SR-BI is also involved in reverse cholesterol transport from peripheral tissues into the liver. Previous studies using SR-BI genetic knockout mice indicated that the deletion of SR-BI resulted in an accelerated onset of atherosclerosis. We hypothesized that SR-BI dependent lipid dysregulation might disrupt brain function leading to cognitive impairment. Here, we report that very old SR-BI knockout mice show deficient synaptic plasticity (long-term potentiation) in the CA1 region of the hippocampus. Very old SR-BI KO mice also display selective impairments in recognition memory and spatial memory. Thus, SR-BI influences neural and cognitive processes, a finding that highlights the contribution of cholesterol and α-tocopherol homeostasis in proper cognitive function.
doi:10.1016/j.neurobiolaging.2007.07.006
PMCID: PMC2665297  PMID: 17719144
cholesterol; HDL; α-tocopherol; scavenger receptors; lipid metabolism; atherosclerosis; late-onset Alzheimer’s disease; LTP; recognition memory; spatial memory

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