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1.  Triple Isotope Effects Support Concerted Hydride and Proton Transfer and Promoting Vibrations in Human Heart Lactate Dehydrogenase 
Journal of the American Chemical Society  2016;138(45):15004-15010.
Transition path sampling simulations have proposed that human heart lactate dehydrogenase (LDH) employs protein promoting vibrations (PPVs) on the femtosecond (fs) to picosecond (ps) time scale to promote crossing of the chemical barrier. This chemical barrier involves both hydride and proton transfers to pyruvate to form l-lactate, using reduced nicotinamide adenine dinucleotide (NADH) as the cofactor. Here we report experimental evidence from three types of isotope effect experiments that support coupling of the promoting vibrations to barrier crossing and the coincidence of hydride and proton transfer. We prepared the native (light) LDH and a heavy LDH labeled with 13C, 15N, and nonexchangeable 2H (D) to perturb the predicted PPVs. Heavy LDH has slowed chemistry in single turnover experiments, supporting a contribution of PPVs to transition state formation. Both the [4-2H]NADH (NADD) kinetic isotope effect and the D2O solvent isotope effect were increased in dual-label experiments combining both NADD and D2O, a pattern maintained with both light and heavy LDHs. These isotope effects support concerted hydride and proton transfer for both light and heavy LDHs. Although the transition state barrier-crossing probability is reduced in heavy LDH, the concerted mechanism of the hydride–proton transfer reaction is not altered. This study takes advantage of triple isotope effects to resolve the chemical mechanism of LDH and establish the coupling of fs-ps protein dynamics to barrier crossing.
Graphical abstract
PMCID: PMC5244818  PMID: 27766841
2.  Point/Counterpoint: Is stereotactic radiosurgery needed following resection of brain metastasis? 
Neuro-Oncology  2015;18(1):12-15.
PMCID: PMC4677423  PMID: 26667138
brain metastasis; postoperative radiosurgery; whole brain radiotherapy
3.  Diffusion tensor imaging measures of white matter compared to myelin basic protein immunofluorescence in tissue cleared intact brains 
Data in Brief  2016;10:438-443.
We provide datasets from combined ex vivo diffusion tensor imaging (DTI) and Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY) performed on intact mouse brains. DTI-derived measures of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were compared to antibody-based labeling of myelin basic protein (MBP), as measured by fluorescence microscopy. We used a customized CLARITY hydrogel solution to facilitate whole brain tissue clearing and subsequent immunolabeling. We describe how CLARITY was made compatible with magnetic resonance imaging with the intention of facilitating future multimodal imaging studies that may combine noninvasive imaging with 3D immunohistochemistry. These data and methods are related to the accompanying research article entitled, ‘The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains’ (E.H. Chang, M. Argyelan, M. Aggarwal, T-S. Chandon, K.H. Karlsgodt, S. Mori, A.K. Malhotra, 2016) [1].
PMCID: PMC5198630  PMID: 28054004
DTI; CLARITY; Multimodal imaging; Myelination; Radial diffusivity
4.  Mechanism of Thermal Adaptation in the Lactate Dehydrogenases 
The journal of physical chemistry. B  2015;119(49):15256-15262.
The mechanism of thermal adaptation of enzyme function at the molecular level is poorly understood but is thought to lie within the structure of the protein or its dynamics. Our previous work on pig heart lactate dehydrogenase (phLDH) has determined very high resolution structures of the active site, via isotope edited IR studies, and has characterized its dynamical nature, via laser-induced temperature jump (T-jump) relaxation spectroscopy on the Michaelis complex. These particular probes are quite powerful at getting at the interplay between structure and dynamics in adaptation. Hence, we extend these studies to the psychrophilic protein cgLDH (Champsocephalus gunnari; 0 °C) and the extreme thermophile tmLDH (Thermotoga maritima LDH; 80 °C) for comparison to the mesophile phLDH (38–39 °C). Instead of the native substrate pyruvate, we utilize oxamate as a nonreactive substrate mimic for experimental reasons. Using isotope edited IR spectroscopy, we find small differences in the substate composition that arise from the detailed bonding patterns of oxamate within the active site of the three proteins; however, we find these differences insufficient to explain the mechanism of thermal adaptation. On the other hand, T-jump studies of reduced β-nicotinamide adenine dinucleotide (NADH) emission reveal that the most important parameter affecting thermal adaptation appears to be enzyme control of the specific kinetics and dynamics of protein motions that lie along the catalytic pathway. The relaxation rate of the motions scale as cgLDH > phLDH > tmLDH in a way that faithfully matches kcat of the three isozymes.
PMCID: PMC4679558  PMID: 26556099
5.  High Resolution Qualitative and Quantitative MR Evaluation of the Glenoid Labrum 
To implement qualitative and quantitative MR sequences for the evaluation of labral pathology.
Six glenoid labra were dissected and the anterior and posterior portions were divided into normal, mildly degenerated, or severely degenerated groups using gross and MR findings. Qualitative evaluation was performed using T1-weighted, proton density-weighted (PD), spoiled gradient echo (SPGR) and ultra-short echo time (UTE) sequences. Quantitative evaluation included T2 and T1rho measurements as well as T1, T2*, and T1rho measurements acquired with UTE techniques.
SPGR and UTE sequences best demonstrated labral fiber structure. Degenerated labra had a tendency towards decreased T1 values, increased T2/T2* values and increased T1 rho values. T2* values obtained with the UTE sequence allowed for delineation between normal, mildly degenerated and severely degenerated groups (p<0.001).
Quantitative T2* measurements acquired with the UTE technique are useful for distinguishing between normal, mildly degenerated and severely degenerated labra.
PMCID: PMC4644441  PMID: 26359581
6.  Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue 
Schizophrenia research  2015;168(0):402-410.
The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental timepoints in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions, and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20 μM], but this increase was blocked by the N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, were also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps towards understanding the biological function of ZNF804A in the mammalian brain.
PMCID: PMC4591171  PMID: 26164821
ZNF804A; Zfp804a; neurodevelopment; gene expression; in situ hybridization; schizophrenia
7.  Leptospira Immunoglobulin-Like Protein B (LigB) Binds to Both the C-Terminal 23 Amino Acids of Fibrinogen αC Domain and Factor XIII: Insight into the Mechanism of LigB-Mediated Blockage of Fibrinogen α Chain Cross-Linking 
PLoS Neglected Tropical Diseases  2016;10(9):e0004974.
The coagulation system provides a primitive but effective defense against hemorrhage. Soluble fibrinogen (Fg) monomers, composed of α, β and γ chains, are recruited to provide structural support for the formation of a hemostatic plug. Fg binds to platelets and is processed into a cross-linked fibrin polymer by the enzymatic clotting factors, thrombin and Factor XIII (FXIII). The newly formed fibrin-platelet clot can act as barrier to protect against pathogens from entering the bloodstream. Further, injuries caused by bacterial infections can be confined to the initial wound site. Many pathogenic bacteria have Fg-binding adhesins that can circumvent the coagulation pathway and allow the bacteria to sidestep containment. Fg expression is upregulated during lung infection providing an attachment surface for bacteria with the ability to produce Fg-binding adhesins. Fg binding by leptospira might play a crucial factor in Leptospira-associated pulmonary hemorrhage, the main factor contributing to lethality in severe cases of leptospirosis. The 12th domain of Leptospira immunoglobulin-like protein B (LigB12), a leptospiral adhesin, interacts with the C-terminus of FgαC (FgαCC). In this study, the binding site for LigB12 was mapped to the final 23 amino acids at the C-terminal end of FgαCC (FgαCC8). The association of FgαCC8 with LigB12 (ELISA, KD = 0.76 μM; SPR, KD = 0.96 μM) was reduced by mutations of both charged residues (R608, R611 and H614 from FgαCC8; D1061 from LigB12) and hydrophobic residues (I613 from FgαCC8; F1054 and A1065 from LigB12). Additionally, LigB12 bound strongly to FXIII and also inhibited fibrin formation, suggesting that LigB can disrupt coagulation by suppressing FXIII activity. Here, the detailed binding mechanism of a leptospiral adhesin to a host hemostatic factor is characterized for the first time and should provide better insight into the pathogenesis of leptospirosis.
Author Summary
Leptospirosis, caused by pathogenic Leptospira spp., has been increasingly recognized as an emerging zoonosis worldwide. In human cases, clinical presentation can vary from a mild flu-like syndrome to severe multi-organ failure including hepatitis, nephritis and occasionally meningitis. Particularly, pulmonary hemorrhage has become one of the major factors leading to fatality. The host coagulation system normally can be activated to confine damage caused by bacteria. However, this spirochete has developed several virulence proteins to manipulate hemostatic factors including fibrinogen (Fg). Previously, we had observed that Leptospira immunoglobulin-like protein B (LigB) can bind to Fg and inhibit fibrin clot formation. In this study, the LigB binding site on fibrinogen was fine-mapped. The key amino acids contributing to this strong pathogen-host interaction were also identified. In addition, LigB bound to factor XIII and further interfered with the cross-linking of Fg. For the first time, a potential mechanism of leptospiral adhesin binding to fibrinogen was revealed, which should provide a better understanding of the pathogenesis of leptospirosis.
PMCID: PMC5021285  PMID: 27622634
8.  Metastatic papillary serous uterine cancer presenting as a rash 
We report diagnosis and management of stage IV papillary serous uterine cancer with initial clinical presentation as a skin rash.
A 62-year-old postmenopausal female developed an erythematous rash beginning on her right lower abdomen and progressively spreading to her left abdomen, vulva, and neck. After a trial of antibiotic treatment, biopsy of left neck and right thigh skin nodules revealed papillary serous carcinoma. Abdominopelvic tomography revealed endometrial thickening and a 5 cm left adnexal mass. Subsequent endometrial biopsy also revealed papillary serous carcinoma, with pathology similar to that of the skin lesions. She received 6 cycles of carboplatin and paclitaxel chemotherapy with improvement of her skin lesions and overall performance status. However, her CA-125 level continued to rise and she was treated with single-agent carboplatin with progression of both her internal and cutaneous disease. She was transitioned to hospice with palliative radiation and died 2 months after discontinuing chemotherapy, 10 months after presentation.
Cutaneous metastasis is a rare presentation of metastatic uterine cancer. Treatment with chemotherapy may result in a positive response and should be considered.
•The skin is a rare site of metastasis of uterine cancer.•Metastatic uterine cancer can clinically present as skin lesions.•Serous uterine cancer often responds to chemotherapy but is aggressive.
PMCID: PMC5030339  PMID: 27672676
Uterine papillary serous cancer; Cutaneous metastases
9.  UTE-T1ρ is Sensitive to Enzymatic Degeneration of Human Menisci 
To determine if quantitative ultrashort TE (UTE) T1ρ magnetic resonance (MR) measurements are sensitive to proteoglycan (PG) degradation in human menisci by trypsin digestion.
Conventional and quantitative UTE-T1ρ MR sequences were performed on four meniscal samples using a 3T scanner. MR imaging was performed before and after 4, 8, and 12 hours of trypsin solution immersion, inducing PG loss. One sample was utilized as a control. Digest solutions were analyzed for glycosaminoglycan (GAG) content. UTE-T1ρ studies were analyzed for quantitative changes.
Images showed progressive tissue swelling, fiber disorganization and increase in signal intensity after GAG depletion. UTE-T1ρ values tended to increase with time after trypsin treatment (p=0.06). Cumulative GAG loss into the bath showed a trend of increased values for trypsin-treated samples (p=0.1).
UTE-T1ρ measurements can non-invasively detect and quantify severity of meniscal degeneration, which has been correlated with progression of osteoarthritis.
PMCID: PMC4575241  PMID: 25992688
MRI; T1ρ; meniscus; osteoarthritis; cartilage
10.  Osteochondral Allograft MRI Scoring System (OCAMRISS) in the Knee 
Cartilage  2015;6(3):142-149.
Osteochondral allograft (OCA) transplantation is a suitable treatment option for large osteochondral defects. Magnetic resonance imaging (MRI) is an objective, reproducible, noninvasive monitoring tool for postoperative assessment after cartilage surgery.
To correlate Osteochondral Allograft MRI Scoring System (OCAMRISS) in patients undergoing OCA transplantation in the knee with clinical outcomes and determine interobserver agreement of this scoring system.
Fifteen patients underwent OCA transplantation in the knee and received a postoperative MRI. Four examiners read each MRI and completed an OCAMRISS. Interobserver agreement and intraclass correlation coefficients (ICCs) were assessed. Clinical outcomes were evaluated. Correlation between the OCAMRISS and clinical outcomes was calculated using Spearman’s correlation coefficients.
Interobserver agreement on individual features of the OCAMRISS was superior (κ = 0.81-1.0) in 65% of comparisons, substantial (κ = 0.61-0.8) in 14%, moderate (κ = 0.41-0.6) in 18%, and fair (κ = 0.21-0.4) in 3%. Agreement among readers was very strong for the cartilage, bone, ancillary, and total scores with 96% of comparisons having an ICC >0.80. International Knee Documentation Committee (IKDC) function scores were correlated with OCAMRISS cartilage score (ρ = 0.53, P = 0.044) and total score (ρ = 0.67, P = 0.006). The Knee injury and Osteoarthritis Outcome Score (KOOS) sports/recreation subscale was correlated with OCAMRISS ancillary score (ρ = 0.58, P = 0.049) and total score (ρ = 0.64, P = 0.024). No correlation was observed with subchondral bone features of OCAMRISS and any of the outcome scores.
The recently described OCAMRISS is a reproducible grading system for in vivo evaluation after osteochondral allograft transplantation.
PMCID: PMC4481388  PMID: 26175859
knee; cartilage repair; osteochondral allograft transplantation; magnetic resonance imaging
11.  Ultrashort Echo Time Magnetization Transfer (UTE-MT) Imaging of Cortical Bone 
NMR in biomedicine  2015;28(7):873-880.
Magnetization transfer (MT) imaging is one way to indirectly assess pools of protons with fast transverse relaxation. However, conventional MT imaging sequences are not applicable to short T2 tissues such as cortical bone. Ultrashort echo time (UTE) sequences with TEs as low as 8 μs can detect signals from different water components in cortical bone. In this study we aim to evaluate two-dimensional (2D) UTE-MT imaging of cortical bone and its application in assessing cortical bone porosity as measured by μCT and biomechanical properties. In total, 38 human cadaveric distal femur and proximal tibia bones were sectioned to produce 122 rectangular pieces of cortical bone for quantitative UTE-MT MR imaging, microcomputed tomography (μCT), and biomechanical testing. Off-resonance saturation ratios (OSR) with a series of MT pulse frequency offsets (Δf) were calculated and compared with porosity assessed with μCT, as well as elastic (modulus, yield stress, and strain) and failure (ultimate stress, failure strain, and energy) properties, using Pearson correlation and linear regression. A moderate strong negative correlation was observed between OSR and μCT porosity (R2 = 0.46–0.51), while a moderate positive correlation was observed between OSR and yield stress (R2 = 0.25–0.30) and failure stress (R2 = 0.31–0.35), and a weak positive correlation (R2 = 0.09–0.12) between OSR and Young’s modulus at all off-resonance saturation frequencies. OSR determined with the UTE-MT sequence provides quantitative information on cortical bone and is sensitive to μCT porosity and biomechanical function.
Graphical Abstract
UTE-MT imaging of 122 human cortical bone samples: correlation between OSR (at 1.5 kHz) and μCT cortical porosity (A), Young’s modulus (B) and yield stress (C). OSR is negatively correlated with porosity, and positively correlated with Young’s modulus and yield stress.
PMCID: PMC4652942  PMID: 25981914
Magnetization transfer; off-resonance saturation ratio; UTE; porosity; cortical bone
12.  Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature 
Cureus  null;8(4):e585.
Primary intracranial germ cell tumors are rare, representing less than 5% of all central nervous system tumors. Overall, the majority of germ cell tumors are germinomas and approximately one-third are non-germinomatous germ cell tumors (NGGCT), which include teratoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumor), choriocarcinoma, or mixed malignant germ cell tumor. Germ cell tumors may secrete detectable levels of proteins into the blood and/or cerebrospinal fluid, and these proteins can be used for diagnostic purposes or to monitor tumor recurrence. Germinomas have long been known to be highly curable with radiation therapy alone. However, many late effects of whole brain or craniospinal irradiation have been well documented. Strategies have been developed to reduce the dose and volume of radiation therapy, often in combination with chemotherapy. In contrast, patients with NGGCT have a poorer prognosis, with about 60% cured with multimodality chemoradiation. There are no standard approaches for relapsed germ cell tumors. Options may be limited by prior treatment. Radiation therapy has been utilized alone or in combination with chemotherapy or high-dose chemotherapy and transplant. We discuss two cases and review options for frameless radiosurgery or fractionated radiotherapy.
PMCID: PMC4882159  PMID: 27239400
Stereotactic Radiosurgery; frameless stereotactic radiotherapy; radiation oncology; gamma knife; linac; head immobilization; cns germ cell tumor; re-irradiation
13.  UTE Imaging in the Musculoskeletal System 
Tissues, such as bone, tendon, and ligaments, contain a high fraction of components with “short” and “ultrashort” transverse relaxation times and therefore have short mean transverse relaxation times. With conventional MRI sequences that employ relatively long echo times (TEs), there is no opportunity to encode the decaying signal of short and ultrashort T2/T2* tissues before it has reached zero or near zero. The clinically compatible ultrashort TE (UTE) sequence has been increasingly used to study the musculoskeletal system. This article will review the UTE sequence as well as various modifications that have been implemented since its introduction. These modifications have been used to improve efficiency or contrast as well as provide quantitative analysis. This article also reviews several clinical musculoskeletal applications of UTE.
PMCID: PMC4297256  PMID: 25045018
ultrashort TE; musculoskeletal tissues; quantitative MRI; bi-component analysis
14.  Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma 
Neuro-Oncology  2014;17(2):266-273.
Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy.
The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide.
The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia.
The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. identifier
PMCID: PMC4288521  PMID: 25239666
factorial design; glioblastoma; isotretinoin; temozolomide; celecoxib; thalidomide
15.  Effects of Inversion Time on Inversion Recovery Prepared Ultrashort Echo Time (IR-UTE) Imaging of Free and Bound Water in Cortical Bone 
NMR in biomedicine  2014;28(1):70-78.
Water is present in cortical bone in different binding states. In this study we aimed to investigate the effects of inversion time (TI) on the signal from bound and pore water in cortical bone using an adiabatic inversion recovery prepared ultrashort echo time (IR-UTE) sequence on a clinical 3T scanner. In total ten bovine midshaft samples and four human tibial midshaft samples were harvested for this study. Each cortical sample was imaged with the UTE and IR-UTE sequences with a TR of 300 ms and a series of TIs ranging from 10 to 240 ms. Five healthy volunteers were also imaged with the same sequence. Single- and bi-component models were utilized to calculate the T2* and relative fractions of short and long T2* components. Bi-component behavior of the signal from cortical bone was seen with the IR-UTE sequence except with a TI of around 80 ms where the short T2* component alone were seen and a mono-exponential decay pattern was observed. In vivo imaging with the IR-UTE sequence provided high contrast-to-noise images with direct visualization of bound water and reduced signal from long T2 muscle and fat. Our preliminary results demonstrate that selective nulling of the pore water component can be achieved with the IR-UTE sequence with an appropriate TI, allowing selective imaging of the bound water component in cortical bone in vivo using clinical MR scanners.
PMCID: PMC4263352  PMID: 25348196
UTE; IR-UTE; bound water; pore water; cortical bone
16.  The impact of tyrosine kinase inhibitors on the multi-modality treatment of brain metastases from renal cell carcinoma 
This study evaluated the effect of tyrosine kinase inhibitors (TKI’s) on the brain metastasis (BM) local control (LC) and overall survival (OS) of patients with renal cell carcinoma (RCC) with BM.
A retrospective review of patients with RCC BM was conducted. Eligible patients from two eras: pre-TKI, 2002–2003, and post-TKI, 2006–2007, were identified. Prognostic factors, use and type of systemic therapy were noted. The timing, number, size, and treatment modality data for each BM was recorded. Use of TKI and BM treatment modality were correlated to LC and OS.
Eighty-one patients with 216 brain metastases were identified. 37 patients had BM at diagnosis and 44 were found to have BM later. 41 patients never received a TKI and 40 patients received TKI’s. Stereotactic radiosurgery (SRS), surgery, whole brain radiotherapy (WBRT), or no local brain treatment was used for 89, 19, 24, and 75 lesions, respectively. The median OS from BM diagnosis was 5.4 months for the whole group: 4.4 months versus 6.71 months in the never-TKI versus TKI groups, respectively. Patients who received TKI’s post-BM development had a median OS of 23.6 months vs. 2.08 and 4.41 months for the patients who received TKI’s pre-BM or never-TKI, respectively, (p=0.0001). Local control was statistically superior in lesions managed with surgery or SRS vs. the no local therapy.
In patients with RCC and BM, TKI’s are associated with a trend to improved OS, but no significant improvement in LC of BM. They may provide a significant benefit to patients with BM with no prior TKI exposure.
PMCID: PMC4630800  PMID: 22892430
Neuro-Oncology  2014;16(Suppl 5):v209.
Emerging data suggests that post-operative SBRT for malignant spinal tumors may improve local control compared to conventional radiation therapy. However, few guidelines exist. The purpose of this study was to develop consensus guidelines to guide safe, effective treatment. Twenty spine specialists representing 19 centers in 4 countries with a collective experience of >1300 cases completed survey. Responses were defined as follows: 1) consensus: selected by ≥75%, 2) predominant: selected by ≥50%, 3) controversial: no single response selected by a majority of respondents. Consensus indications include: radio-resistant primary, 1-2 levels of adjacent disease and/or prior RT to same site. Contra-indications include: >3 contiguous vertebral bodies involved, ASIA score A (complete spinal cord injury without preservation of motor or sensory function), post-operative Bilsky grade 3 residual (cord compression without any CSF around the cord). For treatment planning, predominance of physicians co-register pre-operative MRI and post-operative T1 post-gadolinium MRI and delineate cord on T2 variant MRI or CT myelogram in cases of significant hardware artifact. Consensus GTV is post-operative residual tumor based on MRI. CTV is predominantly post-operative bed defined as entire extent of pre-operative tumor & anatomic compartment plus residual disease. Consensus is that hardware and scar do not need to be included. PTV expansion is controversial (range: 0-2 mm). Predominant prescription dose for initial treatment is 18 Gy x 1 with max point to cord <12-14 Gy (prescription range: 16-48.5 Gy in 1-10 fractions). For re-treatment, physicians predominantly account for repair and time interval between prior RT and spinal SBRT in calculating cord constraints. Acceptable PTV coverage is controversial, but physicians predominantly compromise coverage to meet cord constraint and/or fractionate to improve coverage while meeting cord constraint. Future investigation will be critical in better understanding areas of controversy including circumferential treatment of epidural space, margin for paraspinal extension and optimal dose/fractionation.
PMCID: PMC4218565
18.  Dorsal Muscle Group Area and Surgical Outcomes in Liver Transplantation 
Clinical transplantation  2014;28(10):1092-1098.
Better measures of liver transplant risk stratification are needed. Our previous work noted a strong relationship between psoas muscle area and survival following liver transplantation. The dorsal muscle group is easier to measure but it is unclear if they are also correlated with surgical outcomes.
Our study population included liver transplant recipients with a preoperative CT scan. Cross-sectional areas of the dorsal muscle group at the T12 vertebral level were measured. The primary outcomes for this study were 1 and 5-year mortality and 1-year complications. The relationship between dorsal muscle group area and post-transplantation outcome was assessed using univariate and multivariate techniques.
Dorsal muscle group area measurements were strongly associated with psoas area (r = 0.72; p < 0.001). Postoperative outcome was observed from 325 patients. Multivariate logistic regression revealed dorsal muscle group area to be a significant predictor of 1-year mortality (odds ratio [OR] = 0.53, p = 0.001,) and 5-year mortality (OR = 0.53, p < 0.001), and 1-year complications (OR = 0.67, p = 0.007).
Larger dorsal muscle group muscle size is associated with improved post-transplantation outcomes. The muscle is easier to measure and may represent a clinically relevant postoperative risk factor.
PMCID: PMC4205192  PMID: 25040933
Dorsal muscle group; Psoas muscle; Morphometric measure; Liver transplant; End-stage liver disease; Sarcopenia; Surgical Outcome; Risk stratification
19.  Hematuria following Botox treatment for upper limb spasticity: a case report 
Journal of Pain Research  2015;8:619-622.
Hematuria is a documented side effect of botulinum toxin injection and has only been reported when it is used for overactive bladder. Here we report a rare case of hematuria following onabotulinumtoxin A (Botox) injection for upper limb spasticity in a 29-year-old male with a history of traumatic brain injury and hemophilia. Hematuria resolved without further complication after self-injection of factor VIII as recommended by his hematologist. Botulinum toxin binds peripheral cholinergic nerve endings to prevent acetylcholine and norepinephrine exocytosis. Studies have shown that both of these compounds are involved in antifibrinolytic activation, suggesting botulinum toxin may play a role in the coagulation cascade by preventing formation of fibrin. This is further supported by resolution of hematuria in our patient after self-injection of factor VIII. As such, botulinum toxin injection may result in mild spontaneous hemorrhage in patients with underlying hematological deficiencies. Further studies are needed to elucidate its effects in coagulation.
Video abstract
PMCID: PMC4576889  PMID: 26396542
hematuria; botulinum toxin; upper limb spasticity; hemophilia
20.  Resolution of chronic migraine headaches with intrathecal ziconotide: a case report 
Journal of Pain Research  2015;8:603-606.
Migraine headaches are a common and functionally debilitating disorder affecting approximately 17% of women and 5.6% of men. Compared to episodic migraine patients, chronic migraineurs are more likely to be occupationally disabled, miss family activities, have comorbid anxiety and/or chronic pain disorders, and utilize significantly more health care dollars. Ziconotide is a calcium channel blocker used for the treatment of chronic severe pain without issues of tolerance or dependency found with opioid therapy.
A 59-year-old female had an intrathecal baclofen pump placed for spasticity secondary to multiple sclerosis. Her symptoms also included lower extremity neuropathic pain and severe migraine headaches with 22 migraine headache days per month. Prior treatments included non-steroidal anti-inflammatory drugs, triptans, anticonvulsants, antihypertensives, and Botox injections which reduced her symptoms to four migraine days per month at best. While her spasticity had markedly improved with intrathecal baclofen, ziconotide was added to help her neuropathic pain complaints. Following initiation of low-dose ziconotide (1 µg/day), the patient noted both lower extremity pain improvement and complete resolution of migraine headaches resulting in zero migraine days per month. She has now been migraine free for 8 months.
Upon review of the available literature, there are no published cases of migraine improvement with intrathecal ziconotide. This represents the first case describing resolution of migraine symptoms with low-dose ziconotide.
PMCID: PMC4573200  PMID: 26392785
ziconotide; migraine; symptoms; chronic pain; intrathecal pump
21.  Spinal cord stimulation for treatment of the pain associated with hereditary multiple osteochondromas 
Journal of Pain Research  2015;8:557-560.
Hereditary multiple osteochondromas (HMO) usually presents with neoplastic lesions throughout the skeletal system. These lesions frequently cause chronic pain and are conventionally treated with surgical resection and medication. In cases where conventional treatments have failed, spinal cord stimulation (SCS) could be considered as a potential option for pain relief. The objective of this case was to determine if SCS may have a role in treating pain secondary to neoplastic lesions from HMO.
Case presentation
We report a 65-year-old female who previously received both surgical and pharmacological interventions for treating HMO neoplastic pain in the lumbar, pelvis, femur, and tibial regions. These interventions either failed to offer significant pain relief or caused excessive lethargy. A SCS trial was then offered with a dual 16-contact lead trial leading to 70%–80% improvement in pain from baseline and 85% reduction in oxycodone IR intake. This was followed by permanent implantation of two 2×8 contact paddle leads (T7–T8 and T9–T10 interspaces). After 8-week follow-up, settings were further optimized resulting in an additional 30% improvement in pain compared to last visit. At 6-month follow-up, the patient reported continued pain relief.
This case demonstrates the first successful use of SCS to treat both HMO and nonmalignant neoplastic-related pain. The patient reported pain improvement from baseline, reduced pain medication requirements, and subjective improvement in quality of life. Additionally, this case demonstrates the potential advantage of trialing multiple painful areas with a 16-contact lead in order to avoid multiple trials and placement.
PMCID: PMC4547638  PMID: 26316806
Exostoses; bone neoplasms/pathology; hereditary exostoses/multiple; back pain/therapy; pain management; spinal cord stimulation; treatment outcome; chronic pain; case reports
22.  Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation 
Cell reports  2015;12(3):511-524.
Basal-like breast cancers (BLBCs) are aggressive, and their drivers are unclear. We have found that wild-type N-RAS is overexpressed in BLBCs, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpression enhances these processes even in preinvasive BLBC cells. We identified N-Ras-responsive genes, most of which encode chemokines, e.g., IL8. Expression levels of these chemokines and N-RAS in tumors correlate with outcome. N-Ras, but not K-Ras, induces IL8 by binding and activating the cytoplasmic pool of JAK2; IL8 then acts on both the cancer cells and stromal fibroblasts. Thus BLBC progression is promoted by increasing activities of wild-type N-Ras, which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells.
Graphical Abstract
PMCID: PMC4512851  PMID: 26166574
23.  Quantitative bi-component T2* analysis of histologically normal Achilles tendons 
the aim of this pilot study was to implement ultrashort echo time (UTE) MRI with bi-component analysis on grossly normal Achilles tendons with histologic correlation.
Materials and methods
six tendon samples which were grossly normal on visual inspection and palpation were harvested. A 2D UTE pulse sequence was implemented on a 3T MR scanner and bi-component and single-component T2* analysis was performed. Tendon samples were histologically processed and evaluated.
mean short T2* fraction was 79.2% (95% confidence interval [CI], 70.1 – 88.3%), mean short T2* was 1.8 ms (95% CI, 1.3 – 2.3 ms), mean long T2* fraction was 20.8% (95% CI, 11.7 – 29.9%), mean long T2* was 9.2 ms (95% CI, 5.1 – 13.3 ms), and mean single-component T2* was 2.5 ms (95% CI, 1.8 – 3.1 ms).
2D UTE MRI with bi-component and single-component T2* analysis was successfully implemented. Inter-individual variation can be demonstrated in grossly and histologically normal Achilles tendons.
PMCID: PMC4496019  PMID: 26261782
tendon; ultrashort TE; bi-component analysis
24.  The Intrinsically Disordered C-RING Biomineralization Protein, AP7, Creates Protein Phases That Introduce Nanopatterning and Nanoporosities into Mineral Crystals 
Biochemistry  2014;53(27):4317-4319.
We report an interesting process whereby the formation of nanoparticle assemblies on and nanoporosities within calcite crystals is directed by an intrinsically disordered C-RING mollusk shell nacre protein, AP7. Under mineralization conditions, AP7 forms protein phases that direct the nucleation of ordered calcite nanoparticles via a repetitive protein phase deposition process onto calcite crystals. These organized nanoparticles are separated by gaps or spaces that become incorporated into the forming bulk crystal as nanoporosities. This is an unusual example of organized nanoparticle biosynthesis and mineral modification directed by a C-RING protein phase.
PMCID: PMC4215888  PMID: 24977921
25.  Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor 
EBioMedicine  2015;2(7):755-764.
Patients with systemic lupus erythematosus (SLE) experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present.
•Lupus patients with NMDAR-reactive antibodies (DNRAbs) show impaired spatial memory.•Mice in which DNRAbs penetrate the hippocampus have defective CA1 place cells.•CA1 and CA3 pyramidal cells exposed to DNRAbs display reduced dendritic processes.•DNRAb exposure initiates a progressive compromise in pyramidal neurons.•Lupus antibody effects evolve even after DNRAbs are no longer present in the brain.
PMCID: PMC4534689  PMID: 26286205
AP, alkaline phosphatase; BBB, blood–brain barrier; BDI, Beck depression index; CA1, cornus ammonis area 1 of the hippocampus; CNS, central nervous system; CSF, cerebrospinal fluid; C3, C4, complements 3 and 4, respectively; DMARD, disease-modifying drugs; DNRAb, anti-DNA antibody reactive to the GluN2A and GluN2B subunits of the NMDAR; dsDNA, double stranded DNA; DWEYS, amino acid consensus sequence (D/E, W, D/E, Y, S/G) for DNRAb binding; FA, Freund's adjuvant; HC, healthy control; HEK-293T, human embryonic kidney 293 T cell; IgG, immunoglobulin G; i.p, intraperitoneally; LPS, lipopolysaccharide; MAP, multi-antigenic polylysine backbone; NMDAR, N-methyl-d-aspartate receptor; NOR, novel object recognition; NPSLE, neuropsychiatric lupus; OPM, object place memory; SELENA, safety of estrogens in lupus erythematosus national assessment; SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index; SLICCDI, systemic lupus international collaborating clinics damage index; Lupus; Neuropsychiatric lupus; CA1 place cell; Hippocampus; Mouse lupus model

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