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Redox metabolism plays essential functions in the pathology of cancer. As tumor redox profiles uniquely reflect cancer stage and in select cases, therapeutic sensitivity, the capability to image redox molecular features is essential to improve diagnosis, treatment, and overall quality-of-life (QOL) of cancer patients. While a number of radiotracers for imaging redox metabolism have been developed, there are no reports of radiotracers for in vivo imaging of protein oxidation. Here we take the first step towards this goal and describe the synthesis and kinetic properties of a new positron emission tomography (PET) [18F]DCP radiotracer for in vivo imaging of protein sulfenylation. Time course biodistribution and PET/CT studies using xenograft animal models of Head and Neck Squamous Cell Cancer (HNSCC) demonstrate feasibility of diagnosing radiation resistant tumors, which display lower [18F]DCP signal. These findings are consistent with our previous reports of decreased protein sulfenylation in clinical specimens of radiation resistant HNSCC. We anticipate further development and implementation of this concept in clinical practice to improve the diagnosis of patients with radiation resistant tumors and the accuracy of prognosis for patients undergoing radiation treatment.Single Sentence SummaryThe study introduces a new PET radiotracer for profiling tumor protein oxidation as a prognostic indicator of resistance to radiation therapy.

Ustekinumab is a human interleukin (IL)12/23 antagonist with US Food and Drug Administration indications to treat moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn's disease. Because of the blockade of the IL-12/IL-13 pathway, which mediates antitumor and antiviral responses, ustekinumab has significant immunosuppressive characteristics and can lead to an increased risk of infection, reactivation of latent infection, and malignancy in patients. We present a case of a patient with psoriasis and psoriatic arthritis on ustekinumab who had disseminated verrucae shortly after initiating treatment.

Silver nanoparticles (AgNPs) are widely used nanomaterials in both commercial and clinical biomedical applications, due to their antibacterial properties. AgNPs are also being explored for the treatment of cancer in particular in combination with ionizing radiation. In this work, we studied the effects of AgNPs and ionizing radiation on mitochondrial redox state and function in a panel of lung cell lines (A549, BEAS-2B, Calu-1 and NCI-H358). The exposure to AgNPs caused cell cycle arrest and decreased cell proliferation in A549, BEAS-2B and Calu-1, but not in NCI-H358. The mitochondrial reactive oxygen species (ROS) and protein oxidation increased in a time- and dose-dependent manner in the more sensitive cell lines with the AgNP exposure, but not in NCI-H358. While ionizing radiation also induced changes in the mitochondrial redox profiles, in general, these were not synergistic with the effects of AgNPs with the exception of NCI-H358 and only at a higher dose of radiation.

Redox-mediated protein modifications control numerous processes in both normal and disease metabolism. Protein sulfenic acids, formed from the oxidation of protein cysteine residues, play a critical role in thiol-based redox signaling. The reactivity of protein sulfenic acids requires their identification through chemical trapping, and this paper describes the use of the triphenylphosphonium (TPP) ion to direct known sulfenic acid traps to the mitochondria, a verified source of cellular reactive oxygen species. Coupling of the TPP group with the 2,4-(dioxocyclohexyl)propoxy (DCP) unit and the bicyclo[6.1.0]nonyne (BCN) group produces two new probes, DCP-TPP and BCN-TPP. DCP-TPP and BCN-TPP react with C165A AhpC-SOH, a model protein sulfenic acid, to form the expected adducts with second-order rate constants of k = 1.1 M(−1) s(−1) and k = 5.99 M(−1) s(−1), respectively, as determined by electrospray ionization time-of-flight mass spectrometry. The TPP group does not alter the rate of DCP-TPP reaction with protein sulfenic acid compared to dimedone but slows the rate of BCN-TPP reaction compared to a non-TPP-containing BCN-OH control by 4.6-fold. The hydrophobic TPP group may interact with the protein, preventing an optimal reaction orientation for BCN-TPP. Unlike BCN-OH, BCN-TPP does not react with the protein persulfide, C165A AhpC-SSH. Extracellular flux measurements using A549 cells show that DCP-TPP and BCN-TPP influence mitochondrial energetics, with BCN-TPP producing a drastic decrease in basal respiration, perhaps due to its faster reaction kinetics with sulfenylated proteins. Further control experiments with BCN-OH, TPP-COOH, and dimedone provide strong evidence for mitochondrial localization and accumulation of DCP-TPP and BCN-TPP. These results reveal the compatibility of the TPP group with reactive sulfenic acid probes as a mitochondrial director and support the use of the TPP group in the design of sulfenic acid traps.

Mitochondrial reactive oxygen species (ROS) are essential regulators of cellular signaling, metabolism and epigenetics underlying the pathophysiology of numerous diseases. Despite the critical function of redox regulation in mitochondria, currently there are limited methods available to monitor protein oxidation in this key subcellular organelle. Here, we describe compounds for imaging sulfenylated proteins in mitochondria: DCP-NEt2-Coumarin (DCP-NEt2C) and rhodamine-based DCP-Rho1. Side-by-side comparison studies are presented on the reactivity of DCP-NEt2C and DCP-Rho1 with a model protein sulfenic acid (AhpC-SOH) and mitochondrial localization to identify optimized experimental conditions for labeling and visualization of protein sulfenylation that would be independent of mitochondria membrane potential and would not impact mitochondrial function. These probes are applied to image mitochondrial protein sulfenylation under conditions of serum starvation and in a cell culture model of lung cancer exposed to ionizing radiation and silver nanoparticles, agents serving dual functions as environmental stressors and cancer therapeutics.

Silver nanoparticles (AgNP) are widely applied nanomaterials for both commercial and clinical biomedical applications. AgNP have been shown to have cytotoxicity in various cancer cell lines, as well as radiosensitizing properties. The AgNPs may induce free radicals via Fenton-type reactions, but the cellular mechanisms related to reactive oxygen species (ROS) production remain largely unknown. Both ionizing radiation (IR) and AgNP exposure lead to apoptotic and necrotic cell death through mechanisms that involve DNA damage and induction of oxidative stress, possibly targeting mitochondria. Changes in the thiol redox state of mitochondrial proteins, such as protein sulfenylation, play an important role in a number of cellular processes, and mitochondrial damage and dysfunction along with increased mitochondrial ROS are implicated in a range of human diseases such as cancer. In this work we studied the molecular effects of AgNP exposure with and without IR in a panel of lung cell lines (three cancer cell lines: A549, Calu-1 and NCI-H358 and one immortalized lung epithelial cell line: BEAS-2B). Both AgNP and IR exposures increased mitochondrial protein oxidation detected by a recently developed mitochondria targeted probe for protein sulfenylation (DCP-NEt2C). This increase in DCP-NEt2C labeling was dose and time dependent and the exposures also showed a combined effect. Moreover, the exposures induced changes in cell cycle and decreased cellular proliferation. There were marked differences between different cell lines, likely reflecting differences in the cellular redox state and metabolism. In conclusion, the AgNP and IR exposures increase the mitochondrial ROS as demonstrated by increased protein oxidation and have effects on the cell cycle and cell proliferation. They also appear to have a combined effect which might have implications for clinical applications as well as environmental risk assessment. Citation Format: Reetta J. Holmila, Stephen A. Vance, Ravi Singh, S. Bruce King, Cristina M. Furdui. Silver nanoparticles and ionizing radiation induce mitochondrial protein oxidation and effects on cell cycle and proliferation in lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 887.

Interleukin 6 (IL6), an inflammatory response protein has major implications in immune-related inflammatory diseases. Identification of aptamers for the IL6 protein aids in diagnostic, therapeutic, and theranostic applications. Three different DNA aptamers and their interactions with IL6 protein were extensively investigated in a phosphate buffed saline (PBS) solution. Molecular-level modeling through molecular dynamics provided insights of structural, conformational changes and specific binding domains of these protein–aptamer complexes. Multiple simulations reveal consistent binding region for all protein–aptamer complexes. Conformational changes coupled with quantitative analysis of center of mass (COM) distance, radius of gyration (Rg), and number of intermolecular hydrogen bonds in each IL6 protein–aptamer complex was used to determine their binding performance strength and obtain molecular configurations with strong binding. A similarity comparison of the molecular configurations with strong binding from molecular-level modeling concurred with Surface Plasmon Resonance imaging (SPRi) for these three aptamer complexes, thus corroborating molecular modeling analysis findings. Insights from the natural progression of IL6 protein–aptamer binding modeled in this work has identified key features such as the orientation and location of the aptamer in the binding event. These key features are not readily feasible from wet lab experiments and impact the efficacy of the aptamers in diagnostic and theranostic applications.

While research indicates that sentencing guidelines systems often reduce sentencing disparity, few studies have examined whether sentencing guidelines shift discretion and disparity from judges to prosecutors. Some critics assert that guidelines do shift judicial discretion to prosecutors, but empirical evidence is scarce. This study seeks to provide some empirical data on the underresearched topic of hydraulic displacement of discretion. Using data from the District of Columbia Superior Court, the study asked whether charge bargaining practices changed after the District of Columbia adopted a regime of sentencing guidelines. The analyses indicate that some changes in the plea bargaining process did occur after the guidelines were implemented but that most were not statistically significant. Policy implications of the displacement thesis and the current findings are discussed.

Sensitive and selective methods for the detection of human growth hormone (hGH) over a wide range of concentrations (high levels of 50-100 ng ml(-) (1) and minimum levels of 0.03 ng ml(-) (1)) in circulating blood are essential as variable levels may indicate altered physiology. For example, growth disorders occurring in childhood can be diagnosed by measuring levels of hGH in blood. Also, the misuse of recombinant hGH in sports not only poses an ethical issue it also presents serious health threats to the abuser. One popular strategy for measuring hGH misuse, relies on the detection of the ratio of 22 kDa hGH to total hGH, as non-22 kDa endogenous levels drop after exogenous recombinant hGH (rhGH) administration. Surface plasmon resonance imaging (SPRi) is an analytical tool that allows direct (label-free) monitoring and visualization of biomolecular interactions by recording changes of the refractive index adjacent to the sensor surface in real time. In contrast, the most frequently used colorimetric method, enzyme-linked immunosorbent assay (ELISA) uses enzyme labeled detection antibodies to indirectly measure analyte concentration after the addition of a substrate that induces a color change. To increase detection sensitivity, amplified SPRi uses a sandwich assay format and near infrared quantum dots (QDs) to increase signal strength. After direct SPRi detection of recombinant rhGH in spiked human serum, the SPRi signal is amplified by the sequential injection of detection antibody coated with near-infrared QDs (Nano-SPRi). In this study, the diagnostic potential of direct and amplified SPRi was assessed for measuring rhGH spiked in human serum and compared directly with the capabilities of a commercially available ELISA kit.

Diagnostic biomarkers (i.e. proteins) are often in low abundance in bodily fluids presenting many challenges for their detection. In order to extend the application of SPRi systems in detecting biomarkers at ultralow levels, we combine the advantage of aptamer technology with nanomaterials and microwave-assisted surface functionalization. By implementing a sandwich assay through the introduction of aptamer-modified quantum dots (QDs), it was possible to measure 7 zeptomole (at 5 fg/mL) of C-reactive protein (CRP) selectively in spiked human serum. It is expected that the proposed platform will provide new direction in designing ultrasensitive SPRi biosensors with multiplexing capabilities.

Background The hallmark of atherosclerosis is the accumulation of plaque in vessel walls. This process is initiated when monocytic cells differentiate into macrophage foam cells under conditions with high levels of atherogenic lipoproteins. Vulnerable plaque can dislodge, enter the blood stream, and result in acute myocardial infarction and stroke. Imaging techniques such as cardiovascular magnetic resonance (CMR) provides one strategy to identify patients with plaque accumulation. Methods We synthesized an atherosclerotic-targeting contrast agent (ATCA) in which gadolinium (Gd)-containing endohedrals were functionalized and formulated into liposomes with CD36 ligands intercalated into the lipid bilayer. In vitro assays were used to assess the specificity of the ATCA for foam cells. The ability of ATCA to detect atherosclerotic plaque lesions in vivo was assessed using CMR. Results The ATCA was able to detect scavenger receptor (CD36)-expressing foam cells in vitro and were specifically internalized via the CD36 receptor as determined by focused ion beam/scanning electron microscopy (FIB-SEM) and Western blotting analysis of CD36 receptor-specific signaling pathways. The ATCA exhibited time-dependent accumulation in atherosclerotic plaque lesions of ApoE −/− mice as determined using CMR. No ATCA accumulation was observed in vessels of wild type (C57/b6) controls. Non-targeted control compounds, without the plaque-targeting moieties, were not taken up by foam cells in vitro and did not bind plaque in vivo. Importantly, the ATCA injection was well tolerated, did not demonstrate toxicity in vitro or in vivo, and no accumulation was observed in the major organs. Conclusions The ATCA is specifically internalized by CD36 receptors on atherosclerotic plaque providing enhanced visualization of lesions under physiological conditions. These ATCA may provide new tools for physicians to non-invasively detect atherosclerotic disease.

Parton energy loss in Au+Au collisions at RHIC energies is studied by numerically solving the relativistic Boltzmann equation for the partons including $2 \leftrightarrow 2$ and $2 \to 2 + final state radiation$ collision processes. Final particle spectra are obtained using two hadronization models; the Lund string fragmentation and independent fragmentation models. Recent, preliminary $\pi^0$ transverse momentum distributions from central Au+Au collisions at RHIC are reproduced using gluon-gluon scattering cross sections of 5-12 mb, depending upon the hadronization model. Comparisons with the HIJING jet quenching algorithm are made., Comment: 6 pages, 6 figures, attached files are replaced (wrong files were uploaded in version 1)

The effect of scattering with nonzero impact parameters between constituents in relativistic heavy-ion collisions is investigated. In solving the relativistic Boltzmann equation, the characteristic range of the collision kernel is varied from approximately 1.0 fm to zero while leaving the mean free path unchanged. Modifying this range is shown to significantly affect spectra and flow observables. The finite range is shown to provide effective viscosities, shear, bulk viscosity, and heat conductivity, with the viscous coefficients being proportional to the square of the interaction range.

The microscopic origin of the strangeness enhancements observed in PbPb collisions at the SPS is studied by testing the effects of three mechanisms. First, the junction processes found in the HIJING/BBbar event generator are reviewed showing that they can account for only part of the observed hyperon enhancements. Second, the efficient final state chemical changing processes (e.g. Lambda + K -> Xi + pi) are included by adding the General Cascade Program (GCP) to HIJING/BBbar. While these processes are shown to further enhance multistrange baryon production, HIJING/BBbar+GCP is still unable to fully describe either the large hyperon yields or the increasing K+/pi+ ratio. Finally, the addition of transient field fluctuations or ropes to HIJING/BBbar+GCP is shown to be needed to account for the large hyperon yields and for the behavior of the K+/pi+ ratio., To appear in the proceedings of Strangeness 2000, the 5th International Conference on Strangeness in Quark Matter, July 20-25, 2000, Berkeley, CA

The baryon junction exchange mechanism recently proposed to explain valence baryon number transport in nuclear collisions is extended to study midrapidity anti-hyperon production. Baryon junction-anti-junction (J anti-J) loops are shown to enhance anti-Lambda, anti-Xi, anti-Omega yields as well as lead to long range rapidity correlations. Results are compared to recent WA97 Pb + Pb -> Y + anti-Y + X data., 10 pages, 4 figures

This manuscript describes a general and simple method to carbon-coat quantum dots (QDs) using microwave-assisted technology. By coating QDs with carbohydrates, you extend their application for bioimaging (in vitro and in vivo) as the metal core is now shielded by a protective coating layer. XRD and TEM verified that nanoparticles were coated with a layer of carbon-based material (reduced sucrose). In addition, we demonstrated the versatility of this approach by coating other types of nanoparticles (i.e. gold). UV–Visible spectroscopic analysis presented a red shift in absorbance after carbon coating which further confirmed that the surface of these nanoparticles was modified. QDs emission wavelength was not altered but experienced an increase in intensity. The carbon-coated QDs and gold nanoparticles generated in this study measured 14 nm and 60 nm, respectively.

• Persistent memory problems were reported by a 39-year-old man who suffered a penetrating brain wound while serving in Vietnam 15 years earlier. Neuropsychological testing indicated an unusually isolated memory impairment. Computed tomography revealed transection of the columns of the fornix cerebri with no temporal-lobe involvement and minimal thalamic damage. We suggest that the fornix cerebri has a role in the maintenance of information accessibility to both encoding and recall during post-working memory processing and in the organization of verbal information during encoding and/or retrieval for declarative (recall) purposes. These processes are not essential for verbal recognition but can result in decrements on specific laboratory tasks and in social adjustment.

We compared the neurologic and cognitive performance of 15 young veterans who suffered unilateral penetrating missile wounds to the basal forebrain 15 years ago in the Vietnam War with uninjured controls and patients with lesions elsewhere in the brain. The subjects performed worse on tests of episodic memory, reasoning, and arithmetic and had more prolonged unconsciousness after injury; but their performance usually compared favorably with that of uninjured controls on tests of intelligence, attention, and language and was not consistent with that of a demented patient. The data suggest that the basal forebrain is functionally related to the reticular formation and to the basal forebrain is functionally related to the reticular formation and to the limbic-hippocampal memory system.

The extent to which intellectual processes are preserved as a function of preinjury 'intelligence' and of size and location of the brain lesions was evaluated in Vietnam war veterans who survived penetrating missile wounds. With regard to an overall postinjury intelligence test score, preinjury intelligence was most predictive, size of lesion was next most predictive and lesion location was least important. For subtest scores from the same intelligence test, lesion location assumed much greater predictive value. Specifically, left temporal and occipital lesions impaired performance on subtests assessing vocabulary and object-function matching ability.

The relationship of preinjury left-hand dominance for motor performance to postinjury distal motor skills following penetrating brain wounds in patients without overt hemiplegia was examined. We studied 13 controls, 13 right-hemisphere brain-damaged patients, and 11 left-hemisphere brain-damaged patients on motor tasks measuring reaction time, strength, and coordination. Our results indicated that no persistent deficits were seen on distal motor tasks in left-handed adults who suffered a penetrating brain wound. These findings are compatible with the relative sparing of persistent neuropsychological deficits in left-handers following brain damage.

We examined the relationship of preinjury intelligence, a lesion- severity variable (brain-tissue loss volume), and lesion location to the persistence of cognitive deficits in Vietnam veterans with penetrating brain wounds. Using stepwise multiple linear regression procedures, we found that preinjury intelligence predicted a significant amount of the variance on postinjury cognitive testing, being a better predictor for tests requiring a number of complementary cognitive processes (e.g., intelligence tests) than for tests measuring a specific cognitive process (e.g., face recognition). Brain-tissue volume loss was found to play a larger role when a global cognitive measure was used, but a smaller role when a specific cognitive process was measured. Finally, lesion location was shown to be a significant predictor of performance only for specific cognitive processes. Nevertheless, preinjury intelligence/education appears to play an even larger role in postinjury performance than either brain-tissue loss volume or a particular structural loss.

• Using data derived from a 15-year follow-up study of 520 veterans surviving penetrating brain wounds received in the Vietnam war, we have developed a predictive formula and tables for posttraumatic epilepsy based on time elapsed postinjury and presence of specific clinical and computed tomographic scan risk factors. Such patients remain at some increased risk for epilepsy even ten to 15 years postinjury, although most can be 95% certain of avoiding epilespy if they have been seizure free for three years posttrauma. Epilepsy onset latency was independent of any risk factors identified.

A group of Vietnam veterans with penetrating brain wounds to the orbitofrontal, dorsofrontal, and nonfrontal cortex were compared with a stratified control group on self-report and observed measures of mood state and cognition. In particular, hypotheses regarding the regulation of anxiety by frontal cortical mechanisms were evaluated. Results indicated that patients with right orbitofrontal lesions were prone to abnormally increased ‘edginess’/anxiety and depression, whereas patients with left dorsofrontal lesions were prone to abnormally increased anger/hostility. A working model of mood state regulation is presented which represents the thesis that mood sensations are subject to numerous cognitive and biological influences that result in a variety of expressions of a particular mood disorder.

Somatosensory evoked potentials were obtained after median nerve stimulation in 500 Vietnam veterans surviving penetrating head wounds 12-16 years earlier and 76 age-matched, uninjured controls. The results were studied in relation to neurologic history and findings, anatomical data provided by CT scan, and information derived from electroencephalograms. Thirty-five percent of head-injured individuals had abnormal SEPs and 76% of SEP abnormalities consisted of absence of N20 or N20/P25 complex. SEP abnormality correlated (P greater than 0.001) with the extent of total brain volume loss, sensory deficits (especially position and cortical discriminatory modalities), hemiparesis, organic mental disorder, CT evidence of parietal or thalamic injury, and centro-parietal EEG abnormalities. Recovery from hemiparesis was correlative with patients who subsequently had normal SEPs.

Among 342 men who survived severe penetrating brain wounds, only 15% had prolonged unconsciousness and 53% had no or momentary unconsciousness after injury, emphasizing the focal nature of these wounds. The left (or language-dominant) hemisphere was dominant for the "wakefulness" component of consciousness. The areas most associated with unconsciousness included the posterior limb of the left internal capsule, left basal forebrain, midbrain, and hypothalamus. Left dominance was not seen for posttraumatic amnesia after elimination of the wakefulness variable, suggesting that wakefulness may be linked to the role of the left hemisphere in verbal memory.

Of 421 veterans who had penetrating brain wounds in Vietnam 15 years ago, 53% had posttraumatic epilepsy, and one-half of those still had seizures 15 years after injury. The relative risk of developing epilepsy dropped from about 580 times higher than the general age-matched population in the first year to 25 times higher after 10 years. Patients with focal neurologic signs or large lesions had increased risk of epilepsy, and site of the lesion may have been more important than size in determining occurrence. Family history of epilepsy or preinjury intelligence had no effect on seizure occurrence. Seizure frequency in the first year predicted future severity of seizures. Phenytoin therapy in the first year after injury did not prevent later seizures.