Advanced Targeting Systems (United States)

Abstract Background In 2022 the European Society of Cardiology published a consensus paper with six definitions of extreme cardiovascular (CV) risk. In secondary the gold standard is definition 2: two cardiovascular events within two years. Commonly used are also acute coronary syndrome (ACS) combined with peripheral or polyvascular disease (definition 3) and ACS with multivessels coronary artery disease (definition 4). The aim of our study was to evaluate the diagnostic accuracy of definitions 3 and 4 compared to the gold standard in a population of ACS patients. Methods The study included 1061 ACS patients admitted to the intensive cardiac care unit (ICCU) of our hospital from 2014 to 2020. The primary composite outcome was time to first ischaemic events (myocardial infarction or stroke or peripheral artery event) or CV death. The follow-up was updated in June 2021 and events in the first 2 years since diagnosis were registered. Results Among the 1061 ACS patients analyzed, the primary composite outcome was observed in 225 (21%) patients, with higher incidence in patients fulfilling criteria of definitions 3 and 4 compared to the general ACS cohort. At multivariate analysis the increased risk was still significant only for definition 4 (HR 1.44; 95% CI 1.03 - 2.01, p=0.031) while the increase in risk was not significant for definition 3 (HR 1.31; 95% CI 0.94 - 1.82, p=0.114;). When definitions 3 and 4 were compared to definition 2 in order to test their discrimination accuracy for early recurring events, we found that they both presented poor predictive performance (definition 3: sensitivity 23.5%, specificity 87.5%, positive predictive values 35.7%; definition 4: sensitivity 25.5%, specificity 85.3%, positive predictive values 32.1%; the percentage of correctly classified patients was 73% for both definitions). Conclusion Among the current definitions of extreme CV risk the one based on the presence of ACS combined with multivessel coronary artery disease most effectively identifies subjects likely to experience early (within 2 years) recurrence. Both definitions, however, showed higher specificity than sensitivity, highlighting their limitations in detecting all individuals at extreme risk within ACS populations. These findings underscore the need for refinement of extreme risk criteria to improve prognostic accuracy and guide targeted interventions.

Substance P-saporin (SP-SAP) has covalent bonds between the biological toxin, saporin (SAP), and the endogenous peptide, substance P (SP). SAP targets the toxin to the subset of neurons expressing the NK1 receptor. SP-SAP is currently in a phase I clinical trial and is unique as it is the only targeted toxin for pain to undergo human testing. This chapter reviews the history of SP-SAP and related NK1-receptor targeted toxins, animal data on the safety and efficacy of SP-SAP for the treatment of pain (in light of the results of NK1 receptor antagonists and knockouts/knockdowns of either SP or the NK1 receptor), and mechanisms of action of SP-SAP.

Silicon photon detectors and focal plane arrays (FPAs) are fabricated in many varieties 1,2 . Their function depends on the detector architecture, dopants, and operating temperature. DRS has fabricated silicon pin detectors that cover the visible spectral range and blocked impurity band (BIB) detectors that cover the very-long-wavelength infrared (VLWIR) region 3 . Imaging arrays of silicon pin-diodes utilize the intrinsic bandgap of silicon to provide high photo response over the 0.4 – 1.0 μm spectral range. The detectors operate at or near room temperature as required. Silicon pin -diode arrays are particularly attractive as an alternative to charge-coupled devices (CCDs) for space applications where radiation hardening is needed. Pros and cons of CCD and pin diode architectures are listed in Reference 4 .

Abstract Basigin-2 (EMMPRIN, CD147) is widely expressed on the surface of numerous tumor types and is associated with poor prognosis. Basigin is an integral membrane glycoprotein also expressed on numerous normal cell types. Several functions have been described for basigin-2 within both normal and malignant tissues. The best characterized is its ability to induce the expression of matrix metalloproteinases in stromal cells. As such, it is suggested to play a role in tumor metastasis. Because of its association with poor prognosis and possible role in metastasis, we examined the ability of basigin-2 to be targeted on the cell surface and internalized as a possible gateway for entry into tumor cells, or for down-regulation for inhibition of metastasis. Belton et al. have documented internalization of basigin-2 by a recombinant soluble protein corresponding to the extracellular domain (ECD) of basigin-2 (J Biol Chem, 2008, 283:17805). We have extended this investigation to examine antibody-mediated endocytosis. A monoclonal antibody to the basigin ECD (also reported in Belton et al.) has been used in an internalization assay using biotinylated antibody mixed with streptavidinylated-saporin (the ribosome-inactivating protein). This complex will eliminate cells only if there is antibody-mediated endocytosis, since saporin has no mechanism of cell entry. HeLa cells, which are known to express basigin-2, were challenged and a potent cytotoxicity was observed: the ED50 of the biotinylated antibody-streptavidin-saporin complex is 370 pM. This is evidence that the antibody internalizes in HeLa cells. Similar data were observed with ovarian carcinoma cells (OVCAR3, SKOV3). Non-tumor cells with low expression have low sensitivity to the complex and there was a correlation between basigin-2 expression on the cell surface and cytotoxicity. We conclude that basigin-2 internalizes in response to antibody binding. Further work is necessary to determine if this can be used for introduction of molecules into basigin-2-expressing cells or if down-regulation would have an effect on metastasis promoted by this poor prognosis molecule. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2244.

Visible light photon counters (VLPCs) offer many attractive features as photon detectors, such as high quantum efficiency and photon number resolution. We report measurements of the single-photon timing jitter in a VLPC, a critical performance factor in a time-correlated single-photon counting measurement, in a fiber-coupled closed-cycle cryocooler. The measured timing jitter is 240 ps full-width-at-half-maximum at a wavelength of 550 nm, with a dark count rate of 25 000 counts per second. The timing jitter increases modestly at longer wavelengths to 300 ps at 1000 nm, and increases substantially at lower bias voltages as the quantum efficiency is reduced.

The Wide-field Infrared Survey Explorer is a NASA Midex mission launching in late 2009 that will survey the entire sky at 3.3, 4.7, 12, and 23 microns (PI: Ned Wright, UCLA). Its primary scientific goals are to find the nearest stars (actually most likely to be brown dwarfs) and the most luminous galaxies in the universe. WISE uses three dichroic beamsplitters to take simultaneous images in all four bands using four 1024×1024 detector arrays. The 3.3 and 4.7 micron channels use HgCdTe arrays, and the 12 and 23 micron bands employ Si:As arrays. In order to make a 1024×1024 Si:As array, a new multiplexer had to be designed and produced. The HgCdTe arrays were developed by Teledyne Imaging Systems, and the Si:As array were made by DRS. All four flight arrays have been delivered to the WISE payload contractor, Space Dynamics Laboratory. We present initial ground-based characterization results for the WISE arrays, including measurements of read noise, dark current, flat field and latent image performance, etc. These characterization data will be useful in producing the final WISE data product, an all-sky image atlas and source catalog.

The high-operating-temperature (HOT) midwave infrared (MWIR) n-on-p detector has been pursued using the high-density vertically integrated photodiode (HDVIP®) architecture. In this device, arsenic-doped HgCdTe grown by liquid-phase epitaxy (LPE) is used, passivated on both surfaces with interdiffused CdTe. Dark current densities on these diodes as low as 2.5 mA/cm2 normalized to a 5 μm cutoff at 250 K have been demonstrated. 1/f noise at 1 Hz, measured at 250 K, is found to be 6 × 10−11 A/rHz-cm measured on a cutoff of 4.43 μm. These results agree with the theoretical predictions for the devices made.

The National Polar-orbiting Operational Environmental Satellite System (NPOESS), is overseen by the Integrated Program Office (IPO), a joint effort of the Department of Defense, Department of Commerce and NASA. One of the instruments on the NPOESS satellite is the Cross-track Infrared Sounder (CrIS) instrument. CrIS is a Fourier Transform interferometric infrared (FTIR) sensor used to measure earth radiance at high spectral resolution to derive pressure, temperature, and moisture profiles of the atmosphere from the ground on up. Each CrIS instrument contains three different cutoff wavelength (λ_c)focal plane modules (FPMs): an SWIR FPM [λ_c(98 K) ~ 5 mm], MWIR FPM [λ_c(98 K) ~ 9 mm] and a LWIR FPM [λ_c(81 K) ~ 15.5 mm]. There are nine large (850 mm diameter) photodiodes per FPM, the nine detectors being arranged in a 3 x 3 array. The nine detectors are placed under tight tolerances in the X, Y, and Z dimensions. The steps involved in the transfer of photodiodes as part of a newly fabricated wafer to the mounting of the photodiodes on the FPM involves many processing steps including a significant amount of dicing, cleaning, wire bonding and baking at elevated temperatures. Quantum efficiency and 1/f noise in Hg_1-xCd_xTe photodiodes are critical parameters that limit the sensitivity of infrared sounders. The ratio α, defined as the noise current in unit bandwidth i_n(f = 1 Hz, V_d, Δf = 1 Hz) to the dark current I_d(V_d), that is, α = i_n/I_d is one of the parameters used to select photodiodes for placement in FPMs. α is equivalent to √α_H/N that appears in the well-known Hooge expression. For the sixty-one, λ_c ~ 9 μm photodiodes measured at 60 mV reverse bias and at 98 K, the average value of α_dark = 1.3 x 10^-4 in the dark and α_PHOTO = i_n/I_PHOTO is ~ 2 x 10^-6 under illuminated conditions. These values of α are a factor of two lower than that reported previously. The λ_c ~ 15.5 μm photodiodes have average α_dark = 1.3 x 10^-5 with the highest performance, diffusion current limited photodiodes having values of α_dark in the mid 10^-6 range. All of the 850 μm diameter, λ_c ~ 15.5 μm photodiodes measured have excess low frequency noise, with the best performers having i_n(f = 100 Hz, V_d =-60 mV , Δf = 1 Hz) ~ 2 x 10^-11 A/Hz^1/2 and the best photodiode α_dark = 3.92 x 10^-6. I-V measurements, noise, and visual inspections are performed at several steps in the photodiodes manufacturing process. It was observed, following FPM fabrication, photodiode dark current and noise had increased from the initial pre-mounting leadless chip carrier (LCC) measurements for some of the nine photodiodes. The performance degradation observed led to an investigation into the cause (baking at elevated temperatures, mechanical handling, electrical stress etc.) of photodiode degradation that occurred between LCC and FPM testing. Correlations between I-V, noise and surface visual defects have been performed on some λ_c ~ 15.5 mm photodiodes. This paper outlines the results of the study, correlating the electrical performance observed to visual defects on the surface and to defects seen following cross sectioning of degraded photodiodes. In addition, other lessons learned and the corrective actions implemented that led to the successful manufacture of SWIR, MWIR and LWIR large photodiodes from the material growth to insertion into and successful demonstration of flight FPMs for the CrIS program are described.

Introduction to Molecular Neurosurgery Ronald G. Wiley and Douglas A. Lappi Ribosome-Inactivating Proteins Fiorenzo Stirpe Biochemical, Physiological, and Behavioral Characterizations of the Cholinergic Basal Forebrain Lesion Produced by 192 IgG-Saporin Jerene J. Waite Basal Forebrain Cholinergic Lesion by 192 IgG-Saporin: A Tool to Assess the Consequences of Cortical Cholinergic Dysfunction in Alzheimer's Disease Reinhard Schliebs 192 IgG-Saporin-Induced Partial Cortical Cholinergic Deafferentation as a Model for Determining the Interactions Between Brain Aging and Neurodevelopmental Defects in the Cortical Cholinergic Input System Martin Sarter and John P. Bruno Exploring the Role of Acetylcholine in Primate Cognition Using Me20.4 IgG-Saporin Rosalind M. Ridley and Harry F. Baker Cortical Cholinergic Deafferentation Induces Ab Deposition: Toward a Physiological Animal Model of Alzheimer's Disease Thomas G. Beach, D. G. Walker, P. E. Potter, L. I. Sue, S. Scott, K. J. Layne, A. J. Newell, P. K. Rauschkolb, M. E. Poston, S. D. Webster, R. A. Durham, M. R. Emmerling, K. Sawada, W. G. Honer, A. Fisher, and A. E. Roher Chemical Dissection of Brain Glucoregulatory Circuitry Sue Ritter, Thu T. Dinh, Kishor Bugarith, and Dawna M. Salter Cardiovascular Deficits After Lesions of C1 Adrenergic Neurons With a Saporin-Based Immunotoxin Patrice G. Guyenet, Ruth L. Stornetta, and Ann M. Schreihofer Saporin Conjugates and Pain Ronald G. Wiley and Douglas A. Lappi The Use of Saporin Conjugates to Dissect Neurons Responsible for Sleep and Wakefulness Carlos Blanco-Centurion, Dmitry Gerashchenko, Eric Murillo-Rodriguez, Frank Desarnaud, and Priyattam J. Shiromani Isolectin B4-Mediated Cytotoxic Targeting of Sensory Neurons Lucy Vulchanova and Christopher N. Honda B Fragment of Cholera ToxinConjugated to Saporin Peter T. Ohara, Kanwarjit Kelley, and Luc Jasmin Index

The term molecular neurosurgery has been applied to several different experimental strategies, including a variety of genetic manipulations. For the purposes of this book, the term is used to refer to the use of targeted cytotoxins to produce highly selective neural lesions. Used in this sense, the term is relevant to both experimental and potential clinical applications. The body of work addressed in this volume grew out of initial experiments in the laboratory of Donald J. Reis in 1980–1981. The initial experimental challenge was how to selectively destroy baroreceptor afferents that make up a small portion of the vagus and glossopharyngeal nerves. The strategy chosen was to develop a technique using toxin retrogradely transported from an application site on the peripheral baroreceptor nerves in the neck. First attempts used low-molecular-weight cytotoxic drugs, such as doxorubicin, and were unsuccessful. Reasoning that the initial lack of success reflected inadequate delivery of toxin to the cell bodies, a plan was developed to attach these drugs to a well-transported agent, such as wheat germ agglutinin, which at the time was introduced as a highly effective anatomical tracer (1). However, a simpler option seemed attractive. If a lectin such as wheat germ agglutinin was well transported, then perhaps a toxic lectin such as ricin or abrin would work. In retrospect, Harper and colleagues (2) had previously shown evidence for retrograde axonal transport of ricin, but this publication was discovered only after the initial suicide transport experiments applied ricin to the vagus nerve (3).