208 research outputs found
Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics
Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint
Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program.
ABSTRACT: BACKGROUND: Violence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them. METHODS: FSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural-biological assessments (IBBAs 2005-2009; administered face-to-face). RESULTS: 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001). CONCLUSIONS: This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights
Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain
peer reviewedAlthough disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [18F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following
Imaging of Alkaline Phosphatase Activity in Bone Tissue
The purpose of this study was to develop a paradigm for quantitative molecular imaging of bone cell activity. We hypothesized the feasibility of non-invasive imaging of the osteoblast enzyme alkaline phosphatase (ALP) using a small imaging molecule in combination with 19Flourine magnetic resonance spectroscopic imaging (19FMRSI). 6, 8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), a fluorinated ALP substrate that is activatable to a fluorescent hydrolysis product was utilized as a prototype small imaging molecule. The molecular structure of DiFMUP includes two Fluorine atoms adjacent to a phosphate group allowing it and its hydrolysis product to be distinguished using 19Fluorine magnetic resonance spectroscopy (19FMRS) and 19FMRSI. ALP-mediated hydrolysis of DiFMUP was tested on osteoblastic cells and bone tissue, using serial measurements of fluorescence activity. Extracellular activation of DiFMUP on ALP-positive mouse bone precursor cells was observed. Concurringly, DiFMUP was also activated on bone derived from rat tibia. Marked inhibition of the cell and tissue activation of DiFMUP was detected after the addition of the ALP inhibitor levamisole. 19FMRS and 19FMRSI were applied for the non-invasive measurement of DiFMUP hydrolysis. 19FMRS revealed a two-peak spectrum representing DiFMUP with an associated chemical shift for the hydrolysis product. Activation of DiFMUP by ALP yielded a characteristic pharmacokinetic profile, which was quantifiable using non-localized 19FMRS and enabled the development of a pharmacokinetic model of ALP activity. Application of 19FMRSI facilitated anatomically accurate, non-invasive imaging of ALP concentration and activity in rat bone. Thus, 19FMRSI represents a promising approach for the quantitative imaging of bone cell activity during bone formation with potential for both preclinical and clinical applications
Quantum saturation and condensation of excitons in CuO: a theoretical study
Recent experiments on high density excitons in CuO provide evidence for
degenerate quantum statistics and Bose-Einstein condensation of this nearly
ideal gas. We model the time dependence of this bosonic system including
exciton decay mechanisms, energy exchange with phonons, and interconversion
between ortho (triplet-state) and para (singlet-state) excitons, using
parameters for the excitonic decay, the coupling to acoustic and low-lying
optical phonons, Auger recombination, and ortho-para interconversion derived
from experiment. The single adjustable parameter in our model is the
optical-phonon cooling rate for Auger and laser-produced hot excitons. We show
that the orthoexcitons move along the phase boundary without crossing it (i.e.,
exhibit a ``quantum saturation''), as a consequence of the balance of entropy
changes due to cooling of excitons by phonons and heating by the non-radiative
Auger two-exciton recombination process. The Auger annihilation rate for
para-para collisions is much smaller than that for ortho-para and ortho-ortho
collisions, explaining why, under the given experimental conditions, the
paraexcitons condense while the orthoexcitons fail to do so.Comment: Revised to improve clarity and physical content 18 pages, revtex,
figures available from G. Kavoulakis, Physics Department, University of
Illinois, Urban
Quantitative Modeling of Cerenkov Light Production Efficiency from Medical Radionuclides
There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use
Mental health challenges and perceived risks among female sex Workers in Nairobi, Kenya
Background: Female sex workers (FSWs) in Kenya are at an increased risk of violence, poverty, police arrest, and problematic alcohol and other substance use, all of which are linked to poor mental health and suicidal ideation. Despite the psychological stressors experienced by FSWs, there is no published qualitative methods research investigating their mental health experiences in Kenya. In this paper, we draw on data from in-depth interviews to examine FSWs’ lifetime mental health experiences and perceived risk factors. Methods: We used baseline in-depth interviews of the Maisha Fiti longitudinal study of FSWs in Nairobi. We randomly selected 40 FSWs from 1003 FSWs who attended a baseline behavioural-biological interview as part of the Maisha Fiti study. The interview guide was semi-structured, and participants were asked to detail their life stories, including narrating specific events such as entry into sex work, experiences of violence, mental health experiences, and use of alcohol and other substances. Interviews were recorded in Kiswahili/ English and transcribed in English. Data were coded and thematically analysed in Nvivo (v.12). Results: Results indicated that the majority of participants understood ‘mental health’ as ‘insanity’, ‘stress’, ‘depression’, and ‘suicide’; nevertheless, a number described mental health symptomatically, while a few believed that mental health problems were caused by witchcraft. Interestingly, poverty, low levels of education, poor job opportunities, a lack of family support, harmful gender norms, intimate partner violence and subsequent relationship breakdowns, and family bereavement all contributed to poor mental health and subsequent entry into sex work. In addition, the consequences of sex work such as sexual risks, and ongoing violence from police and clients, further exacerbated poor mental health. Conclusions: There is a need for both micro- and macro interventions to address poverty and violence against FSWs in Kenya, thereby reducing mental health problems. Addressing violence against women and girls may also reduce entry into sex work. Improving mental health literacy and providing mental health intervention services for ‘at-risk’ populations such as FSWs should enhance coping strategies and help-seeking efficacy
Calibration and Characterization of the IceCube Photomultiplier Tube
Over 5,000 PMTs are being deployed at the South Pole to compose the IceCube
neutrino observatory. Many are placed deep in the ice to detect Cherenkov light
emitted by the products of high-energy neutrino interactions, and others are
frozen into tanks on the surface to detect particles from atmospheric cosmic
ray showers. IceCube is using the 10-inch diameter R7081-02 made by Hamamatsu
Photonics. This paper describes the laboratory characterization and calibration
of these PMTs before deployment. PMTs were illuminated with pulses ranging from
single photons to saturation level. Parameterizations are given for the single
photoelectron charge spectrum and the saturation behavior. Time resolution,
late pulses and afterpulses are characterized. Because the PMTs are relatively
large, the cathode sensitivity uniformity was measured. The absolute photon
detection efficiency was calibrated using Rayleigh-scattered photons from a
nitrogen laser. Measured characteristics are discussed in the context of their
relevance to IceCube event reconstruction and simulation efforts.Comment: 40 pages, 12 figure
A Consensus Map in Cultivated Hexaploid Oat Reveals Conserved Grass Synteny with Substantial Subgenome Rearrangement
Hexaploid oat ( L., 2 = 6 = 42) is a member of the Poaceae family and has a large genome (∼12.5 Gb) containing 21 chromosome pairs from three ancestral genomes. Physical rearrangements among parental genomes have hindered the development of linkage maps in this species. The objective of this work was to develop a single high-density consensus linkage map that is representative of the majority of commonly grown oat varieties. Data from a cDNA-derived single-nucleotide polymorphism (SNP) array and genotyping-by-sequencing (GBS) were collected from the progeny of 12 biparental recombinant inbred line populations derived from 19 parents representing oat germplasm cultivated primarily in North America. Linkage groups from all mapping populations were compared to identify 21 clusters of conserved collinearity. Linkage groups within each cluster were then merged into 21 consensus chromosomes, generating a framework consensus map of 7202 markers spanning 2843 cM. An additional 9678 markers were placed on this map with a lower degree of certainty. Assignment to physical chromosomes with high confidence was made for nine chromosomes. Comparison of homeologous regions among oat chromosomes and matches to orthologous regions of rice ( L.) reveal that the hexaploid oat genome has been highly rearranged relative to its ancestral diploid genomes as a result of frequent translocations among chromosomes. Heterogeneous chromosome rearrangements among populations were also evident, probably accounting for the failure of some linkage groups to match the consensus. This work contributes to a further understanding of the organization and evolution of hexaploid grass genomes
A neural oscillations perspective on phonological development and phonological processing in developmental dyslexia
Children’s ability to reflect upon and manipulate the sounds in words (’phonological awareness’) develops as part of natural language acquisition, supports reading acquisition, and develops further as reading and spelling are learned. Children with developmental dyslexia typically have impairments in phonological awareness. Many developmental factors contribute to individual differences in phonological development. One important source of individual differences may be the child’s sensory/neural processing of the speech signal from an amplitude modulation (~ energy or intensity variation) perspective, which may affect the quality of the sensory/neural representations (’phonological representations’) that support phonological awareness. During speech encoding, brain electrical rhythms (oscillations, rhythmic variations in neural excitability) re-calibrate their temporal activity to be in time with rhythmic energy variations in the speech signal. The accuracy of this neural alignment or ’entrainment’ process is related to speech intelligibility. Recent neural studies demonstrate atypical oscillatory function at slower rates in children with developmental dyslexia. Potential relations with the development of phonological awareness by children with dyslexia are discussed.Medical Research Council, G0400574 and G090237
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