Ultracold collisions in tight harmonic traps: Quantum defect model and application to metastable helium atoms

We analyze a system of two colliding ultracold atoms under strong harmonic confinement from the viewpoint of quantum defect theory and formulate a generalized self-consistent method for determining the allowed energies. We also present two highly efficient computational methods for determining the bound state energies and eigenfunctions of such systems. The perturbed harmonic oscillator problem is characterized by a long asymptotic region beyond the effective range of the interatomic potential. The first method, which is based on quantum defect theory and is an adaptation of a technique developed by one of the authors (GP) for highly excited states in a modified Coulomb potential, is very efficient for integrating through this outer region. The second method is a direct numerical solution of the radial Schr\"{o}dinger equation using a discrete variable representation of the kinetic energy operator and a scaled radial coordinate grid. The methods are applied to the case of trapped spin-polarized metastable helium atoms. The calculated eigenvalues agree very closely for the two methods, and with those computed self-consistently using the generalized self-consistent method.Comment: 11 pages,REVTEX, text substantially revised, title modifie

Adult cortical plasticity depends on an early postnatal critical period

Development of the cerebral cortex is influenced by sensory experience during distinct phases of postnatal development known as critical periods. Disruption of experience during a critical period produces neurons that lack specificity for particular stimulus features, such as location in the somatosensory system. Synaptic plasticity is the agent by which sensory experience affects cortical development. Here, we describe, in mice, a developmental critical period that affects plasticity itself. Transient neonatal disruption of signaling via the C-terminal domain of "disrupted in schizophrenia 1" (DISC1)-a molecule implicated in psychiatric disorders-resulted in a lack of long-term potentiation (LTP) (persistent strengthening of synapses) and experience-dependent potentiation in adulthood. Long-term depression (LTD) (selective weakening of specific sets of synapses) and reversal of LTD were present, although impaired, in adolescence and absent in adulthood. These changes may form the basis for the cognitive deficits associated with mutations in DISC1 and the delayed onset of a range of psychiatric symptoms in late adolescence

Multifaceted roles for BCL3 in cancer: a proto-oncogene comes of age

In the early 1990’s a group of unrelated genes were identified from the sites of recurring translocations in B-cell lymphomas. Despite sharing the nomenclature ‘Bcl’, and an association with blood-borne cancer, these genes have unrelated functions. Of these genes, BCL2 is best known as a key cancer target involved in the regulation of caspases and other cell viability mechanisms. BCL3 on the other hand was originally identified as a non-canonical regulator of NF-kB transcription factor pathways – a signaling mechanism associated with important cell outcomes including many of the hallmarks of cancer. Most of the early investigations into BCL3 function have since focused on its role in NF-kB mediated cell proliferation, inflammation/immunity and cancer. However, recent evidence is coming to light that this protein directly interacts with and modulates a number of other signaling pathways including DNA damage repair, WNT/β-catenin, AKT, TGFβ/SMAD3 and STAT3 – all of which have key roles in cancer development, metastatic progression and treatment of solid tumours. Here we review the direct evidence demonstrating BCL3’s central role in a transcriptional network of signaling pathways that modulate cancer biology and treatment response in a range of solid tumour types and propose common mechanisms of action of BCL3 which may be exploited in the future to target its oncogenic effects for patient benefit

Dual-component structural plasticity mediated by αCaMKII autophosphorylation on basal dendrites of cortical layer 2/3 neurones

Sensory cortex exhibits receptive field plasticity throughout life in response to changes in sensory experience and offers the experimental possibility of aligning functional changes in receptive field properties with underpinning structural changes in synapses. We looked at the effects on structural plasticity of two different patterns of whisker deprivation in male and female mice: chessboard deprivation, which causes functional plasticity; and all deprived, which does not. Using 2-photon microscopy and chronic imaging through a cranial window over the barrel cortex, we found that layer 2/3 neurones exhibit robust structural plasticity, but only in response to whisker deprivation patterns that cause functional plasticity. Chessboard pattern deprivation caused dual-component plasticity in layer 2/3 by (1) increasing production of new spines that subsequently persisted for weeks and (2) enlarging spine head sizes in the preexisting stable spine population. Structural plasticity occurred on basal dendrites, but not apical dendrites. Both components of plasticity were absent in αCaMKII-T286A mutants that lack LTP and experience-dependent potentiation in barrel cortex, implying that αCaMKII autophosphorylation is not only important for stabilization and enlargement of spines, but also for new spine production. These studies therefore reveal the relationship between spared whisker potentiation in layer 2/3 neurones and the form and mechanisms of structural plasticity processes that underlie them

Biodistribution PET/CT study of hemoglobin-DFO-89Zr complex in healthy and lung tumor-bearing mice

Proteins, as a major component of organisms, are considered the preferred biomaterials for drug delivery vehicles. Hemoglobin (Hb) has been recently rediscovered as a potential drug carrier, but its use for biomedical applications still lacks extensive investigation. To further explore the possibility of utilizing Hb as a potential tumor targeting drug carrier, we examined and compared the biodistribution of Hb in healthy and lung tumor-bearing mice, using for the first time 89Zr labelled Hb in a positron emission tomography (PET) measurement. Hb displays a very high conjugation yield in its fast and selective reaction with the maleimide-deferoxamine (DFO) bifunctional chelator. The high-resolution X-ray structure of the Hb-DFO complex demonstrated that cysteine β93 is the sole attachment moiety to the αβ-protomer of Hb. The Hb-DFO complex shows quantitative uptake of 89Zr in solution as determined by radiochromatography. Injection of 0.03 mg of Hb-DFO-89Zr complex in healthy mice indicates very high radioactivity in liver, followed by spleen and lungs, whereas a threefold increased dosage results in intensification of PET signal in kidneys and decreased signal in liver and spleen. No difference in biodistribution pattern is observed between naïve and tumor-bearing mice. Interestingly, the liver Hb uptake did not decrease upon clodronate-mediated macrophage depletion, indicating that other immune cells contribute to Hb clearance. This finding is of particular interest for rapidly developing clinical immunology and projects aiming to target, label or specifically deliver agents to immune cells

Efficient intravenous tumor targeting using the αvβ6 integrin-selective precision virotherapy Ad5NULL-A20

We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes

Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer

Background The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required. Methods A cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease. Results We have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman’s Rank Order Correlation: ρ = − 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease. Conclusions These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients

Active Galactic Nuclei in the Sloan Digital Sky Survey: II. Emission-Line Luminosity Function

The emission line luminosity function of active galactic nuclei (AGN) is measured from about 3000 AGN included in the main galaxy sample of the Sloan Digital Sky Survey within a redshift range of $0<z<0.15$. The \Ha and [OIII]$\lambda 5007$ luminosity functions for Seyferts cover luminosity range of $10^{5-9}$$L_\odot$ in H$\alpha$ and the shapes are well fit by broken power laws, without a turnover at fainter nuclear luminosities. Assuming a universal conversion from emission line strength to continuum luminosity, the inferred B band magnitude luminosity function is comparable both to the AGN luminosity function of previous studies and to the low redshift quasar luminosity function derived from the 2dF redshift survey. The inferred AGN number density is approximately 1/5 of all galaxies and about $6\times 10^{-3}$ of the total light of galaxies in the $r$-band comes from the nuclear activity. The numbers of Seyfert 1s and Seyfert 2s are comparable at low luminosity, while at high luminosity, Seyfert 1s outnumber Seyfert 2s by a factor of 2-4. In making the luminosity function measurements, we assumed that the nuclear luminosity is independent of the host galaxy luminosity, an assumption we test {\it a posteriori}, and show to be consistent with the data. Given the relationship between black hole mass and host galaxy bulge luminosity, the lack of correlation between nuclear and host luminosity suggests that the main variable that determines the AGN luminosity is the Eddington ratio, not the black hole mass. This appears to be different from luminous quasars, which are most likely to be shining near the Eddington limit.Comment: AASTeX v5.02 preprint; 35 pages, including 2 table and 12 figures. To appear in the April 2005 issue of AJ. See astro-ph/0501059 for Paper

Development and characterisation of a new patient-derived Xenograft model of AR-negative metastatic asctration-resistant prostate cancer

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient’s treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease