Humoral and cellular immunopathology of hepatic and cardiac hamster-into-rat xenograft rejection: Marked stimulation of IgM^++bright/IgD^+dull splenic B cells

Normal Lewis rat serum contains antibodies (IgM > IgG) that bind to hamster leukocytes and endothelial cells. Transplantation of either the heart or liver from hamster rat results in release of hamster hematolymphoid cells from the graft, which lodge in the recipient spleen (cell migration), where recipient T- and B-cell populations initiate DNA synthesis within one day. There is marked stimulation of splenic IgM++(bright)/IgD+(dull) B cells in the marginal zone and red pulp, which account for 48% of the total splenic blast cell population by 4 days after liver transplantation. CD4+ predominant T-cell proliferation in the splenic periarterial lymphatic sheath and paracortex of peripheral lymph nodes occurs almost simultaneously. The effector phase of rejection in cardiac recipients is dominated by complement-fixing IgM antibodies, which increase daily and result in graft destruction in 3 to 4 days, even in animals treated with FK506. In liver recipients, combined antibody and cellular rejection, associated with graft infiltration by OX8+ natural killer, and fewer W3/25+ (CD4) lymphocytes, are responsible for graft failure in untreated recipients at 6 to 7 days. FK506 inhibits the T-cell response in liver recipients and significantly prolongs graft survival, but does not prevent the rise or deposition of IgM antibodies in the graft. However, a single injection of cyclophosphamide 10 days before transplantation effectively depletes the splenic IgM++(bright)/IgD+(dull) cells and in combination with FK506, results in 100% survival of both cardiac and hepatic xenografts for more than 60 days. Although extrapolation of morphological findings to functional significance is fraught with potential problems, we propose the following mechanisms of xenograft rejection. The reaction initially appears to involve primitive host defense mechanisms, including an IgM-producing subpopulation of splenic B cells and natural killer cells. Based on the reaction and distribution of OX8+ and W3/25+ cells, antibody dependent cell cytotoxicity and delayed-type hypersensitivity responses seem worthy of further investigation as possible effector mechanisms. Effective control of xenograft rejection is likely to require a dual pharmaceutical approach, one to contain T-cell immunity and another to blunt the primitive B-cell response

A hybrid intelligent agent for notification of users distracted by mobile phones in an urban environment

Mobile devices are now ubiquitous in daily life and the number of activities that can be performed using them is continually growing. This implies increased attention being placed on the device and diverted away from events taking place in the surrounding environment. The impact of using a smartphone on pedestrians in the vicinity of urban traffic has been investigated in a multimodal, fully immersive, virtual reality environment. Based on experimental data collected, an agent to improve the attention of users in such situations has been developed. The proposed agent uses explicit, contextual data from experimental conditions to feed a statistical learning model. The agent’s decision process is aimed at notifying users when they become unaware of critical events in their surroundings

The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis.

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology

Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories

In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphse plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered

Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage

'Designer atoms' for quantum metrology

Entanglement is recognized as a key resource for quantum computation and quantum cryptography. For quantum metrology, the use of entangled states has been discussed and demonstrated as a means of improving the signal-to-noise ratio. In addition, entangled states have been used in experiments for efficient quantum state detection and for the measurement of scattering lengths. In quantum information processing, manipulation of individual quantum bits allows for the tailored design of specific states that are insensitive to the detrimental influences of an environment. Such 'decoherence-free subspaces' protect quantum information and yield significantly enhanced coherence times. Here we use a decoherence-free subspace with specifically designed entangled states to demonstrate precision spectroscopy of a pair of trapped Ca+ ions; we obtain the electric quadrupole moment, which is of use for frequency standard applications. We find that entangled states are not only useful for enhancing the signal-to-noise ratio in frequency measurements - a suitably designed pair of atoms also allows clock measurements in the presence of strong technical noise. Our technique makes explicit use of non-locality as an entanglement property and provides an approach for 'designed' quantum metrology

A thermodynamic unification of jamming

Fragile materials ranging from sand to fire-retardant to toothpaste are able to exhibit both solid and fluid-like properties across the jamming transition. Unlike ordinary fusion, systems of grains, foams and colloids jam and cease to flow under conditions that still remain unknown. Here we quantify jamming via a thermodynamic approach by accounting for the structural ageing and the shear-induced compressibility of dry sand. Specifically, the jamming threshold is defined using a non-thermal temperature that measures the 'fluffiness' of a granular mixture. The thermodynamic model, casted in terms of pressure, temperature and free-volume, also successfully predicts the entropic data of five molecular glasses. Notably, the predicted configurational entropy avoids the Kauzmann paradox entirely. Without any free parameters, the proposed equation-of-state also governs the mechanism of shear-banding and the associated features of shear-softening and thickness-invariance.Comment: 16 pgs double spaced. 4 figure

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use