The bone-forming metastases of prostate cancer result from complex stromal–epithelial interactions within the tumour microenvironment. Autocrine–paracrine signalling pathways between prostate cancer epithelial cells, osteoblasts, and osteoclasts stimulate aberrant bone remodelling, and the activity of these three cell populations can be quantitatively measured using prostate-specific antigen (PSA), bone-specific alkaline phosphatase (BAP) and urine N-telopeptide (uNTx), respectively. The purpose of the present study was to test the hypothesis that serial measurements of BAP and uNTx during therapy would facilitate monitoring of disease activity and predict the overall survival (OS) in patients with metastatic prostate cancer receiving therapy.
Radionuclide bone scan, PSA, BAP, and uNTx data were retrospectively analysed from three clinical trials in patients with metastatic prostate cancer conducted at our institution. Qualitative changes in bone scans and quantitative changes in PSA, BAP, and uNTx concentrations during therapy were correlated with OS.
Baseline levels of BAP, but not PSA, were prognostic for OS in both androgen-dependent and castrate-resistant disease. A reduction in PSA, BAP, uNTx, or BAP/uNTx on therapy was predictive of improved OS in both patient groups. Conversely, an increase in PSA, or BAP on therapy was predictive of worse OS in both patient groups. Baseline number of lesions and response on bone scan during therapy were neither prognostic nor predictive of OS in either patient group.
These observations support the concept that serial measurements of bone turnover metabolites during therapy function as clinically informative predictive biomarkers in patients with advanced prostate cancer and skeletal metastases. PSA measurements and bone scans remain essential to monitor the overall disease activity and determine the anatomic distribution of skeletal metastases.
prostate cancer; bone; predictive biomarkers; metastases
THYmocyte differentiation antigen 1 (Thy-1), is a cell surface glycoprotein found on T cells and neurons and is involved in cell-to-cell interactions. In addition, Thy-1 knockouts (KO) are a potential mouse model of restless legs syndrome (RLS) based on clinical observations and the role of dopamine in the disease. In this study, we analyzed the activity and quantity of tyrosine hydroxylase (TH; the rate-limiting enzyme in dopamine production) and determined phosphorylation levels for the enzyme (phospho-serine-40 (pSer-40)). There was no significant difference in the total TH activity and pSer-40 TH levels between Thy-1 KO and control groups; however, TH specific activity was significantly lower (by 26%) in Thy-1 KO mice. This difference is, in part, due to increased TH protein levels in this group (increased by 29%). When analyzed by gender, we determined that Thy-1 KO female mice striata contained less TH specific activity compared to control females (decreased by 41%) and male control or Thy-1 KO animals (decreased by 30%). TH specific activity and pSer-40 TH levels between male Thy-1 KO and control displayed no differences. However, pSer-40 TH was significantly higher in control females (38%) compared to control or Thy-1 KO males. The Thy-1 KO females exhibited significantly lower (28%) pSer-40 TH (normalized to GAPDH or TH) than control females. Indeed, the Thy-1 KO females had 50% of the pSer-40 TH found in controls. Our results suggest a gender effect on TH specific activity, TH protein levels and serine-40 phosphorylation of TH in Thy-1 KO female mice.
Thy-1; tyrosine hydroxylase; phosphorylation; gender-specific expression
: Haemophilic pseudotumour (HP) is an extremely rare lesion. The purpose of this study was to describe the CT and MRI features of maxillary bone HPs and introduce the key points to differentiate HP from the mimicking entities in the region.
: We retrospectively reviewed three paediatric patients with histology-proven HPs arising from the maxillary bone. All three patients underwent CT and/or MRI. Combined with six previously reported cases in the literature, the imaging features were comprehensively analysed.
: All HPs showed a well-demarcated, multilobulated expansile osteolytic lesion in the maxillary bone. On non-enhanced CT, HPs appeared of mixed density relative to grey matter. The lesions appeared to have markedly heterogeneous signal intensity on both T1 and T2 weighted images, with septa-like enhancement following the administration of contrast material, which corresponded to blood products in various stages of evolution. The lesions caused cortical thinning and even focal disappearance and multiple bone septa were identified within the involved maxillary bone. Some HPs were associated with radiated periosteal proliferation, which can easily be misdiagnosed as a malignant bone tumour.
: A high index of suspicion for HP and a familiarity with imaging findings may help to accurately diagnose this rare entity.
Through silencing tumor suppressor genes, epigenetic changes can activate signaling pathways important to cancer development. In this report, we found an epigenetic contribution to the aberrant activation of wnt signaling in human gastric cancer. CXXC4 (CXXC finger protein 4) was identified as a novel target of EZH2 (enhancer of zeste homolog 2), and EZH2 promotes the activation of wnt singaling by downregulating CXXC4 expression. CXXC4 inhibits the growth of gastric cancer cells both in vitro and in vivo through inactivating wnt signaling. In contrast, depletion of CXXC4 activates wnt signaling and promotes the anchorage-independent growth of nontumor gastric epithelial cells. CXXC4 is downregulated in gastric carcinoma tissues and its downregulation is associated with poor outcome of gastric cancer patients (hazard ratio: 5.053, P<0.05). Through its binding to dishevelled (Dvl), CXXC4 stabilizes the destruction complex of β-catenin to inhibit wnt signaling. Two critical amino acid residues in CXXC4, K161 and T162 were found to be important to its binding to Dvl and the growth inhibitory effect of CXXC4. In summary, EZH2 promotes the activation of wnt signaling in gastric carcinogenesis through the downregulation of CXXC4 expression. CXXC4 is a novel potential tumor suppressor directly regulated by EZH2, and its expression is a significant prognosis factor for patients with early stages of gastric cancer.
EZH2; Wnt/β-catenin signaling; CXXC4; gastric cancer
Sleep disturbance, a correlate of which is daytime napping, has been hypothesised to be associated with risk of breast and other cancers.
We estimated relative risks (RR) of breast and other invasive cancers by the reported frequency of daytime napping in a large prospective cohort of middle-aged women in the UK.
During an average of 7.4 years of follow-up, 20 058 breast cancers and 31 856 other cancers were diagnosed. Over the first 4 years of follow-up, daytime napping (sometimes/usually vs rarely/never) was associated with slightly increased risks of breast cancer (RR=1.10, 95% CI 1.06–1.15) and of other cancers (RR=1.12, 1.08–1.15), but the RRs decreased significantly with increasing follow-up time (P=0.001 and P=0.01, respectively, for trend). Four or more years after baseline, there was no elevated risk of breast cancer (RR=1.00, 0.96–1.05), and only marginally greater risk of other cancers (RR=1.04, 1.01–1.07).
The effect of pre-clinical disease is a likely explanation for the short-term increased risk of breast and other cancers associated with daytime napping.
daytime napping; sleep disturbance; breast cancer; reverse causation; pre-clinical cancer
The wiggler X-ray source of the Materials Science beamline at the Swiss Light Source has been replaced with a 14 mm-period cryogenically cooled in-vacuum undulator. In order to best exploit the increased brilliance of this new source, the entire front-end and optics have been redesigned.
The Materials Science beamline at the Swiss Light Source has been operational since 2001. In late 2010, the original wiggler source was replaced with a novel insertion device, which allows unprecedented access to high photon energies from an undulator installed in a medium-energy storage ring. In order to best exploit the increased brilliance of this new source, the entire front-end and optics had to be redesigned. In this work, the upgrade of the beamline is described in detail. The tone is didactic, from which it is hoped the reader can adapt the concepts and ideas to his or her needs.
beamline upgrade; undulator radiation; X-ray optics; powder diffraction; surface diffraction; coherent X-ray diffraction imaging
A major barrier to effective treatment of glioblastoma multiforme (GBM) is the invasion of glioma cells into the brain parenchyma rendering local therapies such as surgery and radiation therapy ineffective. GBM patients with such highly invasive and infiltrative tumors have poor prognosis with a median survival time of only about a year. However, the mechanisms leading to increased cell migration, invasion and diffused behavior of glioma cells are still poorly understood.
In the current study, we applied quantitative proteomics for the identification of differentially expressed proteins in GBMs as compared to non-malignant brain tissues.
Our study led to the identification of 23 proteins showing overexpression in GBM; these include membrane proteins, moesin and CD44. The results were verified using Western blotting and immunohistochemistry in independent set of GBM and non-malignant brain tissues. Both GBM tissues and glioma cell lines (U87 / U373) demonstrated membranous expression of moesin and CD44, as revealed by immunohistochemistry and immunofluorescence, respectively. Notably, glioma cells transfected with moesin siRNA displayed reduced migration and invasion on treatment with hyaluronan (HA), an important component of the extracellular matrix in GBM. CD44, a transmembrane glycoprotein, acts as a major receptor for hyaluronan (HA). Using co-immunoprecipitation assays, we further demonstrated that moesin interacts with CD44 in glioma cells only after treatment with HA; this implicates a novel role of moesin in HA-CD44 signaling in gliomas.
Our results suggest that development of inhibitors which interfere with CD44-moesin interactions may open a new avenue in the future to mitigate cellular migration in gliomas.
Glioblastoma; CD44; ERM proteins; Moesin
The glass-forming ability (GFA) of alloys with a high-solvent content such as soft magnetic Fe-based and Al-based alloys is usually limited due to strong formation of the solvent-based solid solution phase. Herein, we report that the GFA of soft magnetic Fe-based alloys (with >70 at.% Fe to ensure large saturation magnetization) could be dramatically improved by doping with only 0.3 at.% Cu which has a positive enthalpy of mixing with Fe. It was found that an appropriate Cu addition could enhance the liquid phase stability and crystallization resistance by destabilizing the α-Fe nano-clusters due to the necessity to redistribute the Cu atoms. However, excessive Cu doping would stimulate nucleation of the α-Fe nano-clusters due to the repulsive nature between the Fe and Cu atoms, thus deteriorating the GFA. Our findings provide new insights into understanding of glass formation in general.
Delusions are the false and often incorrigible beliefs that can cause severe suffering in mental illness. We cannot yet explain them in terms of underlying neurobiological abnormalities. However, by drawing on recent advances in the biological, computational and psychological processes of reinforcement learning, memory, and perception it may be feasible to account for delusions in terms of cognition and brain function. The account focuses on a particular parameter, prediction error – the mismatch between expectation and experience – that provides a computational mechanism common to cortical hierarchies, frontostriatal circuits and the amygdala as well as parietal cortices. We suggest that delusions result from aberrations in how brain circuits specify hierarchical predictions, and how they compute and respond to prediction errors. Defects in these fundamental brain mechanisms can vitiate perception, memory, bodily agency and social learning such that individuals with delusions experience an internal and external world that healthy individuals would find difficult to comprehend. The present model attempts to provide a framework through which we can build a mechanistic and translational understanding of these puzzling symptoms.
Delusions; Prediction; Error; Learning; Memory; Reconsolidation; Habit
To investigate the feasibility of converting a computer–aided detection (CAD) scheme for digitised screen–film mammograms to full-field digital mammograms (FFDMs) and assessing CAD performance on a large database.
The database included 6478 FFDM images acquired on 1120 females, with 525 cancer cases and 595 negative cases. The database was divided into five case groups: (1) cancer detected during screening, (2) interval cancers, (3) “high-risk” recommended for surgical excision, (4) recalled but negative and (5) negative (not recalled). A previously developed CAD scheme for masses depicted on digitised images was converted and re-optimised for FFDM images while keeping the same image-processing structure. CAD performance was analysed on the entire database.
The case-based sensitivity was 75.6% (397/525) for the current mammograms and 40.8% (42/103) for the prior mammograms deemed negative during clinical interpretation but “visible” during retrospective review. The region-based sensitivity was 58.1% (618/1064) for the current mammograms and 28.4% (57/201) for the prior mammograms. The CAD scheme marked 55.7% (221/397) and 35.7% (15/42) of the masses on both views of the current and the prior examinations, respectively. The overall CAD-cued false-positive rate was 0.32 per image, ranging from 0.29 to 0.51 for the five case groups.
This study indicated that (1) digitised image-based CAD can be converted for FFDMs while performing at a comparable, or better, level; (2) CAD detects a substantial fraction of cancers depicted on prior examinations, albeit most having been marked only on one view; and (3) CAD tends to mark more false-positive results on “difficult” negative cases that are more visually difficult for radiologists to interpret.
Adipose Derived Stromal/Stem Cells (ASCs) have been gaining recognition as extremely versatile cell source in tissue engineering. The usefulness of ASCs in biofabrication is further enhanced by our demonstration of unique properties of these cells when they are cultured as three dimensional cellular aggregates or spheroids. As described herein, three-dimensional formulations or self-assembling ASC spheroids develop their own extracellular matrix that serves to increase the robustness of the cells to mechanical stresses. The composition of the extracellular matrix can be altered based on the external environment of the spheroids and these constructs can be grown in a reproducible manner and to a consistent size. The spheroid formulation helps preserve the viability and developmental plasticity of ASCs even in defined, serum-free media conditions. For the first time, we show that multiple generations of adherent ASCs produced from these spheroids retain their developmental plasticity and their ability to differentiate into multiple cell/tissue types. These demonstrated properties support the fact that culture expanded ASCs are an excellent candidate cellular material for “organ printing” – the approach of developing complex tissue structures from a standardized cell “ink” or cell formulation.
Racial disparities persist in early childhood wheezing and cannot be completely explained by known risk factors.
To evaluate the associations of genetic ancestry and self-identified race with early childhood recurrent wheezing, accounting for socio-economic status (SES) and early life exposures.
We studied 1034 children in an urban, multi-racial, prospective birth cohort. Multivariate logistic regression was used to evaluate the association of genetic ancestry as opposed to self-identified race with recurrent wheezing (>3 episodes). Sequential models accounted for demographic, socio-economic factors and early life risk factors. Genetic ancestry, estimated using 150 ancestry informative markers, was expressed in deciles.
Approximately 6.1% of subjects (mean age 3.1 years) experienced recurrent wheezing. After accounting for SES and demographic factors, African ancestry (OR: 1.16, 95% CI: 1.02–1.31) was significantly associated with recurrent wheezing. By self-reported race, hispanic subjects had a borderline decrease in risk of wheeze compared with African Americans (OR: 0.44, 95% CI: 0.19–1.00), whereas white subjects (OR: 0.46, 95% CI: 0.14–1.57) did not have. After further adjustment for known confounders and early life exposures, both African (OR: 1.19, 95% CI: 1.05–1.34) and European ancestry (OR: 0.84, 95% CI: 0.74–0.94) retained a significant association with recurrent wheezing, as compared with self-identified race (ORwhites: 0.31, 95% CI: 0.09–1.14; ORhispanic: 0.47, 95% CI: 0.20–1.08). There were no significant interactions between ancestry and early life factors on recurrent wheezing.
Conclusions and Clinical Relevance
In contrast to self-identified race, African ancestry remained a significant, independent predictor of early childhood wheezing after accounting for early life and other known risk factors associated with lung function changes and asthma. Genetic ancestry may be a powerful way to evaluate wheezing disparities and a proxy for differentially distributed genetic and early life risk factors associated with childhood recurrent wheezing.
early childhood; genetic ancestry; race; wheezing
The influenza A virus is a causative agent of influenza, which infects human cells and uses host factors to accomplish viral genome replication as part of its life cycle. The nucleoprotein (NP) and PB2 of the influenza virus associate with importin α1 to gain access to the host nucleus through a ternary import complex. Killer cell-mediated cytotoxicity is the primary mechanism of eliminating the influenza virus. Here, we showed that lymphokine-activated killer cells participated in the elimination of the influenza virus. Granzyme (Gzm) K inhibition elevated viral replication in vitro and aggravated viral infection in vivo. We identified that importin α1 and its transport partner protein importin β are physiological substrates of GzmK. Proteolysis of these two substrates wrecked their association to generate the importin α1/β dimer and disrupted transportation of viral NP to the nucleus, leading to inhibition of influenza virus replication.
granzyme K; importin α1; importin β; influenza A virus; substrate
The temporomandibular joint (TMJ) undergoes degenerative changes among patients who suffer from arthritis, and yet the pathogenesis of TMJ osteoarthritis and rheumatoid arthritis is poorly understood. We hypothesized that sustained inflammation in the TMJ induces structural abnormalities, and accordingly characterized the disc and synovium in a novel model with double injections of complete Freund’s adjuvant (CFA), using behavioral, morphological, cellular, and molecular assessments. Thirty-five days following double CFA injections in seven-week-old female Sprague-Dawley rats, the disc in the CFA-induced inflammation group demonstrated multiple degenerative changes, including marked thickening, opacity, and deformation. The discs in the CFA group further showed significantly greater wet and net weights, and elevated collagen, aggrecan, and total glycosaminoglycan contents. The synovium in the CFA-induced inflammation group showed marked infiltration of mononucleated cells and accumulated sub-synovial adipose tissue. Both the disc and synovium had significantly higher iNOS and IL-1β mRNA expression than controls (saline injections). These findings are consistent with our hypothesis that sustained TMJ inflammation, even within the presently observed 35 days, may be a predisposing factor for structural abnormalities. Insight into TMJ inflammation and degeneration is anticipated to improve our understanding of the pathogenesis of TMJ arthritis and help design clinically relevant strategies for tissue engineering.
inflammation; TMJ; disc; synovium; collagen; degenerative disease
To explore types, levels and patterns of genetic divergence among diploid Gossypium (cotton) genomes, 780 cDNA, genomic DNA and simple sequence repeat (SSR) loci were re-sequenced in Gossypium herbaceum (A1 genome), G. arboreum (A2), G. raimondii (D5), G. trilobum (D8), G. sturtianum (C1) and an outgroup, Gossypioides kirkii. Divergence among these genomes ranged from 7.32 polymorphic base pairs per 100 between G. kirkii and G. herbaceum (A1) to only 1.44 between G. herbaceum (A1) and G. arboreum (A2). SSR loci are least conserved with 12.71 polymorphic base pairs and 3.77 polymorphic sites per 100 base pairs, whereas expressed sequence tags are most conserved with 3.96 polymorphic base pairs and 2.06 sites. SSR loci also exhibit the highest percentage of ‘extended polymorphisms' (spanning multiple consecutive nucleotides). The A genome lineage was particularly rapidly evolving, with the D genome also showing accelerated evolution relative to the C genome. Unexpected asymmetry in mutation rates was found, with much more transition than transversion mutation in the D genome after its divergence from a common ancestor shared with the A genome. This large quantity of orthologous DNA sequence strongly supports a phylogeny in which A–C divergence is more recent than A–D divergence, a subject that is of much importance in view of A–D polyploid formation being key to the evolution of the most productive and finest-quality cottons. Loci that are monomorphic within A or D genome types, but polymorphic between genome types, may be of practical importance for identifying locus-specific DNA markers in tetraploid cottons including leading cultivars.
DNA diversity; SNP; evolution; speciation; cotton
Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons.
Case Report and Results:
The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus–specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy (1H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures.
New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. 1H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.
Although cell-in-cell structure was noted 100 years ago, the molecular mechanisms of ‘entering' and the destination of cell-in-cell remain largely unclear. It takes place among the same type of cells (homotypic cell-in-cell) or different types of cells (heterotypic cell-in-cell). Cell-in-cell formation affects both effector cells and their host cells in multiple aspects, while cell-in-cell death is under more intensive investigation. Given that cell-in-cell has an important role in maintaining homeostasis, aberrant cell-in-cell process contributes to the etiopathology in humans. Indeed, cell-in-cell is observed in many pathological processes of human diseases. In this review, we intend to discuss the biological models of cell-in-cell structures under physiological and pathological status.
cell-in-cell; cannibalism; entosis; emperitosis; biological significance
RAS mutations occur frequently in human cancer and activated RAS signalling contributes to tumour development and progression. Apart from its oncogenic effects on cell growth, active RAS has tumour-suppressive functions via its ability to induce cellular senescence and apoptosis. RAS is known to induce p53-dependent cell cycle arrest, yet its effect on p53-dependent apoptosis remains unclear. We report here that apoptosis-stimulating protein of p53 (ASPP) 1 and 2, two activators of p53, preferentially bind active RAS via their N-terminal RAS-association domains (RAD). Additionally, ASPP2 colocalises with and contributes to RAS cellular membrane localisation and potentiates RAS signalling. In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53. Thus, loss of ASPP1 and ASPP2 in human cancer cells may contribute to the full transforming property of RAS oncogene.
ASPP2; ASPP1; RAS; p53; apoptosis
Quantifying the effect of pollen dispersal and flowering traits on mating success is essential for understanding evolutionary responses to changing environments and establishing strategies for forest tree breeding. This study examined, quantitatively, the effects of male fecundity, interindividual distance and anisotropic pollen dispersal on the mating success of Scots pine (Pinus sylvestris), utilizing a well-mapped Scots pine seed orchard. Paternity analysis of 1021 seeds sampled from 87 trees representing 28 clones showed that 53% of the seeds had at least one potential pollen parent within the orchard. Pronounced variation in paternal contribution was observed among clones. Variations in pollen production explained up to 78% of the variation in mating success, which was 11.2 times greater for clones producing the largest amount of pollen than for clones producing the least pollen. Mating success also varied with intertree distance and direction, which explained up to 28% of the variance. Fertilization between neighboring trees 2.3 m apart was 2.4 times more frequent than between trees 4.6 m apart, and up to 12.4 times higher for trees downwind of the presumed prevailing wind direction than for upwind trees. The effective number of pollen donors recorded in the seed orchard (12.2) was smaller than the theoretical expectation (19.7). Based on the empirical observations, a mating model that best describes the gene dispersal pattern in clonal seed orchards was constructed.
anisotropic pollen dispersal; male fecundity; distance effect; mating model; paternity assignment
Tumor metastasis is the main cause of death in cancer patients. Anoikis resistance is one critical malefactor of metastatic cancer cells to resist current clinical chemotherapeutic treatments. Although endoperoxide-containing compounds have long been suggested as anticancer drugs, few have been clinically employed due to their instability, complex synthesis procedure or low tumor cell selectivity. Herein, we describe a one-pot strategy to synthesize novel amino endoperoxides and their derivatives with good yields and stabilities. In vitro cell-based assays revealed that 4 out of the 14 amino endoperoxides selectively induce metastatic breast carcinoma cells but not normal breast cells to undergo apoptosis, in a dose-dependent manner. Mechanistic studies showed that the most potent amino endoperoxide, 4-Me, is selective for cancer cells expressing a high level of Nox4. The anticancer effects are further shown to be associated with reduced O2−:H2O2 ratio and increased ·OH level in the cancerous cells. Animal study showed that 4-Me impairs orthotopic breast tumor growth as well as tumor cell metastasis to lymph nodes. Altogether, our study suggests that anticancer strategies that focus on redox-based apoptosis induction in tumors are clinically viable.
Nox4; cancer; anoikis; reactive oxygen species; amino endoperoxides
Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, Toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the non-opioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knockouts of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, whilst displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system which amplifies opioid-induced elevations in extracellular dopamine levels and therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.
We propose a new type of momentum spectrometer, which uses the R×B drift effect to disperse the charged particles in a uniformly curved magnetic field, and measures the particles with large phase space acceptance and high resolution. This kind of R×B spectrometer is designed for the momentum analyses of the decay electrons and protons in the PERC (Proton and Electron Radiation Channel) beam station, which provides a strong magnetic field to guide the charged particles in the instrument. Instead of eliminating the guiding field, the R×B spectrometer evolves the field gradually to the analysing field, and the charged particles can be adiabatically transported during the dispersion and detection. The drifts of the particles have similar properties as their dispersion in the normal magnetic spectrometer. Besides, the R×B spectrometer is especially ideal for the measurements of particles with low momenta and large incident angles. We present a design of the R×B spectrometer, which can be used in PERC. For the particles with solid angle smaller than 88 msr, the maximum aberration is below 10−4. The resolution of the momentum spectra can reach 14.4 keV/c, if the particle position measurements have a resolution of 1 mm.
Large acceptance spectrometer; R×B drift effect; PERC; Magnetic field; Adiabatic transport; Neutron decay
Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su.
COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared.
COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy.
COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.
renal cell carcinoma; anti-angiogenic therapy; COX-2 inhibitor; sunitinib