Uptake of IgG in osteosarcoma correlates inversely with interstitial fluid pressure, but not with interstitial constituents

The uptake of therapeutic macromolecules in solid tumours is assumed to be hindered by the heterogeneous vascular network, the high interstitial fluid pressure, and the extracellular matrix. To study the impact of these factors, we measured the uptake of fluorochrome-labelled IgG using confocal laser scanning microscopy, interstitial fluid pressure by the ‘wick-in-needle’ technique, vascular structure by stereological analysis, and the content of the extracellular matrix constituents collagen, sulfated glycosaminoglycans and hyaluronan by colourimetric assays. The impact of the microenvironment on these factors was studied using osteosarcomas implanted either subcutaneously or orthotopically around the femur in athymic mice. The uptake of IgG was found to correlate inversely with the interstitial fluid pressure and the tumour volume in orthotopic, but not subcutaneous tumours. No correlation was found between IgG uptake and the level of any of the extracellular matrix constituents. The content of both collagen and glycosaminoglycans depended on the site of tumour growth. The orthotopic tumours had a higher vascular density than the subcutaneous tumours, as the vascular surface and length were 2–3-fold higher. The data indicate that the interstitial fluid pressure is a dominant factor in controlling the uptake of macromolecules in solid tumours; and the site of tumour growth is important for the uptake of macromolecules in small tumours, extracellular matrix content and vascularization.© 2001 Cancer Research Campaign http://www.bjcancer.co

Controlling the quantum dynamics of a mesoscopic spin bath in diamond

Understanding and mitigating decoherence is a key challenge for quantum science and technology. The main source of decoherence for solid-state spin systems is the uncontrolled spin bath environment. Here, we demonstrate quantum control of a mesoscopic spin bath in diamond at room temperature that is composed of electron spins of substitutional nitrogen impurities. The resulting spin bath dynamics are probed using a single nitrogen-vacancy (NV) centre electron spin as a magnetic field sensor. We exploit the spin bath control to dynamically suppress dephasing of the NV spin by the spin bath. Furthermore, by combining spin bath control with dynamical decoupling, we directly measure the coherence and temporal correlations of different groups of bath spins. These results uncover a new arena for fundamental studies on decoherence and enable novel avenues for spin-based magnetometry and quantum information processing

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice.

Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12mg/kg given i.p.), ACT induced a strong increase in therapeutic efficacy; 120days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT+Abraxane group 100% of the animals were alive after 120days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Drell-Yan production at small q_T, transverse parton distributions and the collinear anomaly

Using methods from effective field theory, an exact all-order expression for the Drell-Yan cross section at small transverse momentum is derived directly in q_T space, in which all large logarithms are resummed. The anomalous dimensions and matching coefficients necessary for resummation at NNLL order are given explicitly. The precise relation between our result and the Collins-Soper-Sterman formula is discussed, and as a by-product the previously unknown three-loop coefficient A^(3) is obtained. The naive factorization of the cross section at small transverse momentum is broken by a collinear anomaly, which prevents a process-independent definition of x_T-dependent parton distribution functions. A factorization theorem is derived for the product of two such functions, in which the dependence on the hard momentum transfer is separated out. The remainder factors into a product of two functions of longitudinal momentum variables and x_T^2, whose renormalization-group evolution is derived and solved in closed form. The matching of these functions at small x_T onto standard parton distributions is calculated at O(alpha_s), while their anomalous dimensions are known to three loops.Comment: 32 pages, 2 figures; version to appear in Eur. Phys. J.

Wave functions and decay constants of BB and DD mesons in the relativistic potential model

With the decay constants of $D$ and $D_s$ mesons measured in experiment recently, we revisit the study of the bound states of quark and antiquark in $B$ and $D$ mesons in the relativistic potential model. The relativistic bound state wave equation is solved numerically. The masses, decay constants and wave functions of $B$ and $D$ mesons are obtained. Both the masses and decay constants obtained here can be consistent with the experimental data. The wave functions can be used in the study of $B$ and $D$ meson decays.Comment: more discussion added, to appear in EPJ

LOFAR/H-ATLAS: The low-frequency radio luminosity - star-formation rate relation

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2018 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society.Radio emission is a key indicator of star-formation activity in galaxies, but the radio luminosity-star formation relation has to date been studied almost exclusively at frequencies of 1.4 GHz or above. At lower radio frequencies the effects of thermal radio emission are greatly reduced, and so we would expect the radio emission observed to be completely dominated by synchrotron radiation from supernova-generated cosmic rays. As part of the LOFAR Surveys Key Science project, the Herschel-ATLAS NGP field has been surveyed with LOFAR at an effective frequency of 150 MHz. We select a sample from the MPA-JHU catalogue of SDSS galaxies in this area: the combination of Herschel, optical and mid-infrared data enable us to derive star-formation rates (SFRs) for our sources using spectral energy distribution fitting, allowing a detailed study of the low-frequency radio luminosity--star-formation relation in the nearby Universe. For those objects selected as star-forming galaxies (SFGs) using optical emission line diagnostics, we find a tight relationship between the 150 MHz radio luminosity ($L_{150}$) and SFR. Interestingly, we find that a single power-law relationship between $L_{150}$ and SFR is not a good description of all SFGs: a broken power law model provides a better fit. This may indicate an additional mechanism for the generation of radio-emitting cosmic rays. Also, at given SFR, the radio luminosity depends on the stellar mass of the galaxy. Objects which were not classified as SFGs have higher 150-MHz radio luminosity than would be expected given their SFR, implying an important role for low-level active galactic nucleus activity.Peer reviewedFinal Published versio

Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production

BACKGROUND: Desflurane and enflurane have been reported to produce substantial amounts of carbon monoxide (CO) in desiccated sodalime. Isoflurane is said to produce less CO and sevoflurane and halothane should produce no CO at all. The purpose of this study is to measure the maximum amounts of CO production for all modern volatile anesthetics, with completely dry sodalime. We also tried to establish a relationship between CO production and temperature increase inside the sodalime. METHODS: A patient model was simulated using a circle anesthesia system connected to an artificial lung. Completely desiccated sodalime (950 grams) was used in this system. A low flow anesthesia (500 ml/min) was maintained using nitrous oxide with desflurane, enflurane, isoflurane, halothane or sevoflurane. For immediate quantification of CO production a portable gas chromatograph was used. Temperature was measured within the sodalime container. RESULTS: Peak concentrations of CO were very high with desflurane and enflurane (14262 and 10654 ppm respectively). It was lower with isoflurane (2512 ppm). We also measured small concentrations of CO for sevoflurane and halothane. No significant temperature increases were detected with high CO productions. CONCLUSION: All modern volatile anesthetics produce CO in desiccated sodalime. Sodalime temperature increase is a poor predictor of CO production

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts

Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome

On The Rate and Extent of Drug Delivery to the Brain

To define and differentiate relevant aspects of blood–brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood–brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr