Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST

Electrical control over single hole spins in nanowire quantum dots

Single electron spins in semiconductor quantum dots (QDs) are a versatile platform for quantum information processing, however controlling decoherence remains a considerable challenge. Recently, hole spins have emerged as a promising alternative. Holes in III-V semiconductors have unique properties, such as strong spin-orbit interaction and weak coupling to nuclear spins, and therefore have potential for enhanced spin control and longer coherence times. Weaker hyperfine interaction has already been reported in self-assembled quantum dots using quantum optics techniques. However, challenging fabrication has so far kept the promise of hole-spin-based electronic devices out of reach in conventional III-V heterostructures. Here, we report gate-tuneable hole quantum dots formed in InSb nanowires. Using these devices we demonstrate Pauli spin blockade and electrical control of single hole spins. The devices are fully tuneable between hole and electron QDs, enabling direct comparison between the hyperfine interaction strengths, g-factors and spin blockade anisotropies in the two regimes

Magnetosphere-Ionosphere Coupling Through E-region Turbulence 1: Energy Budget

During periods of intense geomagnetic activity, strong electric fields and currents penetrate from the magnetosphere into high-latitude ionosphere where they dissipate energy, form electrojets, and excite plasma instabilities in the E-region ionosphere. These instabilities give rise to plasma turbulence which induces non-linear currents and strong anomalous electron heating (AEH) as observed by radars. These two effects can increase the global ionospheric conductances. This paper analyzes the energy budget in the electrojet, while the companion paper applies this analysis to develop a model of anomalous conductivity and frictional heating useful in large-scale simulations and models of the geospace environment. Employing first principles, this paper proves for the general case an earlier conjecture that the source of energy for plasma turbulence and anomalous heating equals the work by external field on the non-linear current. Using a two-fluid model of an arbitrarily magnetized plasma and the quasilinear approximation, this paper describes the energy conversion process, calculates the partial sources of anomalous heating, and reconciles the apparent contradiction between the inherently 2-D non-linear current and the 3-D nature of AEH.Comment: 13 pages, 1 figure; 1st of two companion paper

Pits and fissures: Relative space contribution in fissures from sealants, prophylaxis pastes and organic remnants

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Previous studies by the authors have looked at the nature of the fissure system of human permanent molars and premolars, and has provided evidence for the presence of a prismless layer of enamel. It was noted during these studies that the fissure spaces were often occupied by material other than the fissure sealant. The aim of this study was to define these materials and to look at the percentage contribution of each to the sealed fissure space. MethodS: A sample of teeth, both molars and premolars, were sealed with an unfilled fissure sealant after prophylaxis with a coloured prophylaxis paste. In one group, the crown of the tooth was removed by dissolution in hydrochloric acid following placement of the sealant. This revealed a negative image of the fissure system and its contents. The second group of teeth was sectioned following sealing, and the contents of the fissure space were analyzed. Results: The negative image of the fissure system displayed the fissure contents by colour and the sectioned teeth were able to be computer analyzed to establish the relative contribution of sealant, prophylaxis paste and organic material to the fissure space. Conclusions: Sealant contribution was in the range of 14- 96 per cent, prophylaxis paste from 0-50 per cent and organic remnants 0-55 per cent. The presence of these last two components could contribute to sealant loss

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum