Combination of Vatalanib and a 20-HETE Synthesis Inhibitor Results in Decreased Tumor Growth in an Animal Model of Human Glioma

BACKGROUND: Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N\u27-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. METHODS: U251 human glioma cells (4×10(5)) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8-21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0-21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. RESULTS: Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0-21 days treatment), tumor volume, tumor blood volume, permeability, extravascular and extracellular space volume, tumor cell proliferation, and cell migration were decreased compared with that of the vehicle-treated group. CONCLUSION: HET0016 is capable of controlling tumor growth and migration, but these effects are dependent on the timing of drug administration. The addition of HET0016 to vatalanib may attenuate the unwanted effect of vatalanib

Trigonocephaly pre- and post-operative evaluation by multidetector computed tomography

Trigonocephaly is the third most common single suture synostosis which is seen as bulging of the forehead due to early fusion of themetopic suture. It is linked with an increased level of neurodevelopmental delays. On imaging, multidetector computed tomographyshows anterior fontanelle ossification, hypoteliorism, narrowing of the anterior cranial fossa, and compensatory increase of themiddle cranial fossa with atrophic features of brain. Its reported incidence is 1 in 700-15,000 live births. Operative multipleosteotomies were done and imaged in follow-up

Feedback-cooling the fundamental torsional mechanical mode of a tapered optical fiber to 30 mK

Tapered optical fibers (TOFs) are used in many areas of physics and optical technologies ranging from coupling light into nanophotonic components to optical sensing and amplification to interfacing quantum emitters. Here, we study the fundamental torsional mechanical mode of the nanofiber-waist of a TOF using laser light. We find that this oscillator features a quality factor of up to $10^7$ and a $Qf$ product of 1 THz. We damp the thermal motion from room temperature to 28(7) mK by means of active feedback. Our results might enable new types of fiber-based sensors and lay the foundation for a novel hybrid quantum optomechanical platform

MRI to assess chemoprevention in transgenic adenocarcinoma of mouse prostate (TRAMP)

<p>Abstract</p> <p>Background</p> <p>The current method to determine the efficacy of chemoprevention in TRAMP mouse model of carcinoma of prostate (CaP) is by extracting and weighing the prostate at different time points or by immunohistochemistry analysis. Non-invasive determination of volumes of prostate glands and seminal vesicles before, during and after treatment would be valuable in investigating the efficacy of newer chemopreventive agents in CaP. The purpose of this study was to determine whether <it>in vivo </it>magnetic resonance imaging (MRI) using a 3 tesla clinical MRI system can be used to follow the effect of chemoprevention in TRAMP model of mouse CaP.</p> <p>Methods</p> <p>Mice were randomized into control and treated groups. The animals in treated group received 10 µmol/kg of CDDO, 5 days a week for 20 weeks. Animals underwent <it>in vivo </it>MRI of prostate gland and seminal vesicles by a clinical 3 Tesla MRI system just before (at 5 weeks), during and at the end of treatment, at 25 weeks. T1-weighted and fat saturation (FATSAT) multiecho fast spin echo T2- weighted images (T2WI) were acquired. Volume of the prostate glands and seminal vesicles was determined from MR images. T2 signal intensity changes in the seminal vesicles were determined by subtracting higher echo time (TE) from lower TE T2WI. Following treatments all animals were sacrificed, prostate and seminal vesicles collected, and the tissues prepared for histological staining. All data were expressed as mean ± 1 standard deviation. Two-way or multivariate analysis of variance followed by post-hoc test was applied to determine the significant differences. A p-value of <0.05 was considered significant.</p> <p>Results</p> <p>Histological analysis indicated tumor in 100% of control mice, whereas 10% of the treated mice showed tumor in prostate gland. Both MRI and measured prostate weights showed higher volume/weight in control mouse group. MRI showed significantly higher volume of seminal vesicles in control animals and T2 signal intensity changes in seminal vesicles of control mice indicating higher number of tumor foci, which was also proven by histology.</p> <p>Conclusions</p> <p><it>In vivo </it>MRI is helpful in determining the efficacy of chemoprevention of prostate cancer in TRAMP mice.</p

Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma

BACKGROUND: Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N\u27-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. METHODS: U251 human glioma cells (4×10(5)) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8-21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0-21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. RESULTS: Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0-21 days treatment), tumor volume, tumor blood volume, permeability, extravascular and extracellular space volume, tumor cell proliferation, and cell migration were decreased compared with that of the vehicle-treated group. CONCLUSION: HET0016 is capable of controlling tumor growth and migration, but these effects are dependent on the timing of drug administration. The addition of HET0016 to vatalanib may attenuate the unwanted effect of vatalanib

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p \u3c 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p \u3c 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p \u3c 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p \u3c 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model

Endothelial Progenitor Cells (EPCs) as Gene Carrier System for Rat Model of Human Glioma

Due to their unique property to migrate to pathological lesions, stem cells are used as a delivery vehicle for therapeutic genes to tumors, especially for glioma. It is critically important to track the movement, localization, engraftment efficiency and functional capability or expression of transgenes of selected cell populations following transplantation. The purposes of this study were to investigate whether 1) intravenously administered, genetically transformed cord blood derived EPCs can carry human sodium iodide symporter (hNIS) to the sites of tumors in rat orthotopic model of human glioma and express transgene products, and 2) whether accumulation of these administered EPCs can be tracked by different in vivo imaging modalities.Collected EPCs were cultured and transduced to carry hNIS. Cellular viability, differential capacity and Tc-99m uptake were determined. Five to ten million EPCs were intravenously administered and Tc-99-SPECT images were acquired on day 8, to determine the accumulation of EPCs and expression of transgenes (increase activity of Tc-99m) in the tumors. Immunohistochemistry was performed to determine endothelial cell markers and hNIS positive cells in the tumors. Transduced EPCs were also magnetically labeled and accumulation of cells was confirmed by MRI and histochemistry. SPECT analysis showed increased activity of Tc-99m in the tumors that received transduced EPCs, indicative of the expression of transgene (hNIS). Activity of Tc-99m in the tumors was also dependent on the number of administered transduced EPCs. MRI showed the accumulation of magnetically labeled EPCs. Immunohistochemical analysis showed iron and hNIS positive and, human CD31 and vWF positive cells in the tumors.EPC was able to carry and express hNIS in glioma following IV administration. SPECT detected migration of EPCs and expression of the hNIS gene. EPCs can be used as gene carrier/delivery system for glioma therapy as well as imaging probes

Complete Temporal Characterization of Single Photons

Precise information about the temporal mode of optical states is crucial for optimizing their interaction efficiency between themselves and/or with matter in various quantum communication devices. Here we propose and experimentally demonstrate a method of determining both the real and imaginary components of a single photon's temporal density matrix by measuring the autocorrelation function of the photocurrent from a balanced homodyne detector at multiple local oscillator frequencies. We lay the theoretical foundation for our work and describe the experimental methods involved in detail. We show the results of testing our method on single photons heralded from bi-photons generated via four-wave mixing in an atomic vapor. We develop an appropriate theoretical model for our experimental settings and describe the involved calculations explicitly. The obtained experimental results show excellent agreement with theoretical predictions for the various settings involved

Erzeugung von Korrelationen zwischen Photonen durch Wechselwirkung mit in Nanofasern eingeschlossenen Atomen

Abweichender Titel nach Übersetzung der Verfasserin/des VerfassersDie Erzeugung korrelierter Photonen ist eine besondere Herausforderung der modernen Quantenoptik, da Photonen intrinsisch nicht miteinander wechselwirken. Die Wechselwirkungen zwischen unkorrelierten Photonen, verbunden mit dem Ziel komplexe Vielteilchenzustände von Photonen zu erzeugen, wird daher seit Langem angestrebt. Typischerweise erfordern solche Wechselwirkungen eine hohe Nichtlinearität, die durch stark an eine optische Mode gekoppelte Quantenemitter realisiert werden kann. Solche Ansätze werden jedoch oft durch unvermeidliche Dissipation in Form von Photonenverlust erheblich beeinträchtigt, was zu einer Reduktion der Korrelationen führt. In dieser Arbeit demonstriere ich einen experimentellen Ansatz, bei dem wir ein stark dissipatives Medium verwenden, welches schwach an ein Lichtfeld gekoppelt ist, um stark korrelierte Lichtzustände zu erzeugen. Das Herz unseres Systems ist eine optische Nanofaser, deren Durchmesser kleiner ist als die Lichtwellenlänge. An dieser Nanofaser fangen wir neutrale Cäsiumatome in zwei 1-dimensionalen Gittern, die durch eine optische Zweifarben-Dipolfalle erzeugt werden. Die nicht miteinander wechselwirkenden gefangenen Atome koppeln schwach an die in der Nanofaser geführte Mode. Jedes Atom kann einen kleinen Bruchteil des Lichts aus der Faser heraus streuen, was den dissipativen Teil der Atom-Licht-Wechselwirkung darstellt. Dadurch wird die Anzahl unkorrelierter Photonen reduziert. Die Tatsache, dass ein Atom immer nur ein Photon zur gleichen Zeit absorbieren kann, erzeugt jedoch Korrelationen zwischen Photonen, die zur gleichen Zeit am Atom ankommen. Die gestreuten Photonen sind spektral verstimmt und werden daher weniger absorbiert. Die große Anzahl von Atomen im System verstärkt die dissipativen und nichtlinearen Effekte, was zu stark korrelierten Photonen am Ausgang der Nanofaser führt.Wir messen die im transmittierten Lichtfeld induzierten Korrelationen zweiter Ordnung mit Hilfe eines Hanbury-Brown-Twiss-Aufbaus. Dafür senden wir ein schwaches resonantes Lichtfeld durch die Nanofaser, wo es mit einem Ensemble schwach-gekoppelter Atome wechselwirkt. Wir beobachten, dass wir durch Änderung der Anzahl der Atome im Ensemble die Wechselwirkung zwischen den Photonen von “nicht-wechselwirkend“ über “abstoßend“ bis “attraktiv“ einstellen können, was sich in den Messdaten durch den Übergang von “no bunching“ zu “antibunching“ zu “bunching“ äußert. Diese Realisierung einer kollektiv erhöhten Nichtlinearität eröffnet neue Wege zur Erzeugung nicht-klassischer Lichtzustände.Generating correlated photons is an outstanding challenge of modern quantum optics owing to the inherently non-interacting nature of photons. Mediating interactions between uncorrelated photons to generate complex many-body states of photons has therefore been long sought for. Typically, such interactions require a high nonlinearity realized by quantum emitters strongly coupled to an optical mode. However, such approaches are often significantly impaired by unavoidable dissipation in the form of photon loss, which leads to a reduction of the correlations.In this thesis, I will demonstrate an experimental approach where we use a strongly dissipative medium weakly coupled to a light field to generate strongly correlated states of light. Key to our system is a subwavelength diameter optical nanofiber, around which we trap neutral Cesium atoms in two linear arrays using a two-color optical dipole trap. The mutually non-interacting trapped atoms couple weakly to the guided mode of the nanofiber. Each atom can scatter a small fraction of the light out of the fiber which is the dissipative part of the atom-light interaction, thereby, reducing the number of uncorrelated photons. However, the fact that an atom can only absorb one photon at a time, generates correlations between photons that arrive at the atom at the same time. The scattered photons are spectrally detuned and, therefore, less absorbed. The large number of atoms in the system collectively enhances the dissipative and nonlinear effects, leading to highly correlated photons at the output of the nanofiber.In the experiment, we launch a weak resonant light field through the nanofiber where it interacts with an ensemble of weakly-coupled atoms. We measure the second-order correlations induced in the transmitted light field via a Hanbury-Brown-Twiss setup. We observe that by changing the number of atoms in the ensemble, we are able to tune the interaction between the photons from non-interacting to repulsive to attractive, which we observe as a transition from no bunching to antibunching to bunching, respectively. This realization of a collectively enhanced nonlinearity opens new avenues for generating nonclassical states of light.13