Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL

Neuro-ophthalmic complications of vestibular schwannoma resection : current perspectives

Vestibular schwannomas (VSs), also called acoustic neuromas, are benign intracranial neoplasms of the vestibulocochlear (VIII) cranial nerve. Management options include “wait-and-scan,” stereotactic radiosurgery and surgical resection. Due to the proximity of the VIII nerve to the facial (VII) nerve in the cerebello-pontine angle, the VII nerve is particularly vulnerable to the effects of surgical resection. This can result in poor eye closure, lagophthalmos and resultant corneal exposure post VS resection. Additionally, compression from the tumor or resection can cause trigeminal (V) nerve damage and a desensate cornea. The combination of an exposed and desensate cornea puts the eye at risk of serious ocular complications including persistent epithelial defects, corneal ulceration, corneal vascularization, corneal melting and potential perforation. The abducens (VI) nerve can be affected by a large intracranial VS causing raised intracranial pressure (a false localizing sign) or as a result of damage to the VI nerve at the time of resection. Other types of neurogenic strabismus are rare and typically transient. Contralaterally beating nystagmus as a consequence of vestibular dysfunction is common post-operatively. This generally settles to pre-operative levels as central compensation occurs. Ipsilaterally beating nystagmus post-operatively should prompt investigation for post-operative cerebrovascular complications. Papilledema (and subsequent optic atrophy) can occur as a result of a large VS causing raised intracranial pressure. Where papilledema follows surgical resection of a VS, it can indicate that cerebral venous sinus thrombosis has occurred. Poor visual function following VS resection can result as a combination of all these potential complications and is more likely with larger tumors

Quantized charge transport through a static quantum dot using a surface acoustic wave

We present a detailed study of the surface acoustic wave mediated quantized transport of electrons through a split gate device containing an impurity potential defined quantum dot within the split gate channel. A new regime of quantized transport is observed at low RF powers where the surface acoustic wave amplitude is comparable to the quantum dot charging energy. In this regime resonant transport through the single-electron dot state occurs which we interpret as turnstile-like operation in which the traveling wave amplitude modulates the entrance and exit barriers of the quantum dot in a cyclic fashion at GHz frequencies. For high RF powers, where the amplitude of the surface acoustic wave is much larger than the quantum dot energies, the quantized acoustoelectric current transport shows behavior consistent with previously reported results. However, in this regime, the number of quantized current plateaus observed and the plateau widths are determined by the properties of the quantum dot, demonstrating that the microscopic detail of the potential landscape in the split gate channel has a profound influence on the quantized acoustoelectric current transport.Comment: 9 page

Developing a shared decision support framework for aortic root surgery in Marfan syndrome

OBJECTIVE: The study is an early phase of development of a decision support framework for people with Marfan syndrome who are anticipating prophylactic aortic root surgery. Implications of the timing and the nature of the operation chosen were previously elicited in focus groups. In this step, we explored the range of relative values placed by individuals on the implications of decisions made about surgery. METHODS: Following the principles of the Ottawa Decision Support Framework, eight questions in the general form 'How important is it to you …' were framed by a panel. Marfan people, families and specialist doctors answered online. Quantitative and qualitative analyses were performed. RESULTS: Worldwide, 142 responses were received including 25 specialist doctors. Respondents were 55% female and 46% had previous aortic root surgery. Overall, active lifestyle was more important to males (p=0.03). Patients placed more importance than doctors on not deferring surgery (p=0.04) and on avoidance of anticoagulation in the interests of childbearing (p=0.009). Qualitative analysis showed differing but cogently reasoned values that were sometimes polarised, and mainly driven by the wish to maintain a good quality of life and active lifestyle. CONCLUSIONS: Given the cogency of these viewpoints, people anticipating root replacement surgery should have ample opportunity to express them and to have them acknowledged ahead of a consultation when they can then be fully explored in a mutually informed forum. If they differ from local medical practice, they can then be discussed in the process of reaching shared and individualised decisions

Anisotropic optical response of the diamond (111)-2x1 surface

The optical properties of the 2$\times$1 reconstruction of the diamond (111) surface are investigated. The electronic structure and optical properties of the surface are studied using a microscopic tight-binding approach. We calculate the dielectric response describing the surface region and investigate the origin of the electronic transitions involving surface and bulk states. A large anisotropy in the surface dielectric response appears as a consequence of the asymmetric reconstruction on the surface plane, which gives rise to the zigzag Pandey chains. The results are presented in terms of the reflectance anisotropy and electron energy loss spectra. While our results are in good agreement with available experimental data, additional experiments are proposed in order to unambiguously determine the surface electronic structure of this interesting surface.Comment: REVTEX manuscript with 6 postscript figures, all included in uu file. Also available at http://www.phy.ohiou.edu/~ulloa/ulloa.html Submitted to Phys. Rev.

Evidence of Novel Quasiparticles in a Strongly Interacting Two-Dimensional Electron System: Giant Thermopower and Metallic Behaviour

We report thermopower ($S$) and electrical resistivity ($\rho_{2DES}$) measurements in low-density (10$^{14}$ m$^{-2}$), mesoscopic two-dimensional electron systems (2DESs) in GaAs/AlGaAs heterostructures at sub-Kelvin temperatures. We observe at temperatures $\lesssim$ 0.7 K a linearly growing $S$ as a function of temperature indicating metal-like behaviour. Interestingly this metallicity is not Drude-like, showing several unusual characteristics: i) the magnitude of $S$ exceeds the Mott prediction valid for non-interacting metallic 2DESs at similar carrier densities by over two orders of magnitude; and ii) $\rho_{2DES}$ in this regime is two orders of magnitude greater than the quantum of resistance $h/e^2$ and shows very little temperature-dependence. We provide evidence suggesting that these observations arise due to the formation of novel quasiparticles in the 2DES that are not electron-like. Finally, $\rho_{2DES}$ and $S$ show an intriguing decoupling in their density-dependence, the latter showing striking oscillations and even sign changes that are completely absent in the resistivity.Comment: QFS2012 Conference proceedings, Journal of Low Temperature Physics, accepted (figure and discussion added upon referee suggestions

Absence of Host Plasminogen Activator Inhibitor 1 Prevents Cancer Invasion and Vascularization

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis

TESS Reveals HD 118203 b to be a Transiting Planet

The exoplanet HD 118203 b, orbiting a bright (V = 8.05) host star, was discovered using the radial velocity method by da Silva et al., but was not previously known to transit. Transiting Exoplanet Survey Satellite (TESS) photometry has revealed that this planet transits its host star. Nine planetary transits were observed by TESS, allowing us to measure the radius of the planet to be 1.136-0.028 +0.029 R J, and to calculate the planet mass to be 2.166-0.079 +0.074 M J. The host star is slightly evolved with an effective temperature of T eff=5683-85 +84 K and a surface gravity of log\,g=3.889 0.018-0.017. With an orbital period of 6.134985-0.000030 +0.000029 days and an eccentricity of 0.314 ± 0.017, the planet occupies a transitional regime between circularized hot Jupiters and more dynamically active planets at longer orbital periods. The host star is among the 10 brightest known to have transiting giant planets, providing opportunities for both planetary atmospheric and asteroseismic studies