Semiconductor Superlattices: A model system for nonlinear transport

Electric transport in semiconductor superlattices is dominated by pronounced negative differential conductivity. In this report the standard transport theories for superlattices, i.e. miniband conduction, Wannier-Stark-hopping, and sequential tunneling, are reviewed in detail. Their relation to each other is clarified by a comparison with a quantum transport model based on nonequilibrium Green functions. It is demonstrated how the occurrence of negative differential conductivity causes inhomogeneous electric field distributions, yielding either a characteristic sawtooth shape of the current-voltage characteristic or self-sustained current oscillations. An additional ac-voltage in the THz range is included in the theory as well. The results display absolute negative conductance, photon-assisted tunneling, the possibility of gain, and a negative tunneling capacitance.Comment: 121 pages, figures included, to appear in Physics Reports (2001

Efficient measurement of total tumor microvascularity ex vivo using a mathematical model to optimize volume subsampling

We introduce immunofluorescence and automated image processing protocols for serial tumor sections to objectively and efficiently quantify tumor microvasculature following antivascular therapy. To determine the trade-off between tumor subsampling and throughput versus microvessel quantification accuracy, we provide a mathematical model that accounts for tumor-specific vascular heterogeneity. This mathematical model can be applied broadly to define tumor volume samplings needed to reach statistical significance, depending on the biomarker in question and the number of subjects. Here, we demonstrate these concepts for tumor microvessel density and total microvascularity (TMV) quantification in whole pancreatic ductal adenocarcinoma tumors ex vivo. The results suggest that TMV is a more sensitive biomarker for detecting reductions in tumor vasculature following antivascular treatment. TMV imaging is a broadly accessible technique that offers robust assessment of antivascular therapies, and it offers promise as a tool for developing high-throughput assays to quantify treatment-induced microvascular alterations for therapeutic screening and development.National Institutes of Health (U.S.) (Grant P01-CA084203)National Institutes of Health (U.S.) (Grant R01-CA160998

Mitigation of the Surface Oxidation of Titanium by Hydrogen

As a reactive metal, Ti is prone to surface oxidation spontaneously when exposed to environment containing oxygen-a phenomenon also known as surface passivation. It has also been known that titanium hydride (TiH2) is impervious to oxygen. However, it is not clear to date and there is little published report on how and why hydrogen affects the oxidation of Ti. &quot;Impervious&quot; may be an overstatement because TiH2 does oxidize. Because surface oxygen is also a part of the total oxygen in titanium in addition to bulk oxygen and the passivation film affects the properties of titanium, understanding the surface oxidation behavior of titanium and the effects of hydrogen is thus of considerable interest from both fundamental and practical perspectives. This article studies the effect of hydrogen on the surface passivation of titanium from different aspects including (I) the comparison of oxygen contents in alpha-Ti and TiH2 powders when exposed to air, (II) the oxidation states, their relative fractions, and the thickness of the oxidized layers as a function of hydrogen contents, and (III) the characterization of the passivation layer on the surface by high-resolution transmission electron microscope. The experimental data showed that the presence of hydrogen can indeed make titanium metal less prone to oxidation. The alloying of titanium with hydrogen can result in reduced thickness and the relative fraction of titanium in the form of Ti-IV in the passivated surface, effectively minimizing surface oxidation. The fundamental reason for the effect of hydrogen on the surface oxidation of titanium is discussed and attributed to the difference in oxidation behavior of alpha and delta phases.</p

A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways.

Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)--a multikinase inhibitor--encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities

Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors

NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound <b>68</b>, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested