Generation, Spectroscopic Characterization, and Computational Analysis of a Six-Coordinate Cobalt(III)-Imidyl Complex with an Unusual S = 3/2 Ground State that Promotes N-Group and Hydrogen Atom-Transfer Reactions with Exogenous Substrates.

We report the synthesis and characterization of a mononuclear nonheme cobalt(III)-imidyl complex, [Co(NTs)(TQA)(OTf)]+ (1), with an S = 3/2 spin state that is capable of facilitating exogenous substrate modifications. Complex 1 was generated from the reaction of CoII(TQA)(OTf)2 with PhINTs at -20 °C. A flow setup with ESI-MS detection was used to explore the kinetics of the formation, stability, and degradation pathway of 1 in solution by treating the Co(II) precursor with PhINTs. Co K-edge XAS data revealed a distinct shift in the Co K-edge compared to the Co(II) precursor, in agreement with the formation of a Co(III) intermediate. The unusual S = 3/2 spin state was proposed based on EPR, DFT, and CASSCF calculations and Co Kß XES results. Co K-edge XAS and IR photodissociation (IRPD) spectroscopies demonstrate that 1 is a six-coordinate species, and IRPD and resonance Raman spectroscopies are consistent with 1 being exclusively the isomer with the NT ligand occupying the vacant site trans to the TQA aliphatic amine nitrogen atom. Electronic structure calculations (broken symmetry DFT and CASSCF/NEVPT2) demonstrate an S = 3/2 oxidation state resulting from the strong antiferromagnetic coupling of an •NTs spin to the high-spin S = 2 Co(III) center. Reactivity studies of 1 with PPh3 derivatives revealed its electrophilic characteristic in the nitrene-transfer reaction. While the activation of C-H bonds by 1 was proved to be kinetically challenging, 1 could oxidize weak O-H and N-H bonds. Complex 1 is, therefore, a rare example of a Co(III)-imidyl complex capable of exogenous substrate transformations.

Spatially resolved one-dimensional boundary states in graphene-hexagonal boron nitride planar heterostructures.

Two-dimensional interfaces between crystalline materials have been shown to generate unusual interfacial electronic states in complex oxides. Recently, a one-dimensional interface has been realized in hexagonal boron nitride and graphene planar heterostructures, where a polar-on-nonpolar one-dimensional boundary is expected to possess peculiar electronic states associated with edge states of graphene and the polarity of boron nitride. Here we present a combined scanning tunnelling microscopy and first-principles theory study of the graphene-boron nitride boundary to provide a first glimpse into the spatial and energetic distributions of the one-dimensional boundary states down to atomic resolution. The revealed boundary states are about 0.6 eV below or above the Fermi level depending on the termination of the boron nitride at the boundary, and are extended along but localized at the boundary. These results suggest that unconventional physical effects similar to those observed at two-dimensional interfaces can also exist in lower dimensions.

Heteroepitaxial growth of two-dimensional hexagonal boron nitride templated by graphene edges.

By adapting the concept of epitaxy to two-dimensional space, we show the growth of a single-atomic-layer, in-plane heterostructure of a prototypical material system--graphene and hexagonal boron nitride (h-BN). Monolayer crystalline h-BN grew from fresh edges of monolayer graphene with atomic lattice coherence, forming an abrupt one-dimensional interface, or boundary. More important, the h-BN lattice orientation is solely determined by the graphene, forgoing configurations favored by the supporting copper substrate.

Spatially resolved mapping of electrical conductivity across individual domain (grain) boundaries in graphene.

All large-scale graphene films contain extended topological defects dividing graphene into domains or grains. Here, we spatially map electronic transport near specific domain and grain boundaries in both epitaxial graphene grown on SiC and CVD graphene on Cu subsequently transferred to a SiO2 substrate, with one-to-one correspondence to boundary structures. Boundaries coinciding with the substrate step on SiC exhibit a significant potential barrier for electron transport of epitaxial graphene due to the reduced charge transfer from the substrate near the step edge. Moreover, monolayer-bilayer boundaries exhibit a high resistance that can change depending on the height of substrate step coinciding at the boundary. In CVD graphene, the resistance of a grain boundary changes with the width of the disordered transition region between adjacent grains. A quantitative modeling of boundary resistance reveals the increased electron Fermi wave vector within the boundary region, possibly due to boundary induced charge density variation. Understanding how resistance change with domain (grain) boundary structure in graphene is a crucial first step for controlled engineering of defects in large-scale graphene films.

Room-temperature tunneling behavior of boron nitride nanotubes functionalized with gold quantum dots.

One-dimensional arrays of gold quantum dots (QDs) on insulating boron nitride nanotubes (BNNTs) can form conduction channels of tunneling field-effect transistors. We demonstrate that tunneling currents can be modulated at room temperature by tuning the lengths of QD-BNNTs and the gate potentials. Our discovery will inspire the creative use of nanostructured metals and insulators for future electronic devices.

Surface-induced orientation control of CuPc molecules for the epitaxial growth of highly ordered organic crystals on graphene.

The epitaxial growth and preferred molecular orientation of copper phthalocyanine (CuPc) molecules on graphene has been systematically investigated and compared with growth on Si substrates, demonstrating the role of surface-mediated interactions in determining molecular orientation. X-ray scattering and diffraction, scanning tunneling microscopy, scanning electron microscopy, and first-principles theoretical calculations were used to show that the nucleation, orientation, and packing of CuPc molecules on films of graphene are fundamentally different compared to those grown on Si substrates. Interfacial dipole interactions induced by charge transfer between CuPc molecules and graphene are shown to epitaxially align the CuPc molecules in a face-on orientation in a series of ordered superstructures. At high temperatures, CuPc molecules lie flat with respect to the graphene substrate to form strip-like CuPc crystals with micrometer sizes containing monocrystalline grains. Such large epitaxial crystals may potentially enable improvement in the device performance of organic thin films, wherein charge transport, exciton diffusion, and dissociation are currently limited by grain size effects and molecular orientation.

Enhanced electrical conductivity in poly(3-hexylthiophene)/fluorinated tetracyanoquinodimethane nanowires grown with a porous alumina template.

We report on improved electrical conductivity in poly(3-hexylthiophene) (P3HT)/2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) composite nanowires grown using an anodized aluminum oxide (AAO) template. The electrical conductivity of individual nanowire measured by four-probe scanning tunneling microscopy shows that F4-TCNQ molecules are effectively doped into P3HT by capillary force. The resistivity is tuned in the 0.1-10 Ω cm range by changing the F4-TCNQ concentration from 10 to 0.1 wt % and is 2-4 orders of magnitude smaller than that of the corresponding P3HT/F4-TNCQ thin film composites. The AAO template-assisted synthesis approach thus appears to be effective for high chemical doping and for improving the electrical conductivity of the molecular wires.

Nanoscale periodic modulations on sodium chloride surface revealed by tuning fork atomic force microscopy.

The sodium chloride surface is one of the most common platforms for the study of catalysts, thin film growth, and atmospheric aerosols. Here we report a nanoscale periodic modulation pattern on the surface of a cleaved NaCl single crystal, revealed by non-contact atomic force microscopy with a tuning fork sensor. The surface pattern shows two orthogonal domains, extending over the entire cleavage surface. The spatial modulations exhibit a characteristic period of 5.4 nm, along <110> crystallographic directions of the NaCl. The modulations are robust in vacuum, not affected by the tip-induced electric field or gentle annealing (<300 °C); however, they are eliminated after exposure to water and an atomically flat surface can be recovered by subsequent thermal annealing after water exposure. A strong electrostatic charging is revealed on the cleavage surface which may facilitate the formation of the observed metastable surface reconstruction.

Suicide and cancer: a gender-comparative study.

BACKGROUND: Persons with cancer commit suicide more frequently than those without, and males generally commit suicide more frequently than females. A population-based analysis of cancer patients was carried out here, comparing suicide risk between the genders, to elucidate the features specific to each gender. PATIENTS AND METHODS: A total of 1.3 million cancer cases from the Surveillance, Epidemiology, and End Results program were analyzed. Cox proportional hazards models were fitted to personal, tumor-related, and social variates. RESULTS: A total of 265 female and 1307 male suicides were enumerated, reflecting 0.04% and 0.19% from each gender, and providing an overall hazard ratio for male suicide of 6.2 [95% confidence interval (CI) 5.4-7.1]. Females with colorectal (P = 0.01) and cervical (P < 0.0001) cancers showed decreased suicide rates. Males with head and neck cancers (P < 0.0001) and myeloma (P = 0.02) had increased rates, whereas rates were decreased in males with lung cancer (P = 0.01), liver (P = 0.01), brain tumors (P = 0.04), and leukemia (P = 0.007). The hazard ratio associated for male suicide with distant metastasis was 2.84 (95% CI 2.49-3.24); for married status, 0.46 (95% CI 0.39-0.54); and for African-American ancestry, 0.24 (95% CI 0.17-0.34)-comparable ratios were seen here for female suicides. In head and neck cancers, with both genders analyzed together, the suicide hazard was increased if surgery was contraindicated (3.0, 95% CI 1.3-6.8), but not if refused. CONCLUSIONS: The high-risk patient was male, with head and neck cancer or myeloma, advanced disease, little social or cultural support, and limited treatment options. Oncologists and allied health professionals should be aware of the potential for suicide in cancer patients and their associated risk factors.

The size distribution of human hematogenous metastases.

The development of primary cancers and their subsequent metastases occur through a complex sequence of discrete steps. A hypothesis is proposed here whereby the time available for the growth of metastases is normally distributed, presumably as a consequence of the summation of multiple independently distributed time intervals from each of the steps and of the Central Limit Theorem. For exponentially growing metastases, the corresponding size distribution would be lognormal; Gompertzian growth would imply a modified (Gompertz-normal) distribution, where larger metastases would occur less frequently as a consequence of a decreased growth rate. These two size distributions were evaluated against 18 human autopsy cases where precise size measurements had been collected from over 3900 macroscopic hematogenous organ metastases. The lognormal distribution provided an approximate agreement. Its main deficiency was a tendency to over-represent metastases greater than 10 mm diameter. The Gompertz-normal distribution provided more stringent agreement, correcting for this over-representation. These observations supported the hypothesis of normally distributed growth times, and qualified the utility of the lognormal and Gompertz-normal distributions for the size distribution of metastases.

A stochastic model for the self-similar heterogeneity of regional organ blood flow.

The theory of exponential dispersion models was applied to construct a stochastic model for heterogeneities in regional organ blood flow as inferred from the deposition of labeled microspheres. The requirements that the dispersion model be additive (or reproductive), scale invariant, and represent a compound Poisson distribution, implied that the relative dispersion (RD = standard deviation/mean) of blood flow should exhibit self-similar scaling in macroscopic tissue samples of masses m and m(ref) such that RD(m) = RD(m(ref)). (m/m(ref))(1-D), where D was a constant. Under these circumstances this empirical relationship was a consequence of a compound Poisson-gamma distribution that represented macroscopic blood flow. The model also predicted that blood flow, at the microcirculatory level, should also be heterogeneous but obey a gamma distribution-a prediction supported by observation.

Respiratory-induced prostate motion: quantification and characterization.

PURPOSE: The precise localization of the prostate is critical for dose-escalated conformal radiotherapy. This study identifies and characterizes a potential cause of inaccurate prostatic localization-respiratory-induced movement. METHODS AND MATERIALS: Prostate movement during respiration was measured fluoroscopically using implanted gold fiducial markers. Twenty sequential patients with CT(1)-T(3) N(0) M(0) prostate carcinoma were evaluated prone, immobilized in customized thermoplastic shells. A second 20 patients were evaluated both prone (with and without their thermoplastic shells) and supine (without their shells). RESULTS: When the patients were immobilized prone in thermoplastic shells, the prostate moved synchronously with respiration. In the study the prostate was displaced a mean distance of 3.3 +/- 1.8 (SD) mm (range, 1-10.2 mm), with 23% (9/40) of the displacements being 4 mm or greater. The respiratory-associated prostate movement decreased significantly when the thermoplastic shells were removed. CONCLUSION: Significant prostate movement can be induced by respiration when patients are immobilized in thermoplastic shells. This movement presumably is related to transmitted intraabdominal pressure within the confined space of the shells. Careful attention to the details of immobilization and to the possibility of respiratory-induced prostate movements is important when employing small field margins in prostatic radiotherapy.

Fractal heterogeneity of peripheral blood flow: implications for hematogenous metastases.

BACKGROUND AND OBJECTIVES: To determine how inhomogeneities in blood perfusion might affect the number of metastases that develop within an individual with cancer. METHODS: Experiments with lung metastases in mice, involving 320 treatment groups and 3165 mice, were reviewed. Inhomogeneities in the distribution of metastases amongst identically treated mice were analyzed by calculating the relative dispersion and clumping index. RESULTS: The relative dispersion exhibited fractal self-similarity on change of scale, and paralleled the effects observed with pulmonary blood flow. Clustering of metastases was also apparent: a minority of mice developed relatively large numbers of metastases; a majority of mice developed few metastases. CONCLUSIONS: Clustering of lung metastases occurred within groups of identically treated mice, and could be attributed to inhomogeneous blood perfusion. Consequently, the number of metastases in any individual was highly variable and correlated only partly with malignant potential. Inhomogeneities in blood flow favored the development of relatively few metastases, such that solitary or nil metastasis should occur more frequently than expected from chance alone.

Technical report. The application of probability-generating functions to linear-quadratic radiation survival curves.

PURPOSE: To illustrate how probability-generating functions (PGFs) can be employed to derive a simple probabilistic model for clonogenic survival after exposure to ionizing irradiation. METHODS: Both repairable and irreparable radiation damage to DNA were assumed to occur by independent (Poisson) processes, at intensities proportional to the irradiation dose. Also, repairable damage was assumed to be either repaired or further (lethally) injured according to a third (Bernoulli) process, with the probability of lethal conversion being directly proportional to dose. Using the algebra of PGFs, these three processes were combined to yield a composite PGF that described the distribution of lethal DNA lesions in irradiated cells. RESULTS: The composite PGF characterized a Poisson distribution with mean, chiD+betaD2, where D was dose and alpha and beta were radiobiological constants. This distribution yielded the conventional linear-quadratic survival equation. To test the composite model, the derived distribution was used to predict the frequencies of multiple chromosomal aberrations in irradiated human lymphocytes. The predictions agreed well with observation. This probabilistic model was consistent with single-hit mechanisms, but it was not consistent with binary misrepair mechanisms. CONCLUSIONS: A stochastic model for radiation survival has been constructed from elementary PGFs that exactly yields the linear-quadratic relationship. This approach can be used to investigate other simple probabilistic survival models.

Characterization of the frequency distribution for human hematogenous metastases: evidence for clustering and a power variance function.

When groups of mice are injected with cells from a metastasizing tumor, a minority of individuals within a given group tends to sustain disproportionately larger numbers of metastases relative to the remaining group members. This clustering of metastases obeys a power function relationship, sigma2 = amub, between the variance sigma2 and the mean number of lung metastases per animal mu (a and b constant). To see whether such clustering occurs with human lung, brain, and liver metastases, a meta-analysis of clinical and pathological series was performed. Thirty-three published series were identified that provided data regarding the numbers of organ metastases sustained by 5582 people. The data were grouped according to the primary tumor, site of metastasis and method of detection of metastases. Clustering of metastases within individuals of each subgroup (similar to the murine systems) was demonstrated by variance to mean ratios greater than 1, and by a strong correlation to the variance to mean power function (a approximately 0.49, b approximately 2.24, r2 = 96%, p < 10(-6)). The cause of this clustering remains unclear, but it may in part relate to heterogeneities in regional blood flow. As a consequence of this clustering, limited metastases would be expected to occur more frequently than predicted from random chance-providing for some optimism in the management of limited metastasis. As well, the frequency distribution for metastases revealed certain scaling symmetries, likely reflective of the underlying mechanisms of metastasis, that could be of interest to both clinicians and experimentalists working with metastasis.

A closed-form description of tumour control with fractionated radiotherapy and repopulation.

PURPOSE: To derive a closed form expression of tumour control probability (TCP) following the geometric stochastic approach of Tucker and Taylor. METHODS: A model was constructed based upon a Galton-Watson branching process with cell killing represented by a Bernoulli random variable, and repopulation represented by a Yule Fury process. A closed-form expression of the probability-generating function was derived, which yielded an explicit expression for the mean number of surviving clonogens and the TCP. RESULTS: The mean number of surviving cells, after i clonogens have been treated with n fractions of irradiation, was [equation: see text], where s is the surviving fraction, lambda is the rate of cell division, and delta t is the interfraction time interval. The tumour control probability was [equation: see text]. CONCLUSIONS: Tucker and Taylor provided improvements upon the conventional Poisson model for TCP, mainly through numerical simulation. Here a model based upon their geometric stochastic approach has been derived in closed form. The resultant equations provide a simpler alternative to numerical simulation allowing the effects of fractionated radiotherapy on a replicating population of tumour cells to be more easily predicted.

Clustering of murine lung metastases reflects fractal nonuniformity in regional lung blood flow.

In the experimental metastasis assay certain animals, from groups of similarly treated animals, develop more lung metastases than expected from random chance alone. This clustering of metastases is characterized by a power function relationship, sigma(2) = amu(b), between the variance, sigma(2), and mean, mu, of the numbers of lung metastases per animal (a and b are constants). To determine whether this clustering could be an artifact of experimental metastasis, whether it could be influenced by different experimental conditions, and to attempt to clarify its cause, 22 published data sets from experimental metastasis utilizing 2,145 mice, as well as 8 data sets from spontaneous metastasis utilizing 1,020 mice were analyzed. In these experiments cell cloning, cell-cell fusion, treatment with a protein kinase C inhibitor, treatment with cell adhesion compounds, and transfection with either the ras oncogene, the sialidase gene, or the urokinase sense and antisense genes were used to influence metastasis. They employed 14 different cell lines and 6 different strains of inbred mice. Clustering of metastasis was evident in animals from the spontaneous metastasis assays as well as from the experimental metastasis assays. It was apparent whether mice were injected with tumor cells derived from clones or from cell lines. Clustering was demonstrated within each data set, regardless of the experimental conditions employed. A single variance to mean power function (with a = 2.2 and b = 1.51) characterized the clustering in the 30 data sets. The regional distribution of blood flow through lungs and other organs is nonuniform, exhibiting a fractal symmetry on change of scale. This symmetry implies that the variance of a region's blood flow is related to its mean by the same power function as was observed with metastasis. Indeed, measurements of blood flow from isolated canine lungs yield b = 1.56, similar to the corresponding figure from murine lung metastasis. These findings lend support to the hypothesis that the observed clustering of metastases is a consequence of fractal variations in lung blood flow.

Fetal dose for a patient undergoing mantle field irradiation for Hodgkin's disease.

In order to safely treat a 23 weeks pregnant woman for supradiapharagmatic Hodgkin's disease, without compromising the fetus, a custom shielding table was constructed and extensive phantom measurements were performed. For 10 MV photons, the optimal shielding combination was found to consist of a 5 cm thick lead sheet placed onto a 1.25 cm aluminum supporting plate. The structure was placed directly above the phantom, over the region corresponding to the woman's abdomen, without any intervening air gap. By this means the dose to the fetus from machine leakage and collimator scatter was eliminated; the only remaining dose was due to in-phantom scatter. The woman was treated using a mantle field to a dose of 35 Gy in 20 fractions. The accumulated dose to the woman's uterine fundus and to her pubis were monitored with theroluminescent dosimeters. After completion of mantle therapy the doses to the fundus and pubis were 10 and 3 cGy, respectively. The fetal exposure was thus limited to below 10 cGy, within the zone of fetal tolerance. A normal infant was delivered at term.

A perspective on tumour progression.

During their natural history, tumours may acquire new phenotypic traits. This process, tumour progression, becomes clinically important when tumours acquire the ability to invade and metastasize or when they develop drug resistance. An acquired genetic instability modulated by selection likely contributes to this progression. More than one genetic mechanism is probably involved, a small number of point mutations being complemented by karyotypic events, gene amplification and altered gene expression. More complicated traits, such as the ability to invade and metastasize, may be acquired through the inappropriate and disorganized reexpression of genetic programs suppressed during embryologic development.

The role of multiple somatic point mutations in metastatic progression.

To test the hypothesis that the ability to metastasize is determined by multiple point mutations during the expansion of a neoplastic clone, a mathematical model for sequential mutations was derived. Development of the metastatic phenotype was attributed to the mutation of a specific group of genes. The average tumor size was estimated for when a cell should manifest a set number of these mutated genes. In a tumor of 10(9) cells subject to 10(-6) mutations/gene per generation, only one of these genes, on average, should have mutated. To explain the multiplicity of changes associated with the metastatic phenotype, genetic variation at rates greater than 10(-3) variations/gene per generation seems necessary. Possible mechanisms for this variation involve gene amplification, chromosomal aneuploidy, and altered gene regulation rather than point mutation.