The Patient Perspective on Radiogenomics Testing for Breast Radiation Toxicity.

AIMS: In the field of radiogenomics, several potential predictive genetic markers have been identified that are associated with individual susceptibility to radiation toxicity. Predictive models of radiation toxicity incorporating radiogenomics and other biomarkers are being developed as part of the ongoing multicentre REQUITE trial. The purpose of this study was to explore patient attitudes towards future predictive radiogenomics testing for breast radiation toxicity. PATIENTS AND METHODS: Twenty-one semi-structured interviews were conducted with breast cancer patients taking part in the REQUITE study at one centre. We used inductive thematic analysis to generate common themes. RESULTS: We identified three emerging themes describing attitudes and feelings towards a predictive radiogenomics test for breast radiation toxicity: theme 1 - willingness to undergo a test (subthemes - information, trusted expert); theme 2 - implications of a test (subthemes - preparation and planning, anxiety without recourse); theme 3 - impact on treatment decision-making (subthemes - prioritising cancer cure, preserving breast integrity, patient preferences). CONCLUSIONS: Results from the present study indicate that patients support and have confidence in the validity of a radiogenomics test for breast radiation toxicity, but they would prefer the result be provided to healthcare professionals. Except in cases of significant chronic symptoms and pain or significant end-organ damage, participants in this study rarely felt that advance knowledge of their personal risk of breast radiation toxicity would influence their treatment decision-making. These findings provide a number of insights that will allow us to anticipate how patients are likely to engage with predictive radiogenomics testing in the future.

Methods for short time series analysis of cell-based biosensor data.

This paper describes two approaches for sensing changes in spiking cells when only a limited amount of spike data is available, i.e., dynamically constructed local expansion rates and spike area distributions. The two methods were tested on time series from cultured neuron cells that exhibit spiking both autonomously and in the presence of periodic stimulation. Our tested hypothesis was that minute concentrations of toxins could affect the local statistics of the dynamics. Short data sets having relatively few spikes were generated from experiments on cells before and after being treated with a small concentration of channel blocker. In spontaneous spiking cells, local expansion rates show a sensitivity that correlates with channel concentration level, while stimulated cells show no such correlation. Spike area distributions on the other hand showed measurable differences between control and treated conditions for both types of spiking, and a much higher degree of sensitivity. Because these methods are based on analysis of short time series analysis, they might provide novel means for cell drug and toxin detection.

Vagal nerve stimulation: adjustments to reduce painful side effects.

Vagal nerve stimulation is an approved adjunctive treatment for medically intractable epilepsy. Although it is generally well tolerated, some patients experience pain, coughing, or hoarseness during stimulation. Lowering the pulse width in these patients alleviates pain and reduces voice alteration without loss of efficacy. This allows more optimal programming of stimulation intensities.

Immunohistochemical analysis of atypical ductular reaction in the human liver, with special emphasis on the presence of growth factors and their receptors.

AIMS/BACKGROUND: The objective of this study was to characterize the expression of transforming growth factor-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, transforming growth factor-beta/Type I-II transforming growth factor-beta receptors, stem cell factor, urokinase plasminogen activator, smooth muscle actin, CD34 and alpha-fetoprotein in human liver samples with (sub)massive necrosis of different etiology containing atypical ductular reaction. METHODS: Their presence was studied by immunohistochemistry on paraffin-embedded tissue sections. RESULTS: Transforming growth factor-alpha and -beta, hepatocyte growth factor and their receptors were demonstrated in the ductules; additionally stem cell factor and urokinase plasminogen activator were also expressed. The atypical ductules were surrounded by smooth muscle actin-positive activated stellate cells. CONCLUSION: These phenotypic similarities confirm that the atypical ductules in the human liver may be equivalent of oval cells in the rat liver, which are regarded as the progeny of stem cells. That is, the atypical ductular proliferation may correspond to a stem cell-fed regenerative process.

Origin and structural evolution of the early proliferating oval cells in rat liver.

We have analyzed the histological changes in rat liver after 2-acetylaminofluorene (AAF) administration. The data demonstrate that AAF-induced oval cells were preferentially generated by proliferation of the terminal biliary ductules that we suggest constitute the primary hepatic stem cell niche. The oval cells formed ductular structures, representing an extension of the canals of Hering. This histological organization provides continuous bile drainage of the hepatocytes and uninterrupted blood flow in the sinusoids. The oval cell ductules are surrounded by a continuous basement membrane that is intermittently disrupted by processes of stellate cells that form direct cell-cell contact with the oval cells. Although both AAF treatment and bile duct ligation results in proliferation of biliary epithelial cells, the mechanism(s) responsible for the proliferation of the biliary epithelium seems to differ in the two models. In contrast to the biliary proliferation stimulated by bile ligation, AAF-induced oval cell proliferation as well as the capacity of these cells to differentiate into hepatocytes, bile epithelial cells and possibly other cell lineages can be blocked by administration of dexamethasone.

Reconstitution of liver mass via cellular hypertrophy in the rat.

The liver has an extremely effective regenerative capacity. When 70% of a rat liver is removed by surgery, the liver mass regrows in 7 to 10 days by the compensatory hyperplasia of the remnant part. In case of damage to the surviving hepatocytes, the facultative stem-cell compartment is activated and the liver regenerates by means of oval-cell proliferation/differentiation. In the present study, we demonstrate that when both hepatocyte proliferation and stem-cell activation were prevented by dexamethasone (Dex) administration, the liver mass was restored in the absence of DNA synthesis. The restoration of the liver was accomplished by the preferential enlargement/hypertrophy of the periportal hepatocytes. A similar response was observed when cell proliferation was arrested by 5-fluorouracil (FU) following partial hepatectomy. Therefore, the hepatocytic hypertrophy appears to provide an alternative mechanism of liver-mass restoration. This hypertrophic condition of the liver is not stable, because following the withdrawal of Dex, the enlarged hepatocytes entered in the cell cycle and the normal liver structure and DNA content was re-established.

Studies on hepatic gene expression in different liver regenerative models.

We have investigated the expression of several growth-related genes in the liver after partial hepatectomy in three experimental models: normal, Dexamethasone-pretreated, and hypophysectomized rats. Dexamethasone and hypophysectomy resulted in a delay in the peak of cell replication in 6 and 18 h, respectively, when compared to the normal animals. TGFalpha mRNA expression was shifted together with the DNA synthesis, but the expression of c-myc, c-fos, c-jun, HGF, TGFbeta1, IL1beta did not delay. This result suggests that liver-derived TGFalpha but not the other factors are important in the timing of the proliferative response after partial hepatectomy.

Functional brain mapping using positron emission tomography scanning in preoperative neurosurgical planning for pediatric brain tumors.

OBJECT: The purpose of this report is to demonstrate the value of functional brain mapping using the positron emission tomography (PET) method for preoperative neurosurgical planning in children with brain tumors. Brain maps were used to characterize the relationship between potentially resectable tumors and functionally eloquent brain areas. METHODS: Five children, ranging in age from 3 to 13 years, with hemispheric brain tumors adjacent to eloquent cortex were studied. Magnetic resonance (MR) imaging was used to identify the brain tumors; PET imaging after injection of [18F] fluorodeoxyglucose (FDG), [11C]L-methionine (CMET), or a combination of the two was performed to grade the tumors; and a [15O] H2O uptake study was used to characterize the anatomical relationships of the tumors to functional cortex. The cortical activation maps were obtained during control periods and during behavioral tasks and were used to document motor, visual, and speech and language organizational areas. Wada tests were performed in two patients. Language and speech activation was concordant with the results of Wada testing. CONCLUSIONS: Functional brain mapping using PET scans and coregistered MR images provided the neurosurgeon with precise definitions of structural and functional cortical areas; this altered surgical management in some cases and/or was used to predict outcome. The combination of PET imaging with FDG and/or CMET and measurements of [15O] water uptake was useful in characterizing and grading tumors and instrumental in achieving effective neurosurgical planning. Postoperative results in the five cases suggest that preoperative functional brain mapping has the potential to improve outcome by defining a surgical plan to maximize resection and minimize the risk of neurological sequelae.

Self-assembly of helical ribbons.

The self-assembly of helical ribbons is examined in a variety of multicomponent enantiomerically pure systems that contain a bile salt or a nonionic detergent, a phosphatidylcholine or a fatty acid, and a steroid analog of cholesterol. In almost all systems, two different pitch types of helical ribbons are observed: high pitch, with a pitch angle of 54 +/- 2 degrees, and low pitch, with a pitch angle of 11 +/- 2 degrees. Although the majority of these helices are right-handed, a small proportion of left-handed helices is observed. Additionally, a third type of helical ribbon, with a pitch angle in the range 30-47 degrees, is occasionally found. These experimental findings suggest that the helical ribbons are crystalline rather than liquid crystal in nature and also suggest that molecular chirality may not be the determining factor in helix formation. The large yields of helices produced will permit a systematic investigation of their individual kinetic evolution and their elastic moduli.

Chemical hepatocarcinogenesis in transgenic mice overexpressing mature TGF beta-1 in liver.

The role of transforming growth factor beta 1 (TGF-beta 1) in carcinogenesis is a controversial issue. Certain results suggest a promoter role of this growth factor whilst in other experimental models TGF-beta 1 seems to inhibit the process of tumorigenesis. In an attempt to resolve this problem, we have performed chemical hepatocarcinogenesis experiments on transgenic mice expressing a high level of active TGF-beta 1 in their liver. Transgenic production of TGF-beta 1 did not result in spontaneous tumour formation during our observation period. However, two carcinogens, thioacetamide and N-OH acetylaminofluorene, were more potent in transgenic than in wild-type mice, whereas aflatoxin B1 was equally effective in both groups. Our observations suggest that an increased level of TGF-beta 1 in the liver does not provide protection against the effect of chemical carcinogens.

Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver.

Recent advances have implicated the importance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in the regulation of liver growth. Therefore, we studied how dexamethasone, a well-known inhibitor of these cytokines, influences the proliferation of different hepatic cell populations. As we expected, dexamethasone pretreatment suppressed the expression of both TNF and IL-6 after partial hepatectomy and significantly reduced the proliferative response of the hepatocytes. Furthermore, the proliferative response of hepatocytes could be rescued by IL-6 administration. Dexamethasone also severely diminished the induction and expansion of oval cells induced by the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) protocol but did not have any effect on the proliferation of the bile duct cells stimulated by bile duct ligation. The differential inhibition of these two morphologically very similar cell types may be used to characterize divergent regulatory mechanisms responsible for the proliferative response of oval cells and adult bile epithelial cells.

Cooperative chiral order in the B-Z transition in random sequences of DNA.

We present a theory for cooperative chiral order in the transition between right-handed B-DNA and left-handed Z-DNA. This theory, based on the random-field Ising model, predicts the characteristic length scale of Z-DNA segments. This length scale depends on whether the DNA is a homopolymer or a random sequence: it is approximately 4000 nucleotides in a homopolymer but only approximately 25 nucleotides in a random sequence. These theoretical results are consistent with experiments on DNA homopolymers and random sequences.

Chiral molecular self-assembly of phospholipid tubules: a circular dichroism study.

We report on spectroscopic studies of the chiral structure in phospholipid tubules formed in mixtures of alcohol and water. Synthetic phospholipids containing diacetylenic moieties in the acyl chains self-assemble into hollow, cylindrical tubules in appropriate conditions. Circular dichroism provides a direct measure of chirality of the molecular structure. We find that the CD spectra of tubules formed in mixtures of alcohol and water depends strongly on the alcohol used and the lipid concentration. The relative spectral intensity of different circular dichroism bands correlates with the number of bilayers observed using microscopy. The results provide experimental evidence that tubule formation is based on chiral packing of the lipid molecules and that interbilayer interactions are important to the tubule structure.

Diacetylenic lipid tubules: experimental evidence for a chiral molecular architecture.

Molecular self-assembly is of key importance for the rational design of advanced materials. To investigate the causal relation between molecular structure and the consequent self-assembled microstructure, self-assembled tubules of diacetylenic lipids were studied. Circular-dichroism studies give experimental evidence that the formation of tubules is driven by chiral molecular packing, in agreement with recent theories of tubules. On the basis of these results, a molecular mechanism for the formation of tubules is proposed.

Lipid tubules: a paradigm for molecularly engineered structures.

The use of molecular self-assembly to fabricate microstructures suitable for advanced material development is described. Templating techniques that transform biomolecular self-assemblies into rugged and stable nano- and microstructures are described. By using a lipid-based microcylinder (tubule) as a paradigm, the path followed from research and development to emerging technological applications is detailed. This process includes modification of the lipid molecular structure, the formation and subsequent characterization of cylindrical microstructures, the use of these structures as templates for metallization, and the characterization and assessment of these hollow metal microcylinders for several potential applications.

Effect of alcohol chain length on tubule formation in 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine.

Aqueous dispersions of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine, on cooling below the chain melting temperature, form hollow cylindrical structures known as 'tubules'. We have studied the formation of tubules in methanol/water, ethanol/water and n-propanol/water. For each alcohol, there is a defined window of alcohol/water ratios in which the lipid precipitates with the tubule morphology. As the chain length of alcohol is increased, the window shifts towards lower alcohol fraction. Light scattering studies show that at very low lipid concentrations the tubules self-assemble directly from the isotropic phase where as for lipid concentrations greater than 4 mg/ml an intermediate L alpha phase is observed. These results indicate that the mechanism of tubule formation may be dependent on lipid concentration.

Pseudotumor cerebri due to partial obstruction of the sigmoid sinus by a cholesteatoma.

A 62-year-old man with pseudotumor cerebri (PTC) syndrome was discovered to have a cholesteatoma of the left mastoid. The mass indented the sigmoid sinus without occluding it. The PTC resolved postoperatively. To our knowledge, PTC has not been previously reported in association with a cholesteatoma. Additionally, this case demonstrated that a partial obstruction of the venous drainage of the brain may be sufficient to increase intracranial pressure.