Genetics of cutaneous malignant melanoma

Cutaneous malignant melanoma has doubled in incidence in many countries over the past 20 years. The majority of melanomas are sporadic, but up to 5% of melanoma patients have one or more first-degree relatives also affected, and genetic analysis of these families shows germline mutations of CDKN2A in 20-30% of patients. This thesis has investigated 48 Scottish families with cutaneous malignant melanoma and also 28 patients with sporadic melanoma for mutations in the CDKN2A, MCIR and BRAF genes using molecular genetic techniques. The work presented in this thesis adds 32 new melanoma families to the 16 already reported from Scotland (MacKie et al. 1998). In total, 13/48 (27%) Scottish families have detectable CDKN2A mutations. One of the mutations detected (H83N) has not previously been reported in melanoma, and molecular modelling suggests the likely functional result of this mutation. in the course of studying the CDKN2A gene the M531 mutation was identified in six Scottish families making it the most common CDKN2A mutation identified in this thesis from the Scottish melanoma families studied. Haplotype analysis surrounding CDKN2A was therefore performed on the six Scottish families and also examined in 12 M53I carrying families from around the world. This study provides further evidence that the M53I mutation appears to have originated from a common founder and provides further evidence demonstrating common founders for most of the recurrent mutations in the CDKN2A gene. The aim of the analysis of the MCIR gene was to investigate any underlying genetic relationship between MCIR variants and CDKN2A mutations. In total, 13 MCIR variants leading to an amino acid substitution were detected, three of which have not been described elsewhere (L44I, M128K, A171G) and appear to be very rare. Collectively, both familial and sporadic melanoma patients are more likely to carry a MCIR variant than normal control subjects (P = 0.006; OR = 4.485; CI 1.492-12.883) and melanoma patients carry significantly more MCIR variants than control subjects (P = 0.003; OR = 2.696; CI 1.384-5.253). Familial melanoma patients are more likely to carry the R151C variant than normal control subjects (P = 0.043; OR = 2.406; CI 1.062-5.452). CDKN2A positive familial melanoma patients are more likely to carry the V60L and R151C variants than CDKN2A negative familial melanoma patients (P = 0.017; OR = 3.818; CI 1.315-11.084 and P = 0.029; OR = 3.515; CI 1.160-10.650, respectively). Conversely, CDKN2A negative familial melanoma patients are more likely to carry the V92M variant than CDKN2A positive familial melanoma patients (P = 0.021; OR = 9.308; CI 1.112-77.888). The variant R160W is significantly correlated with skin type 1 (P < 0.001) and variants R142H (P = 0.019) and R160W (P = 0.018) are significantly correlated with red hair, although this significance is lost after the Bonferroni correction. During the time of this study Davies et al. (2002) reported that the most frequently targeted gene in melanoma is BRAF. All mutations were within the kinase domain, with a single substitution in exon 15 (V599E) accounting for 80% of mutations. BRAF mutations in germline DNA from familial melanoma patients had not been investigated, and the number of melanoma tissue samples investigated for BRAF mutations was low. One of the aims of this thesis therefore was to screen exon 15 of BRAF to determine if the V599E mutation would contribute to melanoma predisposition in familial melanoma as a germline mutation. The study of this thesis also investigated primary and secondary melanomas for exon 15 BRAF mutations. DNA from the peripheral blood of 42 familial melanoma cases contained no exon 15 BRAF mutations. DNA from two samples of secondary melanoma from two individuals with a family history of melanoma also failed to show exon 15 BRAF mutations. These results therefore suggest that exon 15 BRAF mutations are not causative germline mutations in melanoma. The V599E substitution was however detected in formalin fixed paraffin embedded primary tumour DNA from 13/52 sporadic cases (25%). The V599E substitution was also detected in secondary tumour DNA from 6/22 sporadic cases (27%) of frozen secondary melanoma

Immunosuppression in Head and Neck Cancer: The role of p15E-related immunosuppressive factors

Cancer is the second cause of death for both younger people and older people in the Western world. Although about 50% of patients with diagnosed cancer can be cured with the conventional modalities of cancer treatment, the other half will die of the disease. The chances of survival from cancer strongly cOlTelate with the type of cancer and with the stage of the disease at the time of diagnosis. After a malignant tumor has been diagnosed, the therapy of choice will also depend upon the type of tumor and the tumor stage. Surgery is the most widely used approach in cancer therapy. Surgical excision is both quick and effective and it accounts for the largest number of cures. Unfortunately, this form of treatment has several drawbacks. Removal of the tumor mass visible to the surgeon does not guarantee elimination of all tumor cells. In order to remove all tumor tissue, the surgeon may be forced to cut out healthy tissue and, in doing so, may severely damage the patient's functioning or appearance. Surgery can be combined with radiation therapy to eliminate residual tumor cells or microscopic invasions of malignant cells in slllTounding tissues. Radiation therapy can be preferable to surgety in some instances. Because healthy tissues usually recover from radiation exposure more readily than cancerous cells, radiation therapy can preserve the anatomical structures surrounding the tumor. Still, it should be noted that radiation therapy will cause problems, most of which will disappear when therapy cycles are completed. Radiation therapy is especially important for tumors not accessible for surgety (e.g. some brain tumors) or for treating cancers of the latynx (voice box). In this way cancer of the latynx can be cured without impairing the patient's ability to speak. Chemotherapy is a systemic therapy, required when the tumor cells have all'eady spread throughout the body, or when no solid tumor is present, as is the case in leukemia. A drawback of chemotherapy are the side effects, preliminaty caused by the fact that normal dividing cells are also killed by the chemotherapeutic agent

Restoration-oriented stressors of bereavement

BACKGROUND AND OBJECTIVES: The Dual Process Model of Coping with Bereavement holds that bereaved people who respond flexibly to loss-oriented stressors (i.e., relating to the loss; to the deceased person) and restoration-oriented stressors (i.e., secondary to loss; daily-life changes, taking on new roles) adapt better to bereavement. Despite growing interest in the Dual Process Model, systematic analyses of the prevalence, characteristics, and correlates of restoration-oriented stressors are lacking. Therefore, we aimed to chart restoration-oriented stressors and their relationship with post-loss adaptation. DESIGN AND METHODS: A community sample of 181 bereaved adults (63% women) completed the 20-item expert-construed Restoration-Oriented Stressors Inventory (ROSI) and questionnaires assessing background characteristics, worry, and prolonged grief and depression symptoms. RESULTS: Main findings were that younger people, and those who lost a parent, partner, or child (vs. other relationship) experienced more restoration-oriented stressors and appraised these as more stressful. Stressors' perceived stressfulness, but not their quantity, related positively to worry. Perceived stressfulness predicted prolonged grief and depression symptoms beyond background characteristics, worry, and the number of stressors. CONCLUSION: Restoration-oriented stressors and their appraisal vary and relate to coping and post-loss mental health. Future research should clarify temporal interrelations between stressors, coping mechanisms, and outcomes

Current Profiles of Molecular Nanowires; DFT Green Function Representation

The Liouville-space Green function formalism is used to compute the current density profile across a single molecule attached to electrodes. Time ordering is maintained in real, physical, time, avoiding the use of artificial time loops and backward propagations. Closed expressions for molecular currents, which only require DFT calculations for the isolated molecule, are derived to fourth order in the molecule/electrode coupling.Comment: 21 page

A theoretical approach for the electrochemical characterization of ciliary epithelium

The ciliary epithelium (CE) is the primary site of aqueous humor (AH) production, which results from the combined action of ultrafiltration and ionic secretion. Modulation of ionic secretion is a fundamental target for drug therapy in glaucoma, and therefore it is important to identify the main factors contributing to it. Since several ion transporters have been hypothesized as relevant players in CE physiology, we propose a theoretical approach to complement experimental methods in characterizing their role in the electrochemical and fluid-dynamical conditions of CE. As a first step, we compare two model configurations that differ by (i) types of transporters included for ion exchange across the epithelial membrane, and by (ii) presence or absence of the intracellular production of carbonic acid mediated by the carbonic anhydrase enzyme. The proposed model configurations do not include neurohumoral mechanisms such as P2Y receptor dependent, cAMP or calcium dependent pathways, which occur in the ciliary epithelium bilayer and influence the activity of ion transporters, pumps and channels present in the cell membrane. Results suggest that one of the two configurations predicts sodium and potassium intracellular concentrations and transmembrane potential much more accurately than the other. Because of its quantitative prediction power, the proposed theoretical approach may help relate phenomena at the cellular scale, that cannot be accessed clinically, with phenomena occuring at the scale of the whole eye, for which clinical assessment is feasible

Square Patterns and Quasi-patterns in Weakly Damped Faraday Waves

Pattern formation in parametric surface waves is studied in the limit of weak viscous dissipation. A set of quasi-potential equations (QPEs) is introduced that admits a closed representation in terms of surface variables alone. A multiscale expansion of the QPEs reveals the importance of triad resonant interactions, and the saturating effect of the driving force leading to a gradient amplitude equation. Minimization of the associated Lyapunov function yields standing wave patterns of square symmetry for capillary waves, and hexagonal patterns and a sequence of quasi-patterns for mixed capillary-gravity waves. Numerical integration of the QPEs reveals a quasi-pattern of eight-fold symmetry in the range of parameters predicted by the multiscale expansion.Comment: RevTeX, 11 pages, 8 figure

Net Charge on a Noble Gas Atom Adsorbed on a Metallic Surface

Adsorbed noble gas atoms donate (on the average) a fraction of an electronic charge to the substrate metal. The effect has been experimentally observed as an adsorptive change in the electronic work function. The connection between the effective net atomic charge and the binding energy of the atom to the metal is theoretically explored.Comment: ReVvTeX 3.1 format, Two Figures, Three Table

Technical Note: Calibration and validation of geophysical observation models

We present a method to calibrate and validate observational models that interrelate remotely sensed energy fluxes to geophysical variables of land and water surfaces. Coincident sets of remote sensing observation of visible and microwave radiations and geophysical data are assembled and subdivided into calibration (Cal) and validation (Val) data sets. Each Cal/Val pair is used to derive the coefficients (from the Cal set) and the accuracy (from the Val set) of the observation model. Combining the results from all Cal/Val pairs provides probability distributions of the model coefficients and model errors. The method is generic and demonstrated using comprehensive matchup sets from two very different disciplines: soil moisture and water quality. The results demonstrate that the method provides robust model coefficients and quantitative measure of the model uncertainty. This approach can be adopted for the calibration/validation of satellite products of land and water surfaces, and the resulting uncertainty can be used as input to data assimilation schemes

Electrostatic potential profiles of molecular conductors

The electrostatic potential across a short ballistic molecular conductor depends sensitively on the geometry of its environment, and can affect its conduction significantly by influencing its energy levels and wave functions. We illustrate some of the issues involved by evaluating the potential profiles for a conducting gold wire and an aromatic phenyl dithiol molecule in various geometries. The potential profile is obtained by solving Poisson's equation with boundary conditions set by the contact electrochemical potentials and coupling the result self-consistently with a nonequilibrium Green's function (NEGF) formulation of transport. The overall shape of the potential profile (ramp vs. flat) depends on the feasibility of transverse screening of electric fields. Accordingly, the screening is better for a thick wire, a multiwalled nanotube or a close-packed self-assembled monolayer (SAM), in comparison to a thin wire, a single-walled nanotube or an isolated molecular conductor. The electrostatic potential further governs the alignment or misalignment of intramolecular levels, which can strongly influence the molecular I-V characteristic. An external gate voltage can modify the overall potential profile, changing the current-voltage (I-V) characteristic from a resonant conducting to a saturating one. The degree of saturation and gate modulation depends on the metal-induced-gap states (MIGS) and on the electrostatic gate control parameter set by the ratio of the gate oxide thickness to the channel length.Comment: to be published in Phys. Rev. B 69, No.3, 0353XX (2004

Geometric Phase, Curvature, and Extrapotentials in Constrained Quantum Systems

We derive an effective Hamiltonian for a quantum system constrained to a submanifold (the constraint manifold) of configuration space (the ambient space) by an infinite restoring force. We pay special attention to how this Hamiltonian depends on quantities which are external to the constraint manifold, such as the external curvature of the constraint manifold, the (Riemannian) curvature of the ambient space, and the constraining potential. In particular, we find the remarkable fact that the twisting of the constraining potential appears as a gauge potential in the constrained Hamiltonian. This gauge potential is an example of geometric phase, closely related to that originally discussed by Berry. The constrained Hamiltonian also contains an effective potential depending on the external curvature of the constraint manifold, the curvature of the ambient space, and the twisting of the constraining potential. The general nature of our analysis allows applications to a wide variety of problems, such as rigid molecules, the evolution of molecular systems along reaction paths, and quantum strip waveguides.Comment: 27 pages with 1 figure, submitted to Phys. Rev.