Angiogenic and Metastatic Determinants of Malignant Melanoma

Cutaneous melanoma or malignant melanoma of the skin is a highly metastatic disease, with an increasing rate of incidence, poor prognosis and high resistance to therapeutic intervention. Although early diagnosis and surgical resection of the primary lesion could significantly improve survival, the high propensity of melanomas to disseminate through intradermal, haematogenous and lymphatic routes to regional and visceral sites leads to poor prognosis and high mortality rates. While the clinical staging and progression of melanoma is well defined, the molecular etiology of the disease is less well characterized. The principal goal of this thesis was to obtain novel mechanistic insights into melanoma biology and identify molecular determinants of this disease. We identified the capacity of melanoma-derived small molecules to promote long-term survival of endothelial cells under severe hypoxic conditions. This observation excludes known proangiogenic molecules which have been the focus of anti-angiogenic therapies and sets the stage for the identification of novel regulators with therapeutic potential. Moreover, TIMP3 was identified as a dominant negative regulator of melanoma development. The inhibitory role of TIMP3 in melanoma angiogenesis was validated and further extended to clinical samples from melanoma patients. We showed that promoter methylation mediated TIMP3 silencing impacts clinical outcome in melanoma and also evaluated the implications of the tumor suppressor role of TIMP3 in melanoma metastasis, using matched samples from melanoma patients. A decrease in TIMP3 expression with observed with disease progression and further TIMP3 inhibited melanoma cell migration and invasion. To characterize core mediators of the metastatic cascade of melanomas, we determined the migratory profile of melanoma cell lines and performed correlation analysis to identify potential genetic modulators. WNT5A was identified as a dominant regulator of the metastatic cascade in melanoma and further we show that WNT5A inhibition decreases the migratory and metastatic potential of melanoma cells. Additionally, this thesis describes novel tools to quantitatively characterize several biological processes. The ring barrier-based migration assay enables the quantitative assessment of several parameters of cell migration. The eNOS-Tag-GFP mouse model provides a platform for the in vivo and ex vivo study of early angiogenic events in physiological and pathological conditions. Collectively, the results presented in this thesis identify crucial pathophysiological determinants of melanoma. These insights and tools may further guide the discovery of novel regulators of melanoma biology and result in the implementation of new treatment rationales for therapeutic benefit

Promoting the first generation women entrepreneurs in Sri Lanka: a lesson from India

The women entrepreneurs of Sri Lanka were victims of war. They did not become entrepreneurs out of choice; they became entrepreneurs as a result of war, in their pursuit of supporting themselves and their families. Majority of them were in business for the first time as they lost their husbands and/or children to the war and saw business as a means to end and their success in the venture is making a balance between family and work. These women were educated with a minimum level education and were involved in businesses such as livestock farming, services and craft/textile which did not require a high capital outlay and expert skills and knowledge of the business. While the international attention has somewhat shifted elsewhere, the international community are still trying to play a constructive role in building up a postwar Sri Lanka. What is more difficult to know- is what strategies (long and short term) exists for development in Sri Lanka? How will the civilians more particularly women start a new life after the camps and how will they become self-sufficient? In this context the present paper entitled "Promoting the First Generation Women Entrepreneurs in Sri Lanka: A lesson from India" is a modest attempt to unearth the problems and prospects of women entrepreneurs in retail trade. By taking a sample of 281 women and 161 men retail-traders from India, the results confirm the fact that, though women retail-traders face a lot of problems in transacting their business, still there exists a better scope for growth. The findings of this research are important for several reasons. The women entrepreneurs of the Sri Lanka, like anywhere in the world are powerful driving force for the economic development of the country. The findings of the study will certainly pave the way for the up liftmen of socio-economic status of first generation women entrepreneurs in war-torn areas of Sri Lanka

Pseudo-Schwarzschild Spherical Accretion as a Classical Black Hole Analogue

We demonstrate that a spherical accretion onto astrophysical black holes, under the influence of Newtonian or various post-Newtonian pseudo-Schwarzschild gravitational potentials, may constitute a concrete example of classical analogue gravity naturally found in the Universe. We analytically calculate the corresponding analogue Hawking temperature as a function of the minimum number of physical parameters governing the accretion flow. We study both the polytropic and the isothermal accretion. We show that unlike in a general relativistic spherical accretion, analogue white hole solutions can never be obtained in such post-Newtonian systems. We also show that an isothermal spherical accretion is a remarkably simple example in which the only one information--the temperature of the fluid, is sufficient to completely describe an analogue gravity system. For both types of accretion, the analogue Hawking temperature may become higher than the usual Hawking temperature. However, the analogue Hawking temperature for accreting astrophysical black holes is considerably lower compared with the temperature of the accreting fluid.Comment: Final Version to appear in the journal General Relativity & Gravitation, Volume 27, Issue 11, 2005. 17 pages, Two colour and one black and white figures. Typos corrected. Recent reference on analogue effect in relativistic accretion disc adde

Gauge Theory Correlators from Non-Critical String Theory

We suggest a means of obtaining certain Green's functions in 3+1-dimensional ${\cal N} = 4$ supersymmetric Yang-Mills theory with a large number of colors via non-critical string theory. The non-critical string theory is related to critical string theory in anti-deSitter background. We introduce a boundary of the anti-deSitter space analogous to a cut-off on the Liouville coordinate of the two-dimensional string theory. Correlation functions of operators in the gauge theory are related to the dependence of the supergravity action on the boundary conditions. From the quadratic terms in supergravity we read off the anomalous dimensions. For operators that couple to massless string states it has been established through absorption calculations that the anomalous dimensions vanish, and we rederive this result. The operators that couple to massive string states at level $n$ acquire anomalous dimensions that grow as 2\left (n g_{YM} \sqrt {2 N} )^{1/2} for large `t Hooft coupling. This is a new prediction about the strong coupling behavior of large $N$ SYM theory.Comment: 15 pages, harvmac with btxmac; minor revisions, 1 reference added, the version to appear in Physics Letters

Corporate behaviours towards foreign exchange risk management Practices: an investigative study in Indian scenario

Indian economy in the post-liberalisation era has witnessed increasing awareness of the need for introduction of various risk management products to enable hedging against market risk in a cost effective way. This industry-wide, cross-sectional study concentrates on recent foreign exchange risk management practices and derivatives product usage by large nonbanking Indian-based firms. The study is exploratory in nature and aims at an understanding the risk appetite and FERM (Foreign Exchange Risk Management) practices of Indian corporate enterprises. This study focuses on the activity of end-users of financial derivatives and is confined to 501 non-banking corporate enterprises. A combination of simple random and judgement sampling was used for selecting the corporate enterprises and the major statistical tools used were Correlation and Factor analysis. The factor analysis finds that there are three derived factors of non-usage of derivative products namely, Perceptual Issues, Technical & policy factor and Pricing & Cost considerations. Further, the correlation analysis reveals positive relation between the nine variables representing the reasons as nonusage of derivatives by Indian corporates. The study finds wide usage of derivative products for risk management and the prime reason of hedging is reduction in volatility of cash flows. VAR (Value-at-Risk) technique was found to be the preferred method of risk evaluation by maximum number of Indian corporate. Further, in terms of the external techniques for risk hedging, the preference is mostly in favour of forward contracts, followed by swaps and cross-currency options This article throws light on various concerns of Indian firms regarding derivative usage and reasons for non-usage, apart form techniques of risk hedging, risk evaluation methods adopted, risk management policy and types of derivatives used

Particle Production in Matrix Cosmology

We consider cosmological particle production in 1+1 dimensional string theory. The process is described most efficiently in terms of anomalies, but we also discuss the explicit mode expansions. In matrix cosmology the usual vacuum ambiguity of quantum fields in time-dependent backgrounds is resolved by the underlying matrix model. This leads to a finite energy density for the "in" state which cancels the effect of anomalous particle production.Comment: 24 pages, 1 figure; v2: references added, minor change

HIV infection significantly reduces lipoprotein lipase which remains low after 6 months of antiretroviral therapy

Purpose of the study Fractional clearance rate of apolipoprotein B100-containing lipoproteins is reduced in HIV infection before and after antiretroviral (ARV) treatment [1]. We compared lipoprotein lipase (LPL) activity and gene expression in HIV-positive subjects before and 6 months after ARV with HIV-negative controls. Methods Fasting blood post heparin total and hepatic lipase activity,adiponectin, leptin, insulin, glucose, and lipid measurementswere made in 32 HIV-infected and 15 HIVnegative controls. LPL was estimated by subtractinghepatic lipase from total lipase. Adiponectin, LPL andhormone sensitive lipase (HSL) gene expression weremeasured from iliac crest subcutaneous fat biopsies.Patients were tested before, and 6 months after randomisation to AZT/3TC (n = 15) or TDF/FTC (n = 17) with EFV.Between-group comparison was by Mann-Whitney andpaired samples by the Wilcoxon signed rank tests. Summary of results There were no differences in gender, ethnicity, baseline BMI, regional fat distribution (whole body DEXA) and visceral (VAT) and subcutaneous fat (SAT) measured by abdominal CT scans between controls and patients. Trunk fat/BMI ratio, VAT and VAT:SAT ratio significantly increased after 6-month ARV therapy (p = 0.01). There were no differences between groups in serum NEFA,HOMA and leptin levels. Selected other results are shown in Table 1. Conclusion Post heparin lipoprotein lipase activity is reduced in HIV and does not return to control levels after 6 months of ARV therapy. AZT-containing regimens are associated with a greater increase in LPL, LPL gene expression and plasma adiponectin than TDF

Validity of the zero-thermodynamic law in off-equilibrium coupled harmonic oscillators

In order to describe the thermodynamics of the glassy systems it has been recently introduced an extra parameter also called effective temperature which generalizes the fluctuation-dissipation theorem (FDT) to systems off-equilibrium and supposedly describes thermal fluctuations around the aging state. Here we investigate the applicability of a zero-th law for non-equilibrium glassy systems based on these effective temperatures by studying two coupled subsystems of harmonic oscillators with Monte Carlo dynamics. We analyze in detail two types of dynamics: 1) sequential dynamics where the coupling between the subsystems comes only from the Hamiltonian and 2) parallel dynamics where there is a further coupling between the subsystems arising from the dynamics. We show that the coupling described in the first case is not enough to make asymptotically the effective temperatures of two interacting subsystems coincide, the reason being the too small thermal conductivity between them in the aging state. This explains why different interacting degrees of freedom in structural glasses may stay at different effective temperatures without never mutually thermalizing.Comment: 23 pages, REVTeX, 4 eps figure

On The Problem of Particle Production in c=1 Matrix Model

We reconsider and analyze in detail the problem of particle production in the time dependent background of $c=1$ matrix model where the Fermi sea drains away at late time. In addition to the moving mirror method, which has already been discussed in hep-th/0403169 and hep-th/0403275, we describe yet another method of computing the Bogolubov coefficients which gives the same result. We emphasize that these Bogolubov coefficients are approximately correct for small value of the deformation parameter. We also study the time evolution of the collective field theory stress-tensor with a special point-splitting regularization. Our computations go beyond the approximation of the previous treatments and are valid at large coordinate distances from the boundary at a finite time and up-to a finite coordinate distance from the boundary at late time. In this region of validity our regularization produces a certain singular term that is precisely canceled by the collective field theory counter term in the present background. The energy and momentum densities fall off exponentially at large distance from the boundary to the values corresponding to the static background. This clearly shows that the radiated energy reaches the asymptotic region signaling the space-time decay.Comment: 37 pages, 5 figures. Section 6 is modified to clarify main accomplishments of the paper including a discussion comparing stress-tensor analysis with those preexisted in literature. Other modifications include minor changes in the text and addition of one reference. Version accepted for publication in JHE

On the Nonperturbative Consistency of d=2d=2 String Theory

An infinite number of distinct $d=1$ matrix models reproduce the perturbation theory of $d=2$ string theory. Due to constraints of causality, however, we argue that none of the existing constructions gives a consistent nonperturbative definition of the $d=2$ string.Comment: 10 pages, 2 figures, LaTeX (author's name added