Escape from immunotherapy: possible mechanisms that influence tumor regression/progression

Tumor escape is one major obstacle that has to be addressed prior to designing and delivering successful immunotherapy. There is compelling evidence to support the notion that immunogenic tumors, in murine models and cancer patients, can be rejected by the immune system under optimum conditions for activating adaptive and nonadaptive antitumor immune responses. Despite this capability, a large number of tumors continue to grow and evade recognition and/or destruction by the immune system. The limited success in current immunotherapeutic strategies may be due to a variety of reasons: failure of effector cells to compete with the growing tumor burden, production of humoral factors by tumors that locally block cytotoxicity, antigen/MHC loss, T-cell dysfunction, production of suppressor T cells—to name but a few causes for therapeutic ineffectiveness for the particular malignancy being treated. To optimize immunotherapy strategies, correction of immune-activating signals, eradication of inhibitory factors, and the evasion from newly developed immunoresistant tumor phenotypes need to be simultaneously considered

Sufficient conditions for unique global solutions in optimal control of semilinear equations with C1−C^1-nonlinearity

We consider a $C^1-$semilinear elliptic optimal control problem possibly subject to control and/or state constraints. Generalizing previous work we provide a condition which guarantees that a solution of the necessary first order conditions is a global minimum. A similiar result also holds at the discrete level where the corresponding condition can be evaluated explicitly. Our investigations are motivated by G\"unter Leugering, who raised the question whether our previous results can be extended to the nonlinearity $\phi(s)=s|s|$. We develop a corresponding analysis and present several numerical test examples demonstrating its usefulness in practice

On 3D Minimal Massive Gravity

We study linearized equations of motion of the newly proposed three dimensional gravity, known as minimal massive gravity, using its metric formulation. We observe that the resultant linearized equations are exactly the same as that of TMG by making use of a redefinition of the parameters of the model. In particular the model admits logarithmic modes at the critical points. We also study several vacuum solutions of the model, specially at a certain limit where the contribution of Chern-Simons term vanishes.Comment: 15 pages, no figures, typos fixed, journal versio

Foreign direct investment in Malaysia: Trends and prospects

This paper reports on a study analyzing recent trends, pattern and prospects of the foreign direct investment (FDI) in Malaysia in the post-1997 financial crisis period. Among the ASEAN-4 countries, Malaysia continues to remain as the main centre for attracting FDI.The macroeconomic variables such as GDP, exports and employment are found to be positively influenced by the growth of FDI in Malaysia. To enhance the positive effect of FDI on the growth process of the Malaysian economy the flow of FDI into export-oriented sector and use of domestic inputs by the foreign oriented firms need to be encouraged.It is suggested that for sustained flow of FDI, continual price stability, macroeconomic balances, good governance and economic liberalization reforms are crucially important in the country.In the event of declining inflows of FDI, Malaysia has to shiR towards inward looking policies and search other alternatives to sustain its growth and economic prosperity by seeking more investment oufflows as a global player

A New Weighting Scheme in Weighted Markov Model for Predicting the Probability of Drought Episodes

Drought is a complex stochastic natural hazard caused by prolonged shortage of rainfall. Several environmental factors are involved in determining drought classes at the specific monitoring station. Therefore, efficient sequence processing techniques are required to explore and predict the periodic information about the various episodes of drought classes. In this study, we proposed a new weighting scheme to predict the probability of various drought classes under Weighted Markov Chain (WMC) model. We provide a standardized scheme of weights for ordinal sequences of drought classifications by normalizing squared weighted Cohen Kappa. Illustrations of the proposed scheme are given by including temporal ordinal data on drought classes determined by the standardized precipitation temperature index (SPTI). Experimental results show that the proposed weighting scheme for WMC model is sufficiently flexible to address actual changes in drought classifications by restructuring the transient behavior of a Markov chain. In summary, this paper proposes a new weighting scheme to improve the accuracy of the WMC, specifically in the field of hydrology

Immunotherapeutic potential of DISC-HSV and OX40L in cancer

Several vectors, viral and bacterial, have been developed over the past few years for means of generating an effective anti-tumor immune response. We have developed and studied a “model for immunotherapy” using a viral vector DISC-HSV, which efficiently transduces various tumor cell lines and offers a useful vehicle for the further development of cell based vaccines. The immunotherapeutic potential of DISC-HSV encoding GMCSF was demonstrated in a number of murine carcinoma models, leading to complete regression of well established tumors in up to 70% of the mice. Moreover, the therapeutic potential of DISC-HSV-GMCSF was significantly enhanced when used in combination therapy with either OX40L or dendritic cells (DC), even in poorly immunogenic tumor model. The ability of this vector to accept large gene inserts, its good safety profile, its ability to undergo only a single round of infection, the inherent viral immunostimulatory properties and its ability to infect various tumor cell lines efficiently, make DISC-HSV an ideal candidate vector for immunotherapy. The DISC- CT-26 tumor model has been used to investigate these mechanisms associated with immunotherapy – induced tumor rejection. Although CTL induction, was positively correlated with regression, MHC class I down regulation and accumulation of immature Gr1+ myeloid cells were shown to be the main immuno-suppressor mechanisms operating against regression and associated with progressive tumor growth