Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine.

First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy

Dating the Origin of Language Using Phonemic Diversity

Language is a key adaptation of our species, yet we do not know when it evolved. Here, we use data on language phonemic diversity to estimate a minimum date for the origin of language. We take advantage of the fact that phonemic diversity evolves slowly and use it as a clock to calculate how long the oldest African languages would have to have been around in order to accumulate the number of phonemes they possess today. We use a natural experiment, the colonization of Southeast Asia and Andaman Islands, to estimate the rate at which phonemic diversity increases through time. Using this rate, we estimate that present-day languages date back to the Middle Stone Age in Africa. Our analysis is consistent with the archaeological evidence suggesting that complex human behavior evolved during the Middle Stone Age in Africa, and does not support the view that language is a recent adaptation that has sparked the dispersal of humans out of Africa. While some of our assumptions require testing and our results rely at present on a single case-study, our analysis constitutes the first estimate of when language evolved that is directly based on linguistic data

Dynamic Models of Language Evolution: The Linguistic Perspective

Language is probably the key defining characteristic of humanity, an immensely powerful tool which provides its users with an infinitely expressive means of representing their complex thoughts and reflections, and of successfully communicating them to others. It is the foundation on which human societies have been built and the means through which humanity’s unparalleled intellectual and technological achievements have been realized. Although we have a natural intuitive understanding of what a language is, the specification of a particular language is nevertheless remarkably difficult, if not impossible, to pin down precisely. All languages contain many separate yet integral systems which work interdependently to allow the expression of our thoughts and the interpretation of others’ expressions: each has, for instance, a set of basic meaningless sounds (e.g. [e], [l], [s]) which can be combined to make different meaningful words and parts of words (e.g. else, less, sell, -less ); these meaningful units can be combined to make complex words (e.g. spinelessness, selling ), and the words themselves can then be combined in very many complex ways into phrases, clauses and an infinite number of meaningful sentences; finally each of these sentences can be interpreted in dramatically different ways, depending on the contexts in which it is uttered and on who is doing the interpretation. Languages can be analysed at any of these different levels, which make up many of the sub-fields of linguistics, and the primary job of linguistic theorists is to try to explain the rules which best explain these complex combinations

Maintaining the Environmental–Racial Order in Northern New Mexico

The environmental - racial order in northern New Mexico is maintained through a process of racial triangulation in which Anglos, Native Americans, and Hispanos are valued relative to one another along axes of environmental stewardship and victimization (Kim C J, 1999, "The racial triangulation of Asian Americans" Politics and Society 27 105 - 138). Both axes involve the juxtaposing of three long-standing images: (1) Spanish injustices to the Indians; (2) the inability of Mexicans to manage their land properly; and (3) Indians being preeminent environmental stewards. In contrast to Kim's formulation of racial triangulation, however, the axes also involve imagery that contradicts these images: the debauched, poverty-stricken Indian; and European culture as a despoiler of the environment. Also in contrast to Kim's formulation, racial triangulation can involve the creation of new identities. In the 1960s Hispano activists began claiming to be heirs to a hybrid culture that included elements of both Native American and Spanish cultures. While this claim to hybridity enabled the creation of new oppositional discourses, the reconciling of contradictory imagery by historicizing the discourses and by other means undermines the new Hispano oppositional discourses as well as Hispano identity itself Racial triangulation is thus a fluid and contested process in which identity formation and the interchange between predominant and oppositional discourses are constitutive of power relations. Contradictory imagery in the discourse facilitates the maintenance of the environmental - racial order, even as it enables subordinates to challenge their racialized positions and to effect change in the distribution of material wealth, rights, and privileges

MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells

Despite some progress, treating advanced prostate cancer remains a major clinical challenge. Recent studies have shown that prostate cancer can originate from undifferentiated, rare, stem cell-like populations within the heterogeneous tumor mass, which play seminal roles in tumor formation, maintenance of tumor homeostasis and initiation of metastases. These cells possess enhanced propensity toward chemoresistance and may serve as a prognostic factor for prostate cancer recurrence. Despite extensive studies, selective targeted therapies against these stem cell-like populations are limited and more detailed experiments are required to develop novel targeted therapeutics. We now show that MDA-9/Syntenin/SDCBP (MDA-9) is a critical regulator of survival, stemness and chemoresistance in prostate cancer stem cells (PCSCs). MDA-9 regulates the expression of multiple stem-regulatory genes and loss of MDA-9 causes a complete collapse of the stem-regulatory network in PCSCs. Loss of MDA-9 also sensitizes PCSCs to multiple chemotherapeutics with different modes of action, such as docetaxel and trichostatin-A, suggesting that MDA-9 may regulate multiple drug resistance. Mechanistically, MDA-9-mediated multiple drug resistance, stemness and survival are regulated in PCSCs through activation of STAT3. Activated STAT3 regulates chemoresistance in PCSCs through protective autophagy as well as regulation of MDR1 on the surface of the PCSCs. We now demonstrate that MDA-9 is a critical regulator of PCSC survival and stemness via exploiting the inter-connected STAT3 and c-myc pathways