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By J. Leif. University of the Virgin Islands.

The often multifactorial or buy effexor xr master card, as many geneticists believe order cheap effexor xr line, caused by a combined effects of such factors as age buy effexor xr 150mg without a prescription, sex, education, parental single mutant gene with allelic restriction (5). Medical conditions such as diabetes, lupus ery- yet, no concrete evidence of a connection between genes or thematosus, and phenylketonuria can all result in sequelae that some combination of genes and grammatical abilities, but that can give the appearance of a genetic relationship. However, before learning can begin, children must be Dialects and language-related difficulties, despite recurrence in ready to learn; that is, they must be biologically, socially, and a family, may be due to a shared cultural (rather than genetic) psychologically mature enough to undertake the task. Differences in habits and abuse of drugs or alcohol As Kies reported (22), linguists do not agree on exactly may result in a phenotype that can be misconstrued as being of how biological factors affect language learning, but most agree genetic origin. Foetal alcohol syndrome shows a constellation with Lenneberg (23) that human beings possess a capacity to of features that may include a characteristic facial appearance; learn language that is specific to this species and no other. Lenneberg also suggested that language might be expected from By chance, two members of a family may develop the same the evolutionary process that humans have undergone, and that condition with no underlying genetic or environmental predis- the basis for language might be transmitted genetically. Also, some members of a family may acquire a condi- As part of genetically endowed language abilities, tion for reasons completely unrelated to other members of the Lenneberg (24) hypothesized a “critical period” during which family. A “phenocopy” is an individual with a phenotype simi- language learning proceeds with unmatched ease. A child’s lar to other members of a family but with a different aetiology early years are especially crucial for language development (11). However, some stochastic events may be influenced to because that is the period before the two hemispheres of the some degree by a genetic predisposition (12). As Mendel (13) first delineated the methods by which genetic partial proof of this, Lenneberg discussed cases in which chil- factors are transmitted and first discovered the basis of heredity dren in bilingual communities were able to learn two languages in his studies of peas. Although most communicative disorders fluently and without obvious signs of effort before the age of appear to have a complex inheritance pattern, a select group of about 12. However, learning a second language after the age of communicative disorders has inheritance patterns that directly 12 becomes enormously difficult for most people. Similarly, many neurolinguists have argued that children’s brains are biologically too immature to comprehend several grammatical concepts commonly used in languages around the world. Concepts such as plurals, auxiliary verbs, inflectional end- Language development ings, and temporal words will develop in all languages in stages. One of the earliest scientific studies to record the language The fact that those stages of language development are “identi- development of a child was that by a German biologist cal” and “predictable” in all languages further suggests that there Tiedemann in 1787 (14). He was interested in starting a col- are strong biological preconditions for learning language. The concept of a sentence is the main guiding principle in Interest in language development intensified with the publica- a child’s attempts to organize and interpret the linguistic evi- tion of Darwin’s theory of evolution, and Darwin (15) himself dence that fluent speakers make available to him. These ideas contributed to the study of language development in children, are a part of the “nativist” position discussed later. When the German physi- insufficient evidence to conclusively specify the contribution of ologist Preyer (17) published a detailed descriptive work care- biology to human language, but all linguists acknowledge that fully recording the first three years of his son’s development, the biology does have a role. Even before the child has uttered the first word, ■ Critical periods and “feral” children a long process of growth and language development has already ■ Genetically predetermined aspects of language processing started. For instance, a newborn baby will recog- nize his mother’s voice at birth and can see with perfect visual Preconditions for language development acuity his mother’s face when nursing him, but no further. Although children will begin to vocalise and verbalise at differ- All the neurons are already present at birth. What does ent ages and at different rates, most children learn their first increase after birth is the number of dendrites and synapses. In language, a highly complex and abstract symbol system, without humans, a considerable degree of development continues far Genetics of communicative disorders 175 Figure 12. The brain overproduces neural connections, tribute to increase the speed of neural transmission (Fig. The frontal lobes first kick in at about six months, bring- tiple specific genes involved” (26). The language areas relative importance of environmental influences is just a first become active about 18 months after birth. The area that con- step towards future research to identify specific environments fers understanding (Wernicke) matures before the area that involved. As specific genes and environments are identified, we produces speech (Broca), so there is a short time when toddlers can begin to understand the complex mechanisms of develop- understand more than they can say. Thus, cerebral plasticity that involves lan- With regard to the steps of phonological development as Kaplan guage development continues until the age of seven years. This is, of and the major lines of connection, the “highways” of the brain course, the most obvious and intuitive explanation since the Figure 12. Children employ the face, body movement, cries, and child produces a lot of sound and a greater variety of sounds other preverbal vocalization to communicate their needs, than is actually needed in the adult language. When children Meltzoff and Moore (29–31), newborn children not only imi- babble, their parents attend to them closely and encourage them tate facial expressions but will also attempt to imitate rudimen- to continue talking. The impor- At the age of six months or so, children in all cultures begin tance of the social function of babbling is apparent in children to babble with the production of long sequences of consonants who have been severely neglected during this stage. Furthermore, gestures remain an development is why babbling occurs at more or less the same important part of human communication at all stages of devel- time in all children, since simple observational evidence shows opment (32,33). If all humans grow at approxi- considerably from one child to the next, but the relative order mately the same rate, then children around the world will begin of the stages remains constant for all children. In fact, Lenneberg (24) discovered that reached in the same order, although the time between stages babies who were prevented from any vocalization by disease or may be greater for some children than for others. Consequently, medical procedures would begin to babble spontaneously when it is possible to divide the process of language development into they reached six months of age and their medical condition had a sequence of phases, remembering always that there is no clear improved enough to allow vocalization. The stages always over- that previous practice at vocalization was not necessary for the lap, and the chronological age of the child is only a very rough onset of babbling and that biological maturity was a crucial fac- guide to the stage of language development. Babbling occurs automatically when the relevant structures Learning the grammatical structures of language is no less a in the brain reach a critical level of maturation. By When babbling begins, the nonsense syllables children cre- about 18 to 20 months, the average child is creating his/her first ate develop through a regular progression. Children first pro- two word utterances, and by 25 months, two word utterances duce vowels and later combine consonants and vowels.

In cancers with multi- factorial etiology order effexor xr 150mg free shipping, it may be possible to interrupt one or two steps in the complex pathways buy discount effexor xr on line, thereby hindering the overall evolution of the tumor best purchase for effexor xr. Studies using serial analysis of gene expression have shown that tumor and normal endothelium are distinct at the molecular level, a finding that may have significant implications for the development of antiangiogenic therapies. Mutant mice lacking cyclin D1 are entirely resistant to breast tumors induced by neu and ras, genes implicated in most human breast cancers, but are susceptible to those tumors caused by the other oncogenes c-myc and Wnt-1. Although it remains to be seen whether these findings translate to humans, the results suggest that human breast cancers caused by neu and ras could be treated with anti-cyclin D1 therapy. Use of emerging technologies in early clinical trials is allowing quick assessment of the efficacy of anticancer agents. Cyclacel Ltd has introduced the concept of assembling a toolkit that will allow rational drug development rather than a “trial and error” method. Identification of specific biomarker molecules in tumor tissue will permit prediction of clinical outcomes in response to drug treatment. The cancer clinical trial toolkit, including biomarkers that can detect antitumor activity of anticancer agents, can guide selection of patients for specific drug treatments. Universal Free E-Book Store 258 10 Personalized Therapy of Cancer Personalized Therapy of Cancer Based on Cancer Stem Cells Cancers may rely on “cancer stem cells” that share the self-renewal feature of nor- mal stem cells. This has changed the perspective with regard to new approaches for treating cancer. Cancer stem cells are slow-dividing and inherently drug- resistant, and their eradication would be necessary for long-term success in cancer treatment. The cancer stem cell concept could be used to better tailor treatment strategies to individual patients. Most traditional anticancer agents affect primarily bulk tumor cells by disrupting their proliferation and/or survival. Cancer stem cells are less likely to be killed than bulk tumor cells by these approaches. Improved methods will be required to identify, isolate and genetically profile the stem cell population in cancers from individual patients. Cancer stem cells, amplified from individual clinical specimens, should be tested for gene expression profiles and sensitivity to a battery of agents, leading to indi- vidualized decisions on selection of the best therapeutic strategies. The antineoplas- tic agents of the future will have to target the ancient developmental molecular pathways on which stem cells depend on for replication and survival. Thus, an improved understanding of these pathways and their roles in cancer stem cells could lead to a new generation of more selective and effective antineoplastic treatments. Role of Epigenetics in Development of Personalized Cancer Therapies In addition to having genetic causes, cancer is also an epigenetic disease. Epigenetic regulation of gene transcription is emerged a key biological determinant of cellular differentiation and plays a significant patho- genic role in a number of human diseases, particularly cancer. Disruption of the activity of disease-associated epigenetic enzymes offers a mechanism-based opportunity for pharmacologic intervention in diseases such as cancer. When used in combination with conventional chemotherapeutic agents, epigenetic- based therapies may provide a means to sensitize drug-resistant tumors to estab- lished treatments. Universal Free E-Book Store Design of Future Personalized Cancer Therapies 259 Epizyme Inc is focused on discovering novel, small molecule drugs that act as selective inhibitors of key epigenetic enzymes. Once the methyl group has been deposited on the histone site, the affected genes continue to be regu- lated (turned on or off) until this chemical unit is removed by other enzymes, known as histone demethylases. Aberrant epigenetic modifications are frequently associated with distinct cancer types and have potential utility as biomarkers. Selective Destruction of Cancer Cells While Sparing Normal Cells A problem with conventional chemotherapy or radiotherapy is that damage is not limited to cancer cells but involves normal cells as well. It is easy to kill cells in vitro and many new anticancer drugs are being discovered. However, it is difficult to selectively kill cancer cells in vivo without harming normal cells. Even though some success is achieved in animal experiments, it is difficult to translate these findings into practical management of cancer patients. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from inter- nal sources when external nutrients are unavailable. In contrast, normal cells can adapt to the nutrient stress that kills cancer cells by becoming quiescent and cata- bolic. It is well recognized that hypoxia influences the response of cells and tissues to radiation and increases the resistance of cancer to radiother- apy requiring higher radiation doses that can normal tissues. Cancer cells adapt to this stress to survive, and may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Therefore, targeting this non-oncogene dependency may result in selective death of cancer cells. A cell-based small-molecule screening and quantitative pro- teomics approach led to the unbiased identification of piperlongumine, a small mol- ecule that selectively kills cancer cells but not normal cells (Raj et al. Significant antitu- mor effects were observed in mouse xenograft tumor models treated with piper- longumine, but no toxic effects were observed in normal mice. Moreover, piperlongumine inhibits the growth of spontaneous breast cancers in mice. These findings show that ability a small molecule can selectively induce apoptosis in cells that have a cancer genotype by targeting a non-oncogene dependency acquired through the expression of the cancer genotype in response to oxidative stress induced by malignant transformation. Initial trial with the drug will be a study in patients with breast or ovarian cancers to determine a safe dose. Role of Oncoproteomics in Personalized Therapy of Cancer Clinical proteomics is an exciting new subdiscipline of proteomics that involves the application of proteomic technologies at the bedside, and cancer, in particular, is a model disease for studying such applications. Oncoproteomics is the term used for application of proteomic technologies in oncology. Proteomic technologies are being developed to detect cancer earlier, to discover the next generation of targets and imaging biomarkers, and to tailor the therapy to the patient. Proteomic tech- nologies will be used to design rational drugs according to the molecular profile of the cancer cell and thus facilitate the development of personalized cancer therapy. Proteomic separation and analytical techniques are uniquely capable of detecting tumor-specific alterations in proteins.

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