Disease cloning

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

In 1995, Nagata et al. [16] identified a point mutation consisting of a substitution of valine for aspartic acid in the catalytic domain of c-kit (D816V) in the peripheral blood of patients with mastocytosis and predominately myelodysplastic features. Subsequently, the same mutation was identified in adult patients with different forms of mastocytosis in tissues where mast cells are abundant, such as bone marrow, skin and spleen [17]. It is now believed that more than 90% of adults with mastocytosis have the D816V mutation, if bone marrow mononuclear cells are examined [17]. In a subset of patients, primarily those with more severe disease, the clone expands sufficiently to be detected in peripheral blood [16]. 

Because of the relative ease with which they can be obtained, plasma proteins have been smdied extensively in both humans and animals. Considerable information is available about the biosynthesis, turnover, strucmre, and functions of the major plasma proteins. Alterations of their amounts and of their metabolism in many disease states have also been investigated. In recent years, many of the genes for plasma proteins have been cloned and their stmcmres determined. 

Moss ML, Jin SL, MiUa ME et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385 733-736 Nixon RA, Cataldo AM (2006) Lysosomal system pathways genes to neurodegeneration in Alzheimer s disease. J Alzheimers Dis 9 277-289 Noorbakhsh F, VergnoUe N, HoUenberg MD et al (2003) Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4 981-990... 

Breakdown of tolerance mechanisms. There are at least two mechanisms for maintaining unresponsiveness to self The first is by specific deletion of self-reactive clones and the second by suppression. A failure of either of these two may result in an autoimmune disease. In normal, healthy individuals, antigen-binding, self-reactive B cells and the resultant low litres of autoantibodies are not uncommon. The origin of the self-reactive B cells is not clear, but there are four ways in which they may become activated. 

The ideal of any vaccine is to provide life-long protection to the individual against disease. Immunological memory (Chapter 14) depends upon the survival of cloned populations of small B and T lymphocytes (memory cells). These small lymphocytes have a lifespan in the body of ca. 15-20 years. Thus, if the immune system is not boosted, either by natural exposure to the organism or by re-immunization, then immunity gained in childhood will be attenuated or lost completely by the age of 30. Those vaccines which provide only poor protection against disease have proportionately reduced time-spans of effectiveness. Yellow fever vaccination, which is highly effective, must therefore be repeated at 10-year intervals, whilst typhoid vaccines are only effective for 1-3 years. Whether or not immunization in childhood is boosted at adolescence or in adult life depends on the relative risks associated with the infection as a function of age. 

The genes of the inducible and the constitutively expressed forms of NOS have been cloned and expressed. The expression of inducible NOS in the brain tissue of animals with experimentally induced neurological disorders (boma disease virus and rabies virus in rats), herpes simplex virus (mice) and experimental allergic encephalitis (in rats) suggests that NO produced by induced NOS may be a toxic fector in the pathogenesis of neurological diseases (Koprowski et /., 1993). 

The primary goal in the treatment of CML is to eradicate the Ph-positive clones. Elimination of the Ph is termed cytogenetic complete remission. If treatment produces RT-PCR-negative disease, this is termed molecular complete remission and indicates a several-log reduction over cytogenetic complete remission. An early goal of therapy is to achieve hematologic complete remission or to normalize peripheral blood. 

Linnen, J., era/. (1996). Molecular cloning and disease association of hepatitis G virus A transfusion-transmissible agent. Science 271,505-508. 

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