WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses

Adhesion receptors of the immune system.

Mitogen-dependent progression through the first gap phase (G1) and initiation of DNA synthesis (S phase) during the mammalian cell division cycle are cooperatively regulated by several classes of cyclin-dependent kinases (CDKs) whose activities are in turn constrained by CDK inhibitors (CKIs). CKIs that govern these events have been assigned to one of two families based on their structures and CDK targets. The first class includes the INK4 proteins (inhibitors of CDK4), so named for their ability to specifically inhibit the catalytic subunits of CDK4 and CDK6. Four such proteins [p16 (Serrano et al. 1993), p15 (Hannon and Beach 1994), p18 (Guan et al. 1994; Hirai et al. 1995), and p19 (Chan et al. 1995; Hirai et al. 1995)] are composed of multiple ankyrin repeats and bind only to CDK4 and CDK6 but not to other CDKs or to D-type cyclins. The INK4 proteins can be contrasted with more broadly acting inhibitors of the Cip/Kip family whose actions affect the activities of cyclin D-, E-, and A-dependent kinases. The latter class includes p21 (Gu et al. 1993; Harper et al. 1993; El-Deiry et al. 1993; Xiong et al. 1993a; Dulic et al. 1994; Noda et al. 1994), p27 (Polyak et al. 1994a,b; Toyoshima and Hunter 1994), and p57 (Lee et al. 1995; Matsuoka et al. 1995), all of which contain characteristic motifs within their amino-terminal moieties that enable them to bind both to cyclin and CDK subunits (Chen et al. 1995, 1996; Nakanishi et al. 1995; Warbrick et al. 1995; Lin et al. 1996; Russo et al. 1996). Based largely on in vitro experiments and in vivo overexpression studies, CKIs of the Cip/Kip family were initially thought to interfere with the activities of cyclin D-, E-, and A-dependent kinases. More recent work has altered this view and revealed that although the Cip/Kip proteins are potent inhibitors of cyclin Eand A-dependent CDK2, they act as positive regulators of cyclin Ddependent kinases. This challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes our thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer. Here we focus on the biochemical interactions that occur between CKIs and cyclin Dand E-dependent kinases in cultured mammalian cells, emphasizing the manner by which different positive and negative regulators of the cell division cycle cooperate to govern the G1-to-S transition. To gain a more comprehensive understanding of the biology of CDK inhibitors, readers are encouraged to refer to a rapidly emerging but already extensive literature (for review, see Elledge and Harper 1994; Sherr and Roberts 1995; Chellappan et al. 1998; Hengst and Reed 1998a; Kiyokawa and Koff 1998; Nakayama 1998; Ruas and Peters 1998).

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CDK inhibitors: positive and negative regulators of G1-phase progression

Emerging infectious diseases (EIDs) are a significant burden on global economies and public health. Their emergence is thought to be driven largely by socio-economic, environmental and ecological factors, but no comparative study has explicitly analysed these linkages to understand global temporal and spatial patterns of EIDs. Here we analyse a database of 335 EID 'events' (origins of EIDs) between 1940 and 2004, and demonstrate non-random global patterns. EID events have risen significantly over time after controlling for reporting bias, with their peak incidence (in the 1980s) concomitant with the HIV pandemic. EID events are dominated by zoonoses (60.3% of EIDs): the majority of these (71.8%) originate in wildlife (for example, severe acute respiratory virus, Ebola virus), and are increasing significantly over time. We find that 54.3% of EID events are caused by bacteria or rickettsia, reflecting a large number of drug-resistant microbes in our database. Our results confirm that EID origins are significantly correlated with socio-economic, environmental and ecological factors, and provide a basis for identifying regions where new EIDs are most likely to originate (emerging disease 'hotspots'). They also reveal a substantial risk of wildlife zoonotic and vector-borne EIDs originating at lower latitudes where reporting effort is low. We conclude that global resources to counter disease emergence are poorly allocated, with the majority of the scientific and surveillance effort focused on countries from where the next important EID is least likely to originate.

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Global trends in emerging infectious diseases

Natural selection acts on phenotypes, regardless of their genetic basis, and produces immediate phenotypic effects within a generation that can be measured without recourse to principles of heredity or evolution. In contrast, evolutionary response to selection, the genetic change that occurs from one generation to the next, does depend on genetic variation. Animal and plant breeders routinely distinguish phenotypic selection from evolutionary response to selection (Mayo, 1980; Falconer, 1981). Upon making this critical distinction, emphasized by Haldane (1954), precise methods can be formulated for the measurement of phenotypic natural selection. Correlations between characters seriously complicate the measurement of phenotypic selection, because selection on a particular trait produces not only a direct effect on the distribution of that trait in a population, but also produces indirect effects on the distribution of correlated characters. The problem of character correlations has been largely ignored in current methods for measuring natural selection on quantitative traits. Selection has usually been treated as if it acted only on single characters (e.g., Haldane, 1954; Van Valen, 1965a; O'Donald, 1968, 1970; reviewed by Johnson, 1976 Ch. 7). This is obviously a tremendous oversimplification, since natural selection acts on many characters simultaneously and phenotypic correlations between traits are ubiquitous. In an important but neglected paper, Pearson (1903) showed that multivariate statistics could be used to disentangle the direct and indirect effects of selection to determine which traits in a correlated ensemble are the focus of direct selection. Here we extend and generalize Pearson's major results. The purpose of this paper is to derive measures of directional and stabilizing (or disruptive) selection on each of a set of phenotypically correlated characters. The analysis is retrospective, based on observed changes in the multivariate distribution of characters within a generation, not on the evolutionary response to selection. Nevertheless, the measures we propose have a close connection with equations for evolutionary change. Many other commonly used measures of the intensity of selection (such as selective mortality, change in mean fitness, variance in fitness, or estimates of particular forms of fitness functions) have little predictive value in relation to evolutionary change in quantitative traits. To demonstrate the utility of our approach, we analyze selection on four morphological characters in a population of pentatomid bugs during a brief period of high mortality. We also summarize a multivariate selection analysis on nine morphological characters of house sparrows caught in a severe winter storm, using the classic data of Bumpus (1899). Direct observations and measurements of natural selection serve to clarify one of the major factors of evolution. Critiques of the "adaptationist program" (Lewontin, 1978; Gould and Lewontin, 1979) stress that adaptation and selection are often invoked without strong supporting evidence. We suggest quantitative measurements of selection as the best alternative to the fabrication of adaptive scenarios. Our optimism that measurement can replace rhetorical claims for adaptation and selection is founded in the growing success of field workers in their efforts to measure major components of fitness in natural populations (e.g., Thornhill, 1976; Howard, 1979; Downhower and Brown, 1980; Boag and Grant, 1981; Clutton-Brock et

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1558-5646.1983.tb00236.x

The measurement of selection on correlated characters

The oncogenicity of cells in syngeneic hosts was compared to the regulation of cell growth in vitro. Normal embryonic fibroblasts (LWF cells) were not tumorigenic. Spontaneously “transformed” fibroblastic cells (LW13 cells) and Rous-transformed epithelioid cells (RsK4 cells) grew into sarcomas on subcutaneous or intravenous inoculation. TD50 varied according to the route of administration and dispersion of the cells. Rous-transformed cells gave rise to tumours with a short latent period while the spontaneously transformed cell line showed a biphasic latent period. The histopathology of the two kinds of tumours was similar, with a higher tendency to pleomorphism in the Rous tumours. Normal fibroblasts had low plating efficiency on plastic or in soft gel suspension. LW13 cells plated with high efficiency on plastic but poorly in suspension, and RsK4 cells plated with high efficiency in both situations. Normal cells were highly sensitive to topoinhibition, LW13 cells were moderately sensitive, while LW13 cells explanted from tumours and RsK4 cells were the least sensitive. However, values of topoinhibition and its compensation by serum were themselves found to vary with cell density. RsK4 cells initiated DNA synthesis in low serum medium but normal cells and LW13 cells did not. Neither LW13 nor RsK4 cell proliferation was inhibited by contact with confluent, static 3T3 cells or normal LWF cells. With the cell types examined here an association exists between contact inhibition of cell movement and topoinhibition of growth. The degree to which altered cells respond to the regulatory contact signals of normal cells appears to be the best in vitro indicator of oncogenicity.

Growth regulation and tumour formation of normal and neoplastic rat cells.

Disclosed are various compositions for use in the delivery of nucleic acid to a target cell including: a composition comprising a calcium salt in particulate form, the nucleic acid to be delivered, and one or more further components to enhance the efficiency of delivery of the nucleic acid to a target cell, the nucleic acid and the one or more further components being complexed with the particulate calcium salt; and methods of delivering a nucleic acid to a target cell.

Improvements in or relating to delivery of nucleic acids

Many viruses carry their genetic information in the form of RNA, and with the exception of the retroviruses replicate entirely through RNA intermediates. One such virus is lymphocytic choriomeningitis virus, which has now been caught red-handed in the act of illicit synthesis of DNA — seemingly through the agency of the reverse transcriptase enzyme used by retroviruses to produce DNA from an RNA template. The authors have taken great pains to rule out the possibility that this result is a false-positive artefact of the polymerase chain reaction, leaving a tantalizing puzzle that remains to be solved.

Illicit viral DNA

Kaposi’s sarcoma has emerged from being a rarity to being the most important neoplasm in many sub-Saharan countries. Most investigators involved in Kaposi’s sarcoma research now agree that the gammaherpesvirus human herpesvirus 8 (HHV8), also called Kaposi’s sarcoma-associated herpesvirus (KSHV), is central in the pathogenesis of this disease (1,2). Molecular and seroepidemiologic studies (3,4) have confirmed the association between HHV8 and Kaposi’s sarcoma. However, the role of HHV8 in the initiation and maintenance of proliferation of Kaposi’s sarcoma tumor cells (spindle cells) remains unclear. Before the discovery of HHV8(5), it was thought that cellular cytokines, growth factors, and the human immunodeficiency virus-1 (HIV-1) Tat protein initiate and promote the growth of Kaposi’s sarcoma spindle cells (6). The fact that the incidence of Kaposi’s sarcoma is much higher among HIV-1-infected individuals than among iatrogenic immunosuppressed patients probably reflects the prevalence of HHV8 in different populations, rather than indicates that HIV-1 itself plays a role. Kaposi’s sarcoma, like HHV8, is rare in HIV-positive, injecting drug users and in patients with hemophilia (3). However, rapidly progressive Kaposi’s sarcoma affecting extensive parts of the skin, oral and genital mucosae, and internal organs is seldom seen in HIV-negative patients, even in those iatrogenically immunosuppressed for prolonged periods. This observation favors a synergistic role for HHV8 and for HIV-1 in promoting growth of Kaposi’s sarcoma spindle cells. Previous studies(6,7) have pinpointed the Tat protein of HIV-1 as being an angiogenic factor that can induce the expression of a cascade of cytokines involved in the pathogenesis of Kaposi’s sarcoma. In this issue of the Journal, Prakash et al. (8) show that, when the human Kaposi’s sarcoma SLK cell line was injected subcutaneously into HIV-1 Tat transgenic CD4 + T-celldepleted male mice, the rate of tumor growth was substantially faster than that in non-Tat transgenic animals. Furthermore, transcripts for various cytokines previously shown to be induced by Tat were increased in the tumors of the Tat transgenic animals. The SLK cell line was originally established from a mucosal Kaposi’s sarcoma lesion of an HIV-negative kidney transplant patient(9). Although this cell line expresses, like Kaposi’s sarcoma spindle cells, markers associated with an endothelial origin, the SLK cells are, unlikein situ Kaposi’s sarcoma spindle cells, negative for HHV8. HHV8 is latently present in the vast majority of Kaposi’s sarcoma spindle cells in established lesions (10), and the growth characteristics of SLK cells, therefore, might not be typical of Kaposi’s sarcoma spindle cells. Howver, the notable finding of the article by Prakash et al. is that tumor cells grow fasterin vivo in the presence of circulating HIV-1 Tat. We predict that similar findings might be obtained in Tat transgenic mice injected with tumor cells other than Kaposi’s sarcoma spindle cells. Thus, the tumor-promoting effects of HIV-1 Tat in HIV-1-infected individuals might be important across a broader spectrum of malignancies and might not be restricted to Kaposi’s sarcoma. The fact that the incidence of Kaposi’s sarcoma is higher in African countries where HIV-1 is prevalent than in countries where HIV-2 is more common, despite similar prevalence of antibodies to HHV8(11), has argued in favor of functional differences between HIV-1 and HIV-2 Tat proteins (12).Although the increased incidence in HIV-1-infected individuals of various neoplasia, including Kaposi’s sarcoma, lymphoma, and squamous cell carcinoma, is well documented (13),we are not aware of definitive cancer statistics from HIV-2-prevalent regions. HIV-1 Tat could affect indirectly tumor cell proliferation via the induction of cellular growth and angiogenic factors and/or directly via the activation of transcription regulators like NFkB. Prakash et al. (8) did not demonstrate increased angiogenesis in the Tat transgenic tumors compared with the Tat-negative ones, suggesting that Tat-induced angiogenesis might not be that important in vivo. An interesting study would be to look at the growth characteristics of SLK cells, other Kaposi’s sarcoma cells, and other tumor cell lines in HIV-2 compared with HIV-1 Tat transgenic mice. In other experimental models, HIV and inflammatory cytokines also appear to influence HHV8. In lymphoma cells latently infected with HHV8, HIV activates HHV8 infection (14).HHV8 replication is also activated by HIV-1 Tat in lymphoma cells and in peripheral blood mononuclear cells (15). In addition, interferon gamma reactivates HHV8 lytic replication in lymphoma cells (16). Interferon gamma is present in Kaposi’s sarcoma

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Addressing Controversies Over Kaposi's Sarcoma

Samples e.g. transfusion blood, are assayed for antibodies to retrovirus, e.g. AIDS virus, using an insolubilised antigen comprising retrovirus antigens bound to globulin, the globulin itself being bound to an inert solid support; and an immunoglobulin which contains specific antibody to the retrovirus antigens and which is labelled with a non radio active revealing label, and the liquid phase is then separated from the solid phase and the quantity of revealing label associated with either the liquid or the solid phase determined. The use of enzyme labelled antibody in competition with test sera for binding on the insolubilised antigen permits better identification of antibody containing specimens. The retroviruses may be a HTLV-I, II or III or a new retrovirus isolate CBL-1 etiologically related to AIDS.

Robin A. Weiss

Papers

Growth regulation and tumour formation of normal and neoplastic rat cells.

Improvements in or relating to delivery of nucleic acids

Illicit viral DNA

Addressing Controversies Over Kaposi's Sarcoma

Improvements relating to viral isolates and their use