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D. B. Kellock

Bio: D. B. Kellock is an academic researcher from Guy's Hospital. The author has contributed to research in topics: Autocrine signalling & Viral load. The author has an hindex of 2, co-authored 2 publications receiving 1436 citations.

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Journal ArticleDOI
TL;DR: Data suggest that in normal tissues and lymphoid neoplasms, PCNA immunolocalization can be used as an index of cell proliferation, however, in some forms of neoplasia, including breast and gastric cancer and in vitro cell lines, the simple relation between PCNA expression and cell proliferation is lost.
Abstract: Proliferating cell nuclear antigen (PCNA) is a 36 kD nuclear protein associated with the cell cycle A monoclonal antibody, PC10, that recognizes a fixation and processing resistant epitope has been used to investigate its tissue distribution Nuclear PCNA immunoreactivity is found in the proliferative compartment of normal tissues PCNA immunoreactivity is induced in lectin stimulated peripheral blood mononuclear cells in parallel with bromodeoxyuridine incorporation and the number of cells with PCNA immunoreactivity is reduced by induction of differentiation in HL60 cells In non-Hodgkin's lymphomas a linear relation between Ki67 and PCNA staining was demonstrated These data suggest that in normal tissues and lymphoid neoplasms, PCNA immunolocalization can be used as an index of cell proliferation However, in some forms of neoplasia, including breast and gastric cancer and in vitro cell lines, the simple relation between PCNA expression and cell proliferation is lost In some breast and pancreatic tumours there is apparent deregulation of PCNA with increased expression in tissues adjacent to the tumours The over-expression in some tumours and in adjacent morphologically normal tissue may represent autocrine or paracrine growth factor influence on PCNA gene expression

1,441 citations

Journal ArticleDOI
04 Feb 2022-Science
TL;DR: An exceptionally virulent subtype of HIV that has been circulating in the Netherlands for several years is reported, with more than one hundred individuals infected with a characteristic subtype B lineage of HIV-1 found who experienced double the rate of CD4+ cell count declines than expected.
Abstract: We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence. Description Evolving virulence in HIV Changes in viral load and CD4+ T cell decline are expected signals of HIV evolution. By examining data from well-characterized European cohorts, Wymant et al. report an exceptionally virulent subtype of HIV that has been circulating in the Netherlands for several years (see the Perspective by Wertheim). More than one hundred individuals infected with a characteristic subtype B lineage of HIV-1 were found who experienced double the rate of CD4+ cell count declines than expected. By the time they were diagnosed, these individuals were vulnerable to developing AIDS within 2 to 3 years. This virus lineage, which has apparently arisen de novo since around the millennium, shows extensive change across the genome affecting almost 300 amino acids, which makes it hard to discern the mechanism for elevated virulence. —CA A cluster of HIV-infected individuals with high viral loads, rapid CD4+ cell declines, and increased infectivity has been detected in Europe.

27 citations

Journal ArticleDOI
TL;DR: The notion that Hodgkin's disease can be regarded as a high grade lymphoma, the large Hodgkin’s and Sternberg-Reed cells being the (PCNA positive and AgNOR rich) neoplastic elements with high proliferative capacity is supported.
Abstract: AIM--To define the distribution of proliferating cell nuclear antigen (PCNA) and silver staining nucleolar organiser regions (AgNORs) in Hodgkin's disease. METHODS--PCNA was shown in a series of 34 cases of Hodgkin's disease using immunohistochemical methods. In a second series of 46 cases the AgNOR technique for interphase nucleolar organiser regions was studied. Both series comprised routinely fixed and processed paraffin wax sections of three main Rye subtypes. RESULTS--In all cases, regardless of Rye subtype, most Sternberg-Reed cells and mononuclear Hodgkin cells showed nuclear PCNA immunoreactivity and such cells had 15 or more AgNOR sites. The Hodgkin cells had, in general, about half the number of AgNORs seen in Sternberg-Reed variants. CONCLUSIONS--These data support the notion that Hodgkin's disease can be regarded as a high grade lymphoma, the large Hodgkin's and Sternberg-Reed cells being the (PCNA positive and AgNOR rich) neoplastic elements with high proliferative capacity. A smaller proportion of the associated cells also showed evidence of proliferation.

17 citations


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TL;DR: Computer analysis of the nucleic acid and the deduced amino acid sequence of the Ki-67 antigen confirmed that the cDNA encodes for a nuclear and short-lived protein without any significant homology to known sequences.
Abstract: The antigen defined by mAb Ki-67 is a human nuclear protein the expression of which is strictly associated with cell proliferation and which is widely used in routine pathology as a "proliferation marker" to measure the growth fraction of cells in human tumors. Ki-67 detects a double band with apparent molecular weights of 395 and 345 kD in immunoblots of proteins from proliferating cells. We cloned and sequenced the full length cDNA, identified two differentially spliced isoforms of mRNA with open reading frames of 9,768 and 8,688 bp encoding for this cell proliferation-associated protein with calculated molecular weights of 358,761 D and 319,508 D, respectively. New mAbs against a bacterially expressed part and a synthetic polypeptide deduced from the isolated cDNA react with the native Ki-67 antigen, thus providing a circle of evidence that we have cloned the authentic Ki-67 antigen cDNA. The central part of the Ki-67 antigen cDNA contains a large 6,845-bp exon with 16 tandemly repeated 366-bp elements, the "Ki-67 repeats", each including a highly conserved new motif of 66 bp, the "Ki-67 motif", which encodes for the epitope detected by Ki-67. Computer analysis of the nucleic acid and the deduced amino acid sequence of the Ki-67 antigen confirmed that the cDNA encodes for a nuclear and short-lived protein without any significant homology to known sequences. Ki-67 antigen-specific antisense oligonucleotides inhibit the proliferation of IM-9 cell line cells, indicating that the Ki-67 antigen may be an absolute requirement for maintaining cell proliferation. We conclude that the Ki-67 antigen defines a new category of cell cycle-associated nuclear nonhistone proteins.

768 citations

Journal ArticleDOI
TL;DR: The cell cycle is a complex process that involves numerous regulatory proteins that direct the cell through a specific sequence of events culminating in mitosis and the production of two daughter cells, and should be considered in the design of studies using such chemicals.
Abstract: The cell cycle is a complex process that involves numerous regulatory proteins that direct the cell through a specific sequence of events culminating in mitosis and the production of two daughter cells. Central to this process are the cyclin-dependent kinases (cdks), which complex with the cyclin proteins. These proteins regulate the cell's progression through the stages of the cell cycle and are in turn regulated by numerous proteins, including p53, p21, p16, and cdc25. Downstream targets of cyclin-cdk complexes include pRb and E2F. The cell cycle can be altered to the advantage of many viral agents, most notably polyomaviruses, papillomaviruses, and adenoviruses. The cell cycle often is dysregulated in neoplasia due to alterations either in oncogenes that indirectly affect the cell cycle or in tumor suppressor genes or oncogenes that directly impact cell cycle regulation, such as pRb, p53, p16, cyclin D1, or mdm-2. The cell cycle has become an intense subject of research in recent years. This research has led to the development of techniques useful for the determination of the effects of drugs and toxins on the cell cycle. Any drug or toxin with DNA damaging ability would be expected to alter cell cycle progression, and therefore, the cell cycle should be considered in the design of studies using such chemicals. With the appropriate techniques, cell cycle alterations may also be detected in tissue sections. Because of the ubiquitous nature of the cell cycle, it deserves consideration in the design and interpretation of studies in a wide variety of disciplines.

560 citations

Journal ArticleDOI
TL;DR: It is shown that the adult human brain harbors a complex population of stem/progenitor cells that can generate neuronal and glial progeny under particular in vitro growth conditions.

556 citations

Journal ArticleDOI
TL;DR: The functions and properties of all three proteins and their use as markers of proliferation in the diagnosis of breast cancer are described and new findings about the role of Ki67 during the mitotic phase of the cell cycle are revealed.

398 citations

Journal ArticleDOI
TL;DR: The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated, and local inflammatory conditions might cause accumulation and activation of T cell in theAD brain.

375 citations