Serrated precursor lesions

The so-called serrated pathway has in recent years been well established as a second route of colorectal carcinogenesis. Sessile serrated polyps, especially sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) were identified as precursor lesions of this pathway. Activating mutations in either the BRAF (in SSAs) or the KRAS oncogene (in TSAs) have been determined as the initiating molecular alterations, followed by epigenetic methylation of CpG islands in promoter regions of genes which are implicated in cell cycle control or DNA repair. These findings have led to a paradigm shift in gastrointestinal pathology as lesions without cytological dysplasia, such as SSAs and certain forms of hyperplastic polyps, are now accepted to be precancerous lesions. In addition, carcinomas that have developed through the serrated pathway of colorectal carcinogenesis show varying biological behavior relevant for the clinical management of these tumors depending on the molecular aberrations.     

Circulating osteogenic precursor cells

Circulating osteogenic precursor (COP) cells are blood-borne cells that express a variety of osteoblastic markers and are able to form bone in vivo. Strong evidence suggests that COP cells are derived from bone marrow and are of hematopoietic origin. The study of COP cells has been limited by several factors, including the difficulty in establishing long-term cultures and lack of a standardized protocol for their isolation and identification. However, experimental evidence supports that COP cells seed sites of injury and inflammation in response to homing signals and are involved in processes of pubertal growth, fracture, and diverse conditions of heterotopic bone formation. The role of COP cells in physiologic and pathophysiologic conditions of de novo bone formation suggests that they may serve as future targets for diagnostic measurements and therapeutic interventions.     

Murine macrophage precursor characterization. II. Monoclonal antibodies against macrophage precursor antigens

The aim of the present study was the phenotypical analysis of early stages in macrophage (M phi) differentiation. For this purpose, we produced a panel of syngeneic rat hybridomas, which secreted antibodies (mAb) against M phi precursor antigens. As immunogens we used immortalized M phi precursors (P.J. M. Leenen et al., Eur. J. Immunol. 1990, 20: 15). We screened the obtained mAb in the following in vitro models of M phi differentiation: (a) a panel of M phi cell lines ordered in a linear differentiated sequence; (b) immature and mature mononuclear phagocytes obtained from bone marrow (BM) culture; (c) a panel of M phi precursor hybrids, and (d) differentiated and control M phi precursor hybrid cells. Four mAb, ER-MP12, ER-MP20, ER-MP54 and ER-MP58, were selected. These mAb recognize antigens which disappear in the course of M phi differentiation. Next, we investigated whether these mAb also recognized M phi precursors in normal BM. For this purpose, ER-MP-positive and -negative BM fractions were isolated using a fluorescence-activated cell sorter. Fractions were cultured in M phi-colony-stimulating factor-containing conditioned medium, and the resulting mature M phi progeny was quantified using the MTT assay. The present experiments indicate that ER-MP12 and ER-MP20 detect a subpopulation of BM M phi precursors, whereas ER-MP58 stains virtually all M phi precursors. Biochemical analysis of radioiodinated antigens revealed that these mAb recognize different molecules. ER-MP12 and ER-MP20 bound to single-chain (glyco)proteins of 140 kDa and 14 kDa, respectively. ER-MP54 precipitated multiple polypeptides, of which the major chains have an apparent molecular mass of 90, 80-85 and 70-75 kDa. Based on the molecular mass of the recognized antigens and the mAb specificities we conclude that ER-MP12, ER-MP54 and ER-MP58 recognize hitherto unknown antigens of murine M phi precursor cells. The antigen detected by ER-MP20 is most likely identical to Ly-6C.     

Murine macrophage precursor characterization. I. Production, phenotype and differentiation of macrophage precursor hybrids

This study reports on the earliest stages of mononuclear phagocyte differentiation. A crucial question in this developmental process is whether mature macrophage (M phi) heterogeneity is already appointed at the precursor cell level. For this purpose, we produced clonal populations of mononuclear phagocytes from bone marrow culture by somatic cell hybridization with two hypoxanthine, aminopterin, thymidine-sensitive myeloid cell lines. A panel of 22 stable hybrids was obtained from these fusions. Differentiation stage analysis of the hybrids indicated that all cell lines had immature mononuclear phagocyte characteristics. The hybrids exhibited typical myeloid morphology and mainly nonadherent growth. Mature M phi features, such as expression of the cell surface antigens Mac-1, Mac-2 and F4/80, phagocytosis of latex beads, and expression of nonspecific esterase and acid phosphatase activity, were virtually absent. The immature M phi markers Thy-1, MIV25 and MIV52, on the other hand, were readily expressed, although heterogeneity was observed among different hybrid cell lines. We then analyzed the differentiation potential of seven hybrids by culture of the cells in the presence of post-lipopolysaccharide serum supplemented with interferon-gamma and found that the expression of mature M phi characteristics was induced. However, the various hybrids showed divergent patterns of mature M phi marker induction. R0C2 cells, for instance, showed extensive morphological and phenotypical differentiation without concomitant induction of phagocytosis. In contrast, W1C4 cells showed significant induction of phagocytosis without simultaneous increase of phosphatase and esterase activity. R1C1 cells were unique in the strong induction of Ia antigen expression. Together, our data indicate that (a) early M phi differentiation stages can be rescued by somatic cell hybridization, and that (b) the obtained cell lines are able to mature according to divergent differentiation programs.     

Fermented papaya preparation attenuates beta-amyloid precursor protein: beta-amyloid-mediated copper neurotoxicity in beta-amyloid precursor protein and beta-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells

Recent studies indicate that the deposition of beta-amyloid (Abeta) is related in the pathogenesis of Alzheimer's disease (AD), but the underlying mechanism is still not clear. The abnormal interactions of Abeta with metal ions such as copper are implicated in the process of Abeta deposition and oxidative stress in AD brains. In the present study, we established a new AD model, using which we found that copper triggered the Abeta neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw) in a concentration dependent manner. Fermented papaya preparation (FPP) has shown high free radical scavenging ability in vivo and in vitro. FPP post-treatment increased cell viability and decreased the intracellular [Ca2+]i, reactive oxygen species (ROS) generation such as hydroxyl free radical and superoxide anion and nitric oxide (NO) accumulation in the cell. Our results also show that FPP prevents the cell apoptosis through bax/bcl-2 sensitive pathway.     

Immunophenotypic patterns in precursor T-cell neoplasm

T-cell lymphoproliferative disorders are a heterogeneous group of lymphoid neoplasm that can mimic both benign conditions and non-hematopoietic tumors. In routine clinical practice, morphology and immunophenotyping forms the basis of their diagnosis. In this retrospective analysis, we evaluate the utility of flow cytometric immunophenotyping patterns in diagnosis of precursor T-cell neoplasm. Aberrant expression of T-cell antigens was found in all the cases of precursor T-cell neoplasm. The residual normal T-lymphocytes, identifiable in majority of cases, were found to be useful in evaluation of quantitative differences in antigen expression by leukemic cells. A careful analysis of flow cytometric immunophenotyping data can provide additional information which is useful for diagnosis of precursor T-cell neoplasm. This information can be further utilized for analysis of minimal residual disease in these tumors.     

Non-serrated precursor lesions of colorectal tumours

Non-serrated precursor lesions of colorectal tumours include conventional adenomas (tubular, tubulovillous and villous), inflammatory bowel disease-associated dysplasia (intraepithelial neoplasia), and hamartoma-associated dysplasia. This short review summarizes the current literature on the adenoma-carcinoma sequence, focusing on colonic stem cells and functional crypt organization, patterns of stem cell division, niche succession and clonal conversion in the formation of a monocryptal adenoma. The process of clonal interaction between neighboring crypts as well as the development of large monoclonal adenomas from small polyclonal precursor lesions is discussed in detail. Finally, the molecular pathogenesis as well as the clinical significance of inflammatory bowel disease- and hamartoma-associated carcinogenesis is addressed.     

Conjunctivochalasis is the precursor to pterygium

Pterygium is a fibrovascular proliferative condition of the ocular surface with no known pathological mechanism. This condition affects vision due to dry eyes, astigmatism or physical occlusion of the visual axis for severe cases. The only definitive treatment for this condition is surgical excision. Interestingly, it is a lesion that may be related to UV radiation and elaboration of proteases. Conjunctivochalasis is a dry eye related condition that is exemplified by excessive conjunctiva or the mucous membrane of the front of the eye around the cornea. Both pterygium and conjunctivochalasis are associated with elaboration of matrix metalloproteinases as well as inflammatory cytokines. We propose that under specific conditions, conjunctivochalasis in the nasal part of the conjunctiva can progress to pterygium. The progression of conjunctivochalasis to pterygium may be related to special kinds of oxidative or inflammatory damage that affects only the part of the loose conjunctival tissue adjacent to the cornea. Protease expressed may then breakdown the conjunctival and corneal epithelium causing the head of pterygium to be very adherent to the cornea. This explains the fact that surgically excised pterygium tissue has stromal tissue enclosed by epithelia on both surfaces. In addition, it explains the existence of a surgical plane when an instrument is passed under the neck of the pterygium tissue but not at the apex. The implications of this hypothesis are first, treatment should be directed to the protection of conjunctivochalasis before it transforms to pterygium. This may be achieved by anti-inflammatory measures, anti-protease treatment, or preventing the triggering of the changes at the head of pterygium, such as avoidance of sunlight. Second, during resection of pterygium, it may not be necessary to resect the pterygium too extensively away from the cornea, since this effectively removes relatively normal conjunctiva.     

Melanoma precursor lesions and borderline melanomas

The histopathological interpretation of melanoma precursor and borderline lesions remains difficult. The natural history of naevi is reviewed and, in the light of this, current views on the histological sub-types of melanoma, precursor lesions and benign lesions which may mimic melanoma are presented. As the criteria for these lesions are now becoming defined they should be applicable by most histopathologists, even those who may see only occasional cases. Childhood and minimal deviation variants, however, are likely to remain problems even for the expert. Fortunately such lesions are uncommon.     

The precursor complex of Pf3 bacteriophage

Filamentous bacteriophage infections give rise to intracellular filamentous precursor complexes composed of a circular single-stranded DNA molecule and on the order of 10(3) copies of a viral-encoded, single-stranded DNA binding protein. A protocol was developed for the purification of the precursor complex from Pf3 phage-infected Pseudomonas aeruginosa cells, and existing protocols for Ff and Pf1 complexes were amended by the introduction of a molecular sieving column step. The Pf3 precursor complex has an average contour length of 500 nm, which is shorter than that of the mature Pf3 virus. M/L (mass/length) values were obtained from turbidity measurements, from scanning-transmission electron microscopy, and from the total particle mass divided by its length. The average M/L obtained was 19,300 Da/nm which is close to that of the Pf3 virion. The complex has a nucleotide/subunit ratio of 6.0. The protein component of the precursor complex has less than 10% alpha-helicity, whereas the protein component of the virus is greater than 90% alpha-helical. The DNA structure in the precursors is very different from that in the virus, so that during virus assembly the DNA structure must change dramatically. The results for the Pf3 system, together with the available information for the Ff and Pf1 filamentous virus systems, indicate that different DNA-protein interactions and packing arrangements are involved in performing equivalent functions.     

Neurite outgrowth and the amyloid protein precursor

Neurite outgrowth in Alzheimer's disease may well be a multifactorial phenomenon. Recent evidence suggests possible roles for the protease inhibitor domain of the 751 amino acid amyloid precursor protein (APP), as well as for the 695 amino acid APP.     

The development of migrating muscle precursor cells

A major subclass of hypaxial muscle groups is derived from long-range migrating precursor cells that delaminate from the dermomyotome. Migrating precursors are generated on particular axial levels only, i.e. occipitally, cervically, and on the levels of the fore and hind limbs. They express the homeobox gene Lbx1, which provides a useful marker for their visualization. In the mouse, migrating precursor cells give rise to muscles of the extremities, the hypoglossal chord, and the diaphragm. We discuss here the development of this migrating lineage, which critically depends on the correct specification of the precursors in the dermomyotome, their delamination and correct migration. Finally, proliferation at the targets is essential to ensure a correct size of the precursor pool and of the muscle that derives thereof.     

Otitis media: precursor of delayed reading

OBJECTIVE: To investigate the connection between otitis media in the language acquisition years and the occurrence of delayed reading between the ages of 8 and 10. METHOD: Participants were 40 children, half of whom had a history of otitis media between the ages of birth and three years and half who were free of the disease. These children, now ages 8-10, were tested with the WISC-R and a variety of reading measures. RESULTS: Children with a history of otitis media scored over a year below grade level in reading and significantly below controls on a variety of literacy measures as well as on the Verbal Comprehension factor on the WISC-R. CONCLUSIONS: Children with early onset otitis media (birth to three years) tend to be at greater risk for delayed reading than age-matched controls.     

Amyloid precursor protein modulates β-catenin degradation

Background  

The amyloid precursor protein (APP) is genetically associated with Alzheimer's disease (AD). Elucidating the function of APP should help understand AD pathogenesis and provide insights into therapeutic designs against this devastating neurodegenerative disease.     

Identification of poliovirus precursor proteins by immunoprecipitation

Precursors of poliovirus capsid polypeptides were detected using immunoprecipitation followed by SDS-PAGE. Two common VPO-3-1 precursors were found, and the occurrence of alternative cleavage pathways was confirmed.     

Caspase-cleaved amyloid precursor protein in Alzheimer's disease

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.     

Unique pattern of nuclear TdT immunofluorescence distinguishes normal precursor B cells (Hematogones) from lymphoblasts of precursor B-lymphoblastic leukemia

Normal precursor B cells or hematogones share morphologic and immunophenotypic similarities with lymphoblasts of precursor B-lymphoblastic leukemia. The numbers are often increased and difficult to distinguish in many patients following chemotherapy for precursor B-lymphoblastic leukemia. The purpose of this study was to establish a unique method for differentiating hematogones from lymphoblasts by evaluating the immunofluorescence pattern of nuclear terminal deoxynucleotidyl transferase (TdT) staining in 29 cases of TdT+ acute leukemia and 20 cases with increased numbers of hematogones. All 29 cases of TdT+ acute leukemia demonstrated a finely granular pattern of TdT immunofluorescence that was uniformly distributed in the nucleus, whereas all 20 cases with increased hematogones demonstrated a coarsely granular or speckled pattern of TdT immunofluorescence, which often intensely aligns the nuclear membrane. The nuclear pattern of immunofluorescence using antibodies to TdT is an effective method for distinguishing hematogones from leukemic blasts.