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Expression of Hodgkin's disease associated antigen BLA.36 in anaplastic large cell lymphomas and lymphomatoid papulosis primarily of T-cell origin.

Monoclonal antibody BLA.36 stains Reed-Sternberg (RS) cells and their mononuclear variants, as well as some benign and malignant cells of B-cell lineage, and retains its immunoreactivity in formalin- and B5-fixed tissue. The origin of the RS cell is controversial and the distinction between Hodgkin's disease (HD), anaplastic large cell lymphoma (ALCL), and lymphomatoid papulosis (LyP) (the latter two primarily T-cell in origin), can be difficult. The authors studied expression of BLA.36 in 22 cases of ALCL, 13 cases of LyP, and 15 cases of HD. Most atypical or malignant cells stained for BLA.36 in 10 of 22 cases of ALCL, 9 of 13 cases of LyP, and 9 of 15 cases of HD. Additional immunohistochemistry or gene rearrangement analysis indicated a T-cell origin for 8 of 10 BLA.36 positive ALCL, and 9 of 9 BLA.36 positive LyP cases. BLA.36 was expressed by T-cell lines derived from two ALCLs and one CD30+ cell line derived from LyP. The authors conclude that BLA.36 is not specific for lymphomas of B-cell origin and cannot be used to distinguish between HD, ALCL, and LyP with RS-like cells. These results further support a relationship between HD, ALCL, and LyP and suggest that RS cells are histogenetically related to both B- and T-lymphocytes.

Antibodies, Monoclonal↗

Tissue-engineered heart valve leaflets: does cell origin affect outcome?

BACKGROUND: We previously reported the successful creation of tissue-engineered valve leaflet constructs and the implantation of these autologous tissue leaflets in the pulmonary valve position in a lamb model. The optimal cell origin for creating these valve leaflets remains unclear. This study was designed to compare dermal with arterial wall myofibroblasts as the cells of origin for the leaflet constructs. METHODS AND RESULTS: Mixed cell populations of endothelial cells and fibroblasts were isolated from ovine femoral arteries or subdermis and then expanded in vitro. A synthetic biodegradable polymer scaffold was then seeded with the cultured cells. The tissue scaffold was composed of a polyglactin woven mesh sandwiched between two nonwoven polyglycolic acid mesh sheets, which measured 3x3 cm in size and 3.2 mm in thickness. The cell-seeded polymer construct was implanted to replace one pulmonary valve leaflet in the same juvenile animal from which the cells had originally been obtained. Using cardiopulmonary bypass, the right posterior leaflet of the pulmonary valve was completely resected and replaced with an autologous engineered valve leaflet. In group D (n=5), the cells were obtained from subdermis, and in group A (n=4), they were obtained from the arterial wall. Eight to 10 weeks after leaflet implantation, the animals were killed, and the implanted valve leaflets were examined histologically, biochemically, and biomechanically. The dimensions of each tissue-engineered leaflet (TEL) were compared with those of the two remaining native valve leaflets to obtain a growth index. A 4-hydroxyproline assay was performed to evaluate collagen content. Leaflet tensile strength was evaluated in vitro by using a Vitrodyne V-1000 mechanical tester. Factor VIII and elastin stains were performed to histologically assess the presence of endothelial cells and elastin, respectively. In all animals, the TEL persisted in the pulmonary valve position after 8 to 10 weeks, and all polyglycolic acid polymer had been degraded. Group A leaflets had a higher growth index (0.86+/-0.11) than group D (0.41+/-0.08) (P<.05). Macroscopically, the group D leaflets appeared thicker and contracted. Histologically, elastic fibers were more abundant in group A than in group D. Total collagen content and biomechanical testing showed no differences between groups. Leaflets from both groups had positive staining for factor VIII on the surface, confirming growth of endothelial cells to cover the TEL. CONCLUSIONS: Autologous TEL derived from vascular fibroblasts seem to develop functionally and morphologically like the native valve leaflets in the pulmonary circulation. Use of arterial myofibroblasts for the creation of TEL seems preferable to dermal fibroblasts with current tissue culture conditions.

Animals↗

Clonotypic IgM V/D/J sequence analysis in Waldenstrom macroglobulinemia suggests an unusual B-cell origin and an expansion of polyclonal B cells in peripheral blood.

Analysis of clonotypic immunoglobulin M (IgM) from 15 patients with Waldenstrom macroglobulinemia (WM) showed a strong preferential use of the VH3/JH4 gene families. Identification of the WM IgM V/D/J was validated using single-cell analysis, confirming its presence in most B cells. Despite the extensive hypermutated VH genes in 13 of 15 patients, statistical analysis of framework/complementary-determining region (FR/CDR) mutation patterns suggests that they might have escaped antigenic selection. Neither intraclonal diversity nor isotype switching was detectable. Membranous and secreted forms of clonotypic IgM transcripts were present in bone marrow and blood. Single-cell analysis showed that clonotypic B cells coexpress CD20, surface IgM (sIgM), and sIgD but that they lack CD138. Most B cells lacked memory marker CD27 despite their hypermutated variable regions otherwise suggestive of memory status. At diagnosis, circulating B cells in WM are largely clonotypic. However, when monoclonal IgM levels are decreased, clonotypic frequencies are substantially reduced despite elevated CD20+ cells, shown to be polyclonal by DNA sequencing and CDR3 fragment analysis. Thus, WM includes the expansion of circulating, polyclonal B cells. Overall, this work suggests that WM may originate from a largely VH3-restricted, somatically mutated, predominantly CD27(-)IgM(+)IgD+ population that cannot undergo class switching, suggestive of B cells that might have bypassed the germinal center.

Antigens↗

Somatic cell origin of teratocarcinomas.

Malignant teratocarcinomas arise from developmentally totipotent normal stem cells. Whether the targets are embryonal somatic cells or germinal cells has long been a matter of controversy. Past experiments on teratocarcinoma induction by ectopic grafting of early rodent embryos or fetal germinal ridges have remained ambiguous because embryos ordinarily soon form germ cells, and parthenogenetic germ cells form "embryos." In order to interrupt the developmental cycle at its most telling point, day 6 (egg-cylinder stage) mouse embryos of genetically sterile types were grafted; in such grafts, only a terminal residue of totipotent embryonal somatic ("ectoderm") cells is available, and subsequent germ cell development is severely impaired. One graft series, from S1(J)/+ matings, comprised 25% S1(J)/S1(J) presumptive sterile embryos; these grafts formed tumors containing embryonal carcinoma cells as often (47%) as did control +/+ grafts (41%) on the same genetic background. In another series, from W/+ matings, tumors of the sterile W/W genotype were individually identified by means of a closely linked marker, phosphoglucomutase (PGM, EC 2.7.5.1; Pgm-1 locus), coding for electrophoretic enzyme variants and incorporated into the stock. Four tumors were obtained (out of 16) that had the PGM-1D phenotype diagnostic for W/W, and that also contained embryonal carcinoma cells. Therefore, the malignancy arises here in susceptible somatic embryonal stem cells at the terminal stage of their capacity for totipotency. Other teratocarcinomas-whether induced or spontaneous-of ostensible germ-cell origin by parthenogenesis may also depend upon development of the same somatic target cells before neoplastic conversion can occur. A general model based on these experiments is proposed for all malignancies: Malignant transformation of a particular kind of normal stem cell may be possible only when that stem cell has progressed to the threshold of further differentiation.

Animals↗

Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice.

C.B-17 scid mice were reconstituted by intraperitoneal injection of human tonsil cells or PBL from EBV-seronegative donors. Subsequent injection of EBV resulted in the rapid development (within 19-33 d) of aggressive, fatal, lymphoproliferative disorders of human B cell origin. Autopsies revealed solid tumors in the abdomen, and occasionally in the liver, thymus, or spleen. Histopathologic analysis showed that the tumors were high-grade immunoblastic lymphomas and FACS analyses of tumor cells indicated that they were of human B-lymphoid origin. The tumor cells grew in vitro and induced new tumors on injection into severe combined immunodeficient (SCID) mice. Karyotypic analysis and Southern blots for c-myc or bcl-2 rearrangements revealed no chromosomal abnormalities and translocations. Southern blot analysis also showed that the cells possessed EBV DNA sequences. Although these tumors undoubtedly reflect infection of the transferred B cells with EBV in vivo, intraperitoneal transfer of short-term lymphoid cell lines transformed in vitro with EBV resulted in ascites production without evidence of tumor formation.

Animals↗

[Malignant lymphoma with medium-sized macronucleolated cells in the dog: involvement of an original cell from the marginal zone of the reactive lymph node].

Among the non-Hodgkin's malignant lymphomas of the dog, which are largely dominated by the centroblastic heterogeneous type, there is an original form of malignant lymphoma which is homogeneous and diffuse, with macronucleolated medium-sized cells. These cells seem to be morphologically very similar to those which constitute the majority population in the marginal zone of the secondary follicle of the lymph node in the dog, and which appear in the course of certain conditions: systemic lupus erythematosus, leishmaniasis, satellite lymph nodes in benign or malignant tumors. The aim of this study was twofold: on the one hand to establish, in the canine species, the identity of the lymphomatous cells and the reactive cells that make up the marginal zone, i.e. the filiation between the hyperplastic marginal zones and the macronucleolated malignant lymphoma with medium-sized cells, and, on the other hand, to compare this type of malignant lymphoma with those which are reputed to originate in the marginal zone in humans, for example the malignant lymphoma of the lymphoid tissue associated with the mucous membranes, and the monocytoid malignant B-cell lymphomas. Ninety four malignant lymphomas were observed between 1989 and 1994 at the Veterinary School in Lyon; these consisted of 71 cases showing medium or high-grade malignancy, 17 cases with small cells, of low-grade malignancy, and 6 cases of mycosis fungoides. Among the 71 cases of medium and high-grade malignancy, 8 were immunoblastic, 5 centroblastic homogeneous, 50 centroblastic heterogeneous, and 8 homogeneous with macronucleolated medium-sized cells. The methods used in these 94 cases were of a morphological type: cytology, histology, transmission microscopy and immunohistochemistry. The cytohistological, ultrastructural and immuno-phenotypical characteristics (CD3-, CIg-, Ki-67- phenotype) of the lymphomatous cells and the cells of the marginal zone were found to be identical, in the dog; this strongly suggests B-lineage cells which do not secrete cytoplasmic immunoglobulins and are not involved in the cell cycle. Finally, these cells seem to us to be morphologically very similar to the minority population described by Van den Oord in the marginal zone of the secondary follicles in the lymph node in humans, in certain reactive situations.

Animals↗

Different genotype distribution of the GNB3 C825T polymorphism of the G protein beta3 subunit in adenomas and differentiated thyroid carcinomas of follicular cell origin.

A C825T polymorphism has been demonstrated in the GNB3 gene that encodes the Gbeta3 subunit of heterotrimeric G proteins. Due to enhanced G protein activation, the GNB3 825T allele is associated with an increased signal transduction activity. To elucidate a possible role in the development and course of thyroid tumours of follicular cell origin, C825T polymorphism genotypes and allele frequencies were investigated in a series of adenomas and differentiated carcinomas. Genotypes and the allele frequency of the Gbeta3 polymorphism were investigated in samples from 361 patients (all white Caucasians) with differentiated thyroid tumours of follicular cell origin [80 adenomas and 95 follicular (FTCs) and 186 papillary carcinomas (PTCs)]. The results were compared with those of 1859 healthy controls. Both the genotype distribution (p = 0.029) and the allele frequency (p = 0.028) of the adenoma group were statistically significantly different from those of the control group. Thyroid adenomas also differed for both parameters significantly from FTCs (p = 0.042 and 0.033, respectively) and PTCs (0.0018 and 0.0081, respectively), whereas no statistical difference was noted between the FTC and PTC groups. Although the biological significance of these observations remains obscure, the results are suggestive of a putative role for the GNB3 polymorphism in thyroid tumour development and/or progression. Further research has to elucidate if, and to what extent, this common germ-line variation influences the TSH-triggered signalling pathways responsible for thyroid function and proliferation.

Adenoma↗

Immunoglobulin gene sequence analysis to further assess B-cell origin of multiple myeloma.

To further characterize the B-cell origin of multiple myeloma, our laboratory performed immunoglobulin gene sequence analyses of four cases of myeloma (three immunoglobulin A and one immunoglobulin G). Three tumors expressed VH3 genes and one expressed a VH1 gene, while the light chains included two V lambda and one V kappa III; one light chain was not isolated. The closest homology to published germ line genes ranged from 91 to 97%. In two cases, the expressed VH genes were compared with the putative germ line precursor VH genes isolated from autologous granulocyte DNA and appeared to have mutated randomly from the germ line gene. By sequencing multiple clonal isolates from each tumor sample, we found no evidence for ongoing mutation in three cases; in one case, however, clonotypic heterogeneity was evident. The analysis of DH- and JH-region genes revealed (i) limited or absent N nucleotide insertions (two of four cases), (ii) the presence of a DH-JH junction resulting from sequence overlap between the DH and JH genes (one of four cases), (iii) the absence of somatic mutations (two of four cases), and (iv) restricted JH gene usage of a JH6 polymorphism (three of four cases). These analyses of DH and JH genes suggest that multiple myeloma, similar to what has been proposed for chronic lymphocytic leukemia, may derive from B cells which have rearranged during fetal development rather than during adult life.

Amino Acid Sequence↗

CD7-positive acute leukemia lacking T cell receptor gene rearrangements and terminal deoxynucleotidyl transferase expression suggesting pre-T cell origin.

In this report, we describe a case of acute leukemia possessing a unique immunophenotype. Leukemic cells isolated from peripheral blood were analyzed by automated fluorescence-activated flow cytometry. They demonstrated the following antigen pattern: CD7+, CD38+, transferrin receptor+, HLA-DR+, common ALL antigen (CALLA)-, and terminal deoxynucleotidyl transferase (TdT)-. No expression of B cell or myeloid antigens was observed. The observed antigen pattern suggests a pre-T cell origin. In addition, the tumor cells contained germline T cell receptor beta (T beta) and gamma (T gamma) chain genes, and a germline immunoglobulin heavy chain (JH) gene. These findings support the concept that pre-T cell leukemias may demonstrate germline T beta and T gamma genes as well as lack TdT expression. In addition, our results suggest that CD7 expression may be one of the earliest events in T cell differentiation, occurring prior to both T beta an T gamma gene rearrangements, and TdT expression.

Acute Disease↗

[Hairy cell leukemia. II.--Critical review of literature. Part 2: the hairy cell origin (author's transl)].

Hairy cell leukemia (in french: leucémie à tricholeucocytes) is a distinctive form of chronic leukemia with splenomegaly, pancytopenia, presence of a particular circulating mononuclear cell, myelofibrosis and leukemic infiltration of the bone marrow. Generally, a tartrate resistant acid phosphatase activity is found in the leukemic cells. Hairy cell leukemia is the main leukemia in which the treatment is first surgical. Splenectomy has a good result for survival median and infectious risk. The disease is still mysterious for the origin of the leukemic cell; monocyte, B lymphocyte or in few cases T lymphocyte, even though a spectrum of immunological patterns pleads for the B lymphocyte origin of the leukemic cells.

Humans↗

Testicular natural killer/t-cell lymphoma, nasal type, of true natural killer-cell origin.

The majority of primary testicular lymphomas are of B-cell type. Other primary lymphomas are rarely encountered in the testes. Natural killer (NK)/T-cell lymphomas of nasal type are aggressive extranodal lymphomas associated with Epstein-Barr virus infection that are usually encountered in the upper aerodigestive tract. They also occur in the skin, soft tissue, and colon. Primary testicular NK/T-cell lymphomas are rarely reported. We describe the case of a 66-year-old Korean man who presented with right-sided painless testicular enlargement and underwent radical orchiectomy. Histologic examination revealed an angiocentric and angioinvasive infiltrate of medium to large tumor cells with moderately abundant pale pink cytoplasm and folded and indented pleomorphic nuclei. Paraffin immunohistochemical studies showed positivity of the tumor cells for CD45, TIA-1, granzyme B, CD56, and CD3 epsilon. In situ hybridization showed diffuse positivity for Epstein-Barr virus-encoding RNA. The results of gene rearrangement studies for the gamma chain of the T-cell receptor were negative. The results of paraffin immunohistochemical studies for CD20, CD8, CD45RO, beta f1, and ALK-1 were negative. An extensive workup showed no evidence of lymphoma outside the testes. We report a rare case of primary testicular NK/T-cell lymphoma of the nasal type of true NK-cell origin.

Aged↗

Lack of T cell antigen expression on hairy cells of B cell origin after in vitro exposure to PHA.

The malignant monoclonal population in hairy cell leukemia (HCL) has been variously ascribed to be of myeloid, B, or even T cell origin. Recent data have been interpreted as suggesting that hairy cells (HC) may concomitantly or serially express both B and T surface determinants, a phenomenon which, if verified, would be unique among the lymphoproliferative malignancies. Data described here, however, demonstrate that (1) at least the majority of HCL are phenotypically of B cell derivation, and (2) the initial B cell phenotype is retained and solely expressed on cultured as well as phytohemagglutinin (PHA) activated monoclonal malignant HC.

Adult↗

Lysosomal localisation of parallel tubular arrays in chronic lymphocytic leukaemia of T cell origin: an ultrastructural cytochemical study.

An ultrastructural cytochemical study of lysosomal acid phosphatase was performed on leukemic cells in a case of chronic lymphocytic leukaemia of T cell origin (T-CLL). The cells showed inclusion bodies known as parallel tubular arrays, which often lay within acid phosphatase-positive, membrane-bound spaces. This suggests their lysosomal location.

Acid Phosphatase↗

Increased growth of human fibroblasts and arterial smooth muscle cells from diabetic patients related to diabetic serum factors and cell origin.

Fibroblasts from 3 diabetic patients (DF) grew faster, resulting in higher cell counts in the stationary phase than fibroblasts from 3 age-matched healthy volunteers (NF). This difference was apparent when DF or NF were cultured in either diabetic (DS) or normal serum (NS). Diabetic serum increased growth of both DF and NF compared with normal serum. Total protein content per plate paralleled the increase of cell number per plate in relation to cell origin and serum type. DS increased growth and total protein per plate in the arterial smooth muscle cell line from a non-diabetic patient in a way similar to in DF and NF. It is concluded that increased growth of DF in vivo could result in an increased turnover of vascular cells with a shortened replicative lifespan, leading to an accumulation of basal lamina. This effect would be even further accentuated by exposure of DF to DS. Taken together with the increased protein synthesis the accelerated development of diabetic angiopathy could be the final consequence.

Adolescent↗

Expression of different phenotypes in cell lines from canine mammary spindle-cell tumours and osteosarcomas indicating a pluripotent mammary stem cell origin.

Mammary spindle-cell tumours and sarcomas seem to be restricted to dogs and humans. Two cell lines from spontaneous primary canine mammary spindle-cell tumours (CMT-U304 and CMT-U309) and two cell lines from spontaneous primary canine mammary osteosarcomas (CMT-U334 and CMT-U335) were established to study the mesenchymal phenotypes of mammary tumours in the female dog. The cells from the spindle-cell tumours expressed cytokeratin, vimentin and smooth muscle actin filaments. When these cells were inoculated subcutaneously into female and male nude mice they formed different types of mesenchymal tumours such as spindle-cell tumours, fibroma and rhabdomyoid tumours (n = 6/8). The cells from the osteosarcomas expressed vimentin filaments and also formed different types of mesenchymal tumours such as chondroid, rhabdomyoid, smooth muscle-like and spindle-cell tumours (n = 6/10). The cell lines CMT-U304, CMT-U309 and CMT-U335 had receptors for progesterone but none of the four cell lines had receptors for estrogen. All four cell lines and their corresponding primary tumours showed identical allelic patterns in microsatellite analysis. By in situ hybridization with genomic DNA we could verify that all formed tumours but one were of canine origin. Our results support the hypothesis that canine mammary tumours are derived from pluripotent stem cells.

Animals↗

Evidence for proximal tubular cell origin of a sarcomatoid variant of human renal cell carcinoma.

A pure sarcomatoid variant of renal cell carcinoma obtained from a hydronephrotic kidney of an elderly white female was grown in tissue culture. Two parallel cell lines, one from the primary neoplasm and the other from a seeded metastasis within the same kidney have been cultured for more than 60 passages over a period of three years. Structural and functional studies of this neoplasm confirmed that it originated from proximal tubular cells.

Animals↗

Death from thyroid cancer of follicular cell origin.

BACKGROUND: Although patients with differentiated thyroid cancer (DTC) of follicular cell origin usually have an excellent prognosis, some patients die from progressive tumor. Numerous postoperative criteria have been used to predict prognosis in patients with DTC. The purpose of this investigation was to determine whether the TNM and metastases, age, completeness of resection, invasion, size (MACIS) classifications predicted survival time and why patients died from DTC. The extent of initial treatment and causes of death were also evaluated in these patients who died from thyroid cancer. STUDY DESIGN: Between 1965 and 1995, 102 of 1,224 patients with DTC treated at the University of California at San Francisco (UCSF) and UCSF/Mount Zion Medical Centers died from DTC. Risk factors including age at diagnosis, gender, histologic characteristics, TNM and MACIS classifications, the intervals among initial treatment, recurrence, and death, and the initial and subsequent treatments were documented in these 102 patients. RESULTS: Among the 102 patients who died of DTC 50% were men and 50% were women. The mean age of patients with DTC at diagnosis was 58 years at recurrence, 62 and 65 years at death. Thirty percent of these patients initially had unilateral thyroid operations and 70% had a bilateral operation. Tumors at presentation ranged from 0.6 to 13.0 cm (mean 4.4 cm); 46% of patients presented with late-stage tumors (TNM stage III, IV; MACIS score > 8). At presentation 46% of the patients had locally recurrent disease or regional metastases and 18% had distant metastases. Patients with persistent disease had a significantly shorter survival time than those with recurrent disease (p < 0.001). Both TNM and MACIS classifications were good predictors of survival time. Reoperations were performed in 51% of papillary, 26% of follicular, and 67% of Hürthle cell thyroid cancer patients. Fifty percent of patients with papillary thyroid cancer, 50% of patients with Hürthle cell thyroid cancer, and 11% of patients with follicular cell thyroid cancer died of locally advanced disease. CONCLUSIONS: As expected, patients with local or regional recurrence and those with TNM stage I or MACIS score < 6 survived longer than patients with distant metastasis and TNM stage III or IV, MACIS score > 6, but some patients thought to be at low risk (TNM stage I; MACIS < 6) also died from thyroid cancer.

Adenocarcinoma, Follicular↗

Influence of mucosal cell origin on the in vitro adherence of Candida albicans: are mucosal cells from different sources equivalent?

The influence of collecting mucosal cells from various anatomical sites, and varying the date of collection and cell donor on adhesion of Candida albicans to human epithelial cells was examined by using an in vitro adherence assay. Examination of buccal mucosal cells from twenty-four donors showed statistically significant differences in the number of attached yeasts between individuals. Sex did not exert a significant influence on adhesion. Examination of buccal mucosal cells from ten donors collected on five different dates revealed that yeast attachment to mucosal epithelial cells varied significantly within subjects across time. Epithelial cells from some donors manifested greater date-to-date variations in yeast adhesion than others. Adherence of Candida to mucosal cells from three anatomical sites (mouth, vagina and urinary tract) collected from ten different donors was also tested. Yeast adherence to buccal cells was highest, lowest using urinary tract cells, while vaginal epithelium was intermediate. Adherence to mucosal cells from three sites was significantly different both within and between individuals although some subjects manifested larger variations than others. These data suggest that the in vitro adherence of Candida albicans is influenced by mucosal cell donor, date of collection and body site of origin. Mucosal cells from different sources do not appear to be equivalent in receptiveness to C. albicans and this might explain some of the discrepancies observed when adhesion studies performed by different investigators are compared. The existing need for a more uniform methodology with which to pursue studies on fungal attachment to mucosal surfaces is emphasized.

Adhesiveness↗