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PubMed2006

[Soft tissue non lymphoid malignant round cell tumors in childhood and adolescence: morphological, immunophenotypic, and molecular features of diagnosis].

Soft tissue non lymphoid malignant round cell tumors observed in children and adolescents are rare and are very different from adult tumors. They are often undifferentiated and distinctive key morphologic features are often lacking, but, on the other hand, specific recurrent genetic alterations, mostly translocations, are distinctive. Immunohistochemical features are also important for the diagnosis, and there is sometimes a strong correlation between the presence or the absence of an immunoreactivity for a specific protein and the presence of a specific genetic alteration. Finally, careful morphologic histological examination and immunohistochemical features will lead to a diagnosis which will be often confirmed by cytogenetics (translocations) or molecular techniques (fusion transcripts, deletion, mutation).

Adolescent↗
PubMed2004

Endometrial glandular dysplasia: a putative precursor lesion of uterine papillary serous carcinoma. Part II: molecular features.

Endometrial glandular dysplasia (EmGD) may be a newly defined precursor lesion of uterine papillary serous carcinoma (UPSC) by morphology. In this report, we studied molecular changes present in EmGD by the loss of heterozygosity (LOH) approach using laser capture microdissected tissue samples. Nineteen uteri showing at least 1 focus of EmGD by morphology were selected. These cases were 12 UPSC, 2 clear cell carcinomas, 1 mixed uterine papillary serous and endometrioid carcinoma, 1 uterine carcinosarcoma, 1 serous endometrial intraepithelial carcinoma (EIC), and 2 EmGD involving endometrial polyps. Seven microsatellite polymorphic DNA markers (TP53 at 17p, D1S211, and D1S162 at 1p32, D17S1323 at 17q21, D17S1330 at 17q25, D5S346 at 5q, and D2S123 at 2p) were utilized. A total of 123 laser-captured microdissection samples from 19 cases was studied with LOH method. The frequencies and patterns of LOH were analyzed and compared among benign resting endometrium (RE), EmGD, serous EIC, and UPSC. LOH was observed for at least 1 of the 7 markers in all categories of lesions, EmGD, serous EIC, and UPSC. The frequency of LOH for EmGD ranged from 4.2% to 31.3%; the range for serous EIC was 5.9% to 78.6%; and that for UPSC was 7.7% to 62.5%. The most frequent LOH in the 3 above-cited categories of lesions was identified at 17p (TP53) and 1p (D1S162). The frequency of LOH in EmGD with markers of TP53 and D1S162 was significantly higher than in RE (p < 0.05). With markers of D1S211 and D2S123, LOH in EmGD was higher than RE, approaching to a statistically significant level. Compared with foci of serous EIC and UPSC, however, the rate of LOH in EmGD was significantly lower only with TP53 locus (31.3% vs more than 60%, p < 0.05). The difference of LOH frequency with other chromosomal markers between EmGD and serous EIC/UPSC did not reach a statistically significant level. A significantly high concordant LOH pattern was found between foci of EmGD and serous EIC/UPSC (p = 0.05). We conclude that EmGD frequently shows LOH at multiple chromosomal loci, particularly at 17p and 1p. Significantly high concordant LOH frequency between EmGD and paired serous EIC or UPSC strongly suggests that EmGD is a noncancerous precursor lesion of UPSC, probably also of serous EIC. The clinical significance of EmGD needs further studies.

Aged↗
PubMed1993

T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node.

Since T cell surveillance depends on movement from blood into tissue and back again, rapid, efficient and selective T cell adhesion to vascular endothelium is essential. This adhesion involves a multistep cascade clarified by a recent consensus model: (1) initial tethering by selectin-mediated interactions; (2) triggering of adhesive function of T cell integrins by ligands at or near the endothelial surface; and (3) strong adhesion mediated by T cell integrins. We recapitulate this model, particularly as it pertains to the lymph node, and explore additional molecular and anatomic elements which contribute to the effectiveness of the adhesion cascades at that site: (1) importance of cytokines/soluble mediators as triggering ligands; (2) role of glycocalyx and proteoglycans on high endothelial venule (HEV) endothelium in capturing and presenting triggering cytokines; (3) remarkable function of what we designate the 'fibroblastic reticular cell (FRC) conduit system' in rapidly transporting cytokines to the HEV; (4) importance of the unique anatomy of the flap-valve junctions between HEV endothelium in enabling intravasation of cytokines and transmigration of lymphocytes. Taken together, these molecular mechanisms and these three anatomic features of lymph node facilitate extremely efficient lymphocyte traffic to this site critical for T cell-mediated immune responses. Analogous mechanisms contribute to T cell interaction with endothelium at other sites.

Animals↗
PubMed2005

Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred.

PURPOSE: Members of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs. PATIENTS AND METHODS: Members of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques. RESULTS: In addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T --> C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY-14,-22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs. CONCLUSION: These studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes.

Adult↗
PubMed2006

Molecular features linked to the growth-inhibitory effects of gemcitabine on human pancreatic cancer cells.

Although gemcitabine (GEM) is widely used in the treatment of pancreatic cancers, the molecular mechanisms that underlie its anti-tumor effects are not fully understood. To clarify the anti-tumor mechanism(s) of GEM, we studied a human pancreatic cancer cell line, YPK-1, that showed a 50% inhibitory concentration (IC50) of GEM of 6.3 x 10(-3) microg/ml after 72 h of exposure. Cell proliferation was perturbed by 6 to 72 h of exposure to GEM concentrations equal to one-half or one-quarter of the IC50. We used cDNA microarrays containing 2976 genes to identify genes with expression affected by exposure to GEM. The self-organizing map identified nine clusters, including 85 and 87 genes, that showed differential expression in response to exposure to one half and one quarter IC50 GEM, respectively. Of these, 24 genes were common to cells exposed to the two different concentrations of GEM. Most are signal transduction or transcription-related genes. The microarray data for two of these genes, SPARC and RPS8, were validated by RT-PCR. Although further studies are needed to examine whether the changes in expression profiles of these genes are specific to cells exposed to GEM, the present data provide insights into the anti-tumor effects of GEM on pancreatic cancers.

Antimetabolites, Antineoplastic↗
PubMed2001

Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice.

Hematopoietic neoplasms developing in AKXD recombinant inbred, NFS.V(+) and ICSBP knockout mice were assessed using morphologic, cytologic and molecular criteria that relate these disorders to human lymphoma and leukemia. Lymphoma types included precursor T-cell and B-cell lymphoblastic, small lymphocytic, splenic marginal zone, follicular, and diffuse large cell (DLCL). In addition to previously defined subtypes of DLCL composed of centroblasts or immunoblasts, two additional subtypes are defined here: lymphoblastic lymphoma like (LL) and lymphoma characterized by a histiocytic reaction (HS). DLCL(HS) were distinguished from true histiocytic lymphomas by the presence of clonal Ig gene rearrangements.

Animals↗
PubMed2005

[Gastrointestinal stromal tumors: definition, histological, immunohistochemical, and molecular features, and diagnostic strategy].

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Major advances in their definition and classification and the understanding of their molecular mechanisms have recently been made. These advances have resulted in the delineation of a treatment that has become a model of targeted therapy in oncology. GISTs are defined as tumors of the gastrointestinal tract, but also of the mesentery and peritoneum, constituted by a proliferation of usually spindle-shaped, rarely epithelioid cells, usually, but not consistently expressing the KIT protein. Most GISTs are associated with molecular abnormalities in two target genes: KIT (which encodes the KIT protein) and PDGFRA (which encodes the A chain of the PDGF receptor). The diagnosis of GIST relies on histological arguments (proliferation of spindle-shaped cells in 70% of cases, of epithelioid cells in 20%; histological variants are rare and sometimes misleading) and on immunohistochemical arguments (expression of KIT in 95%, usually associated with CD34 expression in 60%-70% of cases). The demonstration of mutations in target genes is required only in cases that are histologically suggestive but KIT-negative; beyond this indication, this is only undertaken in research protocols. The differential diagnosis of GIST includes the other mesenchymal tumors of the gastrointestinal tract, such as leiomyomas and leiomyosarcomas, and the digestive locations of some sarcomas; it relies on both histological and immunohistochemical arguments. The evaluation of the prognosis is essential. According to the current concept, every GIST carries a risk of malignancy, which may vary from very low to very high. Prognosis is based on a simple algorithm using two histoprognostic parameters, i.e., tumor size and mitotic index. The treatment of localized GIST is surgical resection, which must be complete; that of advanced or unresectable GIST is based on the use of a targeted therapy, imatinib, which is a pharmacological antagonist of the KIT protein. Proper understanding and utilisation of the diagnostic criteria and classification of GIST by pathologists are essential for good patient management.

Adult↗
PubMed1998

Molecular features associated with polyamine modulation of NMDA receptors.

The effect of 1,3-diamines on basal and spermine-stimulated [3H]MK-801 binding was investigated. Systematic variations in the molecular parameters revealed that, in general, lipophilic 1,3-diamines inhibited and hydrophilic 1,3-diamines enhanced [3H]MK-801 binding in the nominal absence of glutamate and glycine. Furthermore, 1,3-diamines which were highly monoprotonated at physiologic pH were more effective in modulating basal binding (at 100 microM 1,3-diamine) than analogues which were mostly diprotonated or unprotonated. Finally, the internuclear distance between the amino nitrogens and the extent of modulation of basal [3H]MK-801 binding were correlated. Similar, but more modest, effects were seen for spermine-enhanced [3H]MK-801 binding. These results are consistent with the existence of two polyamine binding sites associated with the NMDA receptor complex. One of the sites appears to preferentially recognize lipophilic substances while the other favors hydrophilic materials. Both sites appear to recognize polyamines with at least one charged (protonated) amino group and one uncharged amino group. The distance between amino groups is a determining factor as well.

Animals↗
PubMed2005

[Clinical and molecular features of cardial gastric cancer associated to Epstein Barr virus].

BACKGROUND: Mortality caused by cardial gastric cancer in Chile, is increasing. Previously we demonstrated an association between Epstein Barr virus and this specific location of gastric cancer. AIM: To perform a clinical and molecular characterization of cardial gastric cancer associated to Epstein Barr virus. MATERIAL AND METHODS: Epstein Barr virus was identified in 93 cardial gastric tumors, by in situ hybridization. Clinical and pathological features, survival and expression of p53 and c-erbB2 were compared between tumors with or without the presence of the virus. RESULTS: Twenty two (23.6%) tumors expressed Epstein Barr virus. No difference in sex or age of patients with tumors positive or negative for the virus was observed. Epstein Barr positive tumors had a tendency to have a higher frequency of Bormann III endoscopic appearance and a lower frequency of p53 accumulation (p=0.06). Five years survival was 67% and 42% of tumors positive and negative for the presence of the virus, respectively (p=0.57). CONCLUSIONS: Our results, although not significant, show a tendency towards unique characteristics of cardial gastric tumors associated to Epstein Barr.

Adult↗
PubMed1998

Molecular features in a biphenotypic small cell sarcoma with neuroectodermal and muscle differentiation.

We report a case of a 13-year-old girl with soft tissue sarcoma of the hand, which showed muscle and neuroectodermal immunophenotypes. Molecular studies were performed on RNA collected from fine-needle aspiration (FNA) cytology and peripheral blood samples by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis. This biphenotypic tumor showed simultaneous expression of EWS-FLI1 and PAX3-FKHR transcripts, specific of Ewing family tumors and alveolar rhabdomyosarcoma, respectively. Although childhood sarcomas with simultaneous muscle and neural differentiation have been described to have EWS-FLI1 transcripts, there are no reports of tumors with both transcripts. Cytological specimens are a good source of RNA for molecular studies.

Adolescent↗
PubMed1994

Laron syndrome: clinical features, molecular pathology and treatment.

Primary growth hormone (GH) insensitivity (Laron syndrome) is a hereditary disease due to polymorphic defects in the GH receptor, or in the postreceptor mechanisms, leading to an inability to generate IGF-1. The clinical features and biochemical profiles are indistinguishable from isolated GH deficiency. A diagnostic feature is the lack of rise of serum IGF-1 in response to GH. In most patients growth hormone binding protein is low. Treatment of children with Laron syndrome by biosynthetic IGF-1 accelerates linear growth velocity and head circumference, reduces body fat, and stimulates kidney function.

Adolescent↗
PubMed1997

Generation and analysis of an IgG anti-platelet autoantibody reveals unusual molecular features.

Although serum transfer studies implicate IgG anti-platelet autoantibodies in the premature platelet destruction of idiopathic thrombocytopenic purpura (ITP), many characteristics of these putative pathogenic autoantibodies remain unclear. The inability to obtain relevant monoclonal autoantibodies from patients has prevented their molecular, genetic and functional studies as a homogenous population. We have generated a monoclonal IgG anti-platelet alpha IIb beta 3 autoantibody (termed G1) from an ITP patient. G1 binds human platelets (both resting and activated) and purified alpha IIb beta 3 with a Kd of 1.57 x 10(-8) M. G1 utilizes VH4 and V lambda 2 genes. The G1 VH region apparently has a 30 nucleotide insertion in its second complementarity determining region (CDR). Notably, somatic CDR insertion in the VH region has been observed only in one IgG rheumatoid factor, and not in any characterized polyreactive human autoantibodies reported in the literature. Combined these data suggest G1 may be a disease-relevant autoantibody. Further generation and study of monoclonal IgG anti-platelet antibodies are warranted to determine the significance of such unusual autoantibodies in the immunopathogenesis of chronic ITP.

Adult↗
PubMed2000

Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma.

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel "proto-oncogenes" involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcgammaRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.

Journal Article↗