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PubMed2002

Formation of the killer Ig-like receptor repertoire on CD4+CD28null T cells.

Killer Ig-like receptors (KIRs) are expressed on CD4(+)CD28(null) T cells, a highly oligoclonal subset of T cells that is expanded in patients with rheumatoid arthritis. It is unclear at what stage of development these T cells acquire KIR expression. To determine whether KIR expression is a consequence of clonal expansion and replicative senescence, multiple CD4(+)CD28(null) T cell clones expressing the in vivo dominant TCR beta-chain sequences were identified in three patients and analyzed for their KIR gene expression pattern. Based on sharing of TCR sequences, the clones were grouped into five clone families. The repertoire of KIRs was diverse, even within each clone family; however, the gene expression was not random. Three particular receptors, KIR2DS2, KIR2DL2, and KIR3DL2, had significant differences in gene expression frequencies between the clone families. These data suggest that KIRs are successively acquired after TCR rearrangement, with each clone family developing a dominant expression pattern. The patterns did not segregate with the individual from whom the clones were derived, indicating that peripheral selection in the host environment was not a major shaping force. Several models were examined using a computer algorithm that was designed to simulate the expression of KIRs at various times during T cell proliferation. The computer simulations favored a model in which KIR gene expression is inducible for a limited time during the initial stages of clonal expansion.

Arthritis, Rheumatoid↗
PubMed2025

Genomic and phenotypic insights into ST164 blaNDM-1-positive Acinetobacter baumannii from intestinal colonization in China.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a critical global threat, especially in ICUs. Yet, reports on ST164 CRAB harboring blaNDM-1 remain scarce. This study investigates two clinical CRAB isolates, L4773hy and L4796hy, derived from intestinal colonization in Hangzhou, China, focusing on their phenotypic and genomic characteristics as well as the broader transmission of ST164 A. baumannii. METHODS: Bacterial identification was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) mass spectrometry. Antimicrobial susceptibility was assessed via agar and broth microdilution. Whole-genome sequencing employed Illumina NovaSeq 6000 and Oxford Nanopore platforms. Resistance genes, insertion elements, transposons, and integrons were detected using ResFinder, PlasmidFinder, VFDB, ISFinder, pdifFinder, and IntegronFinder. Strains were typed by MLST, and a phylogenetic tree was constructed with kSNP3.0. Genetic environment diagrams were generated using Easyfig 2.2.5. RESULTS: Two blaNDM-1-carrying A. baumannii isolates exhibiting extensive resistance to carbapenems, cephalosporins, and fluoroquinolones. Whole-genome sequencing and genetic environment analysis revealed the presence of a conserved structural sequence (ISAba14-ISAba14-aphA-ISAba125-blaNDM-1-bleMBL) on their chromosomes. Phylogenetic and clonal dissemination analysis showed that ST164 CRAB is primarily distributed in China and exhibits clonal spread. Pathogenicity studies indicated that blaNDM-1-positive ST164 strains have enhanced survival under immune pressure but do not display increased virulence in infection models. CONCLUSION: This study provides the genomic and phenotypic characterization of intestinally colonized ST164 blaNDM-1 positive CRAB in Hangzhou, China. The elucidation of the genetic environment of blaNDM-1 further confirms the clonal dissemination of ST164 isolates, highlighting the importance of enhanced surveillance and infection control measures to mitigate the spread of these multidrug-resistant pathogens.

Acinetobacter baumannii↗
PubMed2003

Deviation of islet autoreactivity to cryptic epitopes protects NOD mice from diabetes.

To better understand loss of self-tolerance in diabetes-prone NOD mice, we are generating ICA69 transgenes under control of the tetracycline-regulated tet07 minimal promoter. In vitro pilot studies showed leaky transgene expression, but addition of beta-globin genomic insulator flanks prevented leakage and dramatically enhanced transgene expression even in transient transfection, with excellent suppression by Doxycycline. In vivo, the accidental loss of insulator flanks during transgene insertion in one transgenic NOD founder, tet1, re-established leakiness with high level, exclusive ICA69-transgene expression in stromal elements of thymus and spleen. This led to persistent deletion of T cells targeting the immunodominant ICA69 epitope, Tep69, but emergence of T cell pools targeting cryptic ICA69 epitopes not normally generated in sufficient density to select and maintain ICA69-autoreactive T cells. This subtle modification of T cell repertoires reduced insulitis, and protected from diabetes in transgenics and in wild-type mice carrying irradiated tet1 thymus grafts. The low pathogenicity of T cells targeting cryptic epitopes likely reflects the fact that the major ICA69 determinant presented in the islet milieu remains Tep69, while cryptic epitopes are under-represented. Deviation of T cell autoreactivity from major to cryptic target epitopes in tet1 mice provides a fortuitous model to explain previously observed diabetes protection by immunotherapy or autoantigen transgenes despite apparent failure to achieve tolerance to the full length islet antigens.

Adoptive Transfer↗
PubMed2001

Molecular clonality of in-transit melanoma metastasis.

In-transit melanoma is characterized by an aggressive pattern of recurrence that is associated with a poorer prognosis. Because in-transit melanoma is considered to result from the intralymphatic trapping of melanoma cells between the primary tumor and regional lymph nodes, it provides an excellent model to assess genetic events associated with early metastasis. The hypothesis of this study was to determine whether in-transit metastases are clonal in origin and therefore, may have specific genetic alterations uniquely associated with this disease and the development of early metastasis. This was assessed using loss of heterozygosity (LOH) analysis for specific DNA microsatellite loci. Seventy-nine paraffin-embedded in-transit melanoma lesions from 25 patients (range, 2 to 9 lesions per patient; average, 3.4 lesions per patient) were assessed for LOH using eight microsatellite DNA markers on six chromosomes. In 19 of 25 patients (76%) LOH was demonstrated for at least one marker. The most frequent microsatellite marker demonstrating LOH was D9S157 (56%). Using LOH microsatellite markers to assess intertumor heterogeneity, six of 79 tumors (7.6%) demonstrated different profiles when compared to other lesions from the same patient. In-transit metastases from those patients demonstrating intertumor heterogeneity were further assessed using laser capture microdissection and DNA analysis, and revealed no significant intratumor heterogeneity. In conclusion, LOH was frequently observed in in-transit melanoma metastasis. Based on LOH analysis, in-transit metastases are clonal in origin. The establishment of clinically successful in-transit melanoma metastasis requires specific genetic events that seem to be unique and homogeneous for each patient.

Clone Cells↗
PubMed2025

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy.

UNLABELLED: Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors with treatment-naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4, and genetic and pharmacologic modulation of carbonic anhydrase 4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of the treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients. SIGNIFICANCE: G3 medulloblastoma features a prognostic subgroup-specific gene expression signature and can be targeted with a carbonic anhydrase inhibitor to enhance radiosensitivity, reducing the risk of recurrence and improving survival.

Medulloblastoma↗
PubMed2001

CD4(+)CD7(-) T cells compose the dominant T-cell clone in the peripheral blood of patients with Sézary syndrome.

BACKGROUND: Absence of CD7 antigen expression in T cells defines a subset of normal CD4(+) CD45RO(+) CD45RA(-) memory cells and is furthermore observed in Sézary syndrome (SS). OBJECTIVE: Our purpose was to identify circulating T-cell clones in patients with SS and to elucidate whether the dominant T-cell clones express the CD7 antigen. METHODS: Peripheral blood lymphocytes of patients with SS were analyzed by two-color flow cytometry using antibodies to the V beta region of the T cell receptor (TCR) in combination with an antibody to CD7. In addition, T cells were analyzed for TCR-gamma gene rearrangement by polymerase chain reaction (PCR) techniques. RESULTS: Clonal T-cell expansion was detected in 7 patients with SS by immunostaining of the TCR V beta regions. PCR analysis confirmed the presence of dominant T cell clones. Double-immunostaining revealed that in each case cells of the clonal V beta TCR rearrangement homogeneously express the CD4(+)CD7(-) phenotype. Furthermore, CD4(+)CD7(-) cells express the CD15s antigen but lack expression of CD26 and CD49d. CONCLUSION: Expansion of clonal T cells strongly correlates with the expansion of CD4(+)CD7(-) T cells in 7 tested patients with SS. This supports our model that a subset of late differentiated, normal CD4(+)CD7(-) memory T cells may represent the physiologic counterpart of Sézary cells. Monitoring of circulating T cells with the CD4(+)CD7(-)CD15s(+)CD26(-)CD49d(-) phenotype proved to be useful for the identification of clonal T cells in patients with SS.

Aged↗
PubMed2003

Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity.

Aging is the highest risk factor for cancer. Although oxidants are thought to contribute to both aging and cancer, the interplay between oxidative stress, aging, and cancer has not been well studied. Human diploid fibroblasts (HDFs) undergo premature senescence in response to sublethal doses of H(2)O(2). To test the hypothesis that senescent or senescent-like HDFs function as a tumor promoter, we have employed an in vitro skin tumor promotion model, in which colony formation is measured using initiated mouse keratinocyte 308 cells seeded at clonal density. 308 cells form colonies when co-cultured with normal HDFs only in the presence of the tumor promoter phorbol 12-myristate 13-acetate (TPA), which induces an average of 5.75 colonies. When co-cultured with H(2)O(2)-treated HDFs, 308 cells form an average of 30.3 colonies. To understand the mechanism behind this phenomenon, we tested whether conditioned medium of HDFs, HDF extracellular matrix (ECM), density of HDFs, or the contact between keratinocytes and HDFs plays a role in 308 cell colony formation. The conditioned medium from prematurely senescent cells resulted in an average of eightfold more 308 cell colonies formed than the conditioned medium from normal HDFs, and the growth-promoting effect of the conditioned medium was trypsin sensitive. The ECM alone was not able to induce 308 cell colony formation. Increasing the density of normal HDFs or contact with normal HDFs but not senescent-like HDFs was inhibitory to the growth of 308 cells. Measurement of Connexin 43 indicated a decreased expression of the protein, which suggests an impaired gap junction communication in senescent-like HDFs. We conclude that H(2)O(2)-treated fibroblasts not only lose contact inhibition of the growth of initiated keratinocytes perhaps related to reduced gap junction communication but also increase production of secreted protein factors to enhance the growth of 308 keratinocytes.

Carcinogens↗
PubMed2003

Predominance of sexual reproduction in Romanian populations of the aphid Sitobion avenae inferred from phenotypic and genetic structure.

Models of coexistence of sexual and asexual lineages in aphids assume that obligate parthenogenetic lineages predominate in areas with mild winter climate because of their high reproductive output, while sexual lineages predominate in areas with severe winter because they produce eggs resistant to frost. To validate this hypothesis in natural conditions, the reproductive mode of populations of the aphid Sitobion avenae was assessed in two very contrasting climatic situations, Romania (severe winter) and Western France (mild winter). To achieve this, reproductive modes were inferred from both (1) the population composition in sexual and asexual forms in autumn, and (2) the genetic structure of Romanian and French populations of S. avenae using microsatellite markers. Romanian populations encompassed a high proportion of sexual forms and were characterised by a very high genotypic diversity and low linkage disequilibrium. In constrast, the French population showed frequent linkage disequilibria, low genetic diversity, and high level of clonal amplification with two asexual genotypes representing over 60% of the sample. In agreement with the model's predictions, these results clearly indicate that sexual reproduction in S. avenae is predominant under the continental climate of Romania, while asexual lineages prevail under the oceanic climate of Western France.

Animals↗
PubMed2001

K-ras mutational analysis of polyclonal colorectal cancers identifies uniclonal circulating tumor cells.

The clonal development of colorectal carcinoma resulting from specific mutations in certain oncogenes and/or tumor suppressor genes is a well-accepted model. It is increasingly recognized that a majority of colorectal cancers are polyclonal on the basis of molecular analysis that demonstrates cells with different mutations within a given oncogene or tumor suppressor gene in the same tumor. This polyclonal pattern may occur as a result of either clonal convergence or divergence during the many steps of oncogenesis. Further complicating this picture is the fact that metastatic lesions may arise from only one of the clonal populations within a tumor and thereby present only a partial molecular make-up of the whole tumor. There are few data available that define clonal selection or specificity of circulating tumor cells in patients undergoing curative resection of colorectal carcinoma. The purpose of this paper is to describe the clonal distribution of circulating tumor cells in four patients with multiple K-ras mutations present in the primary lesion. Patients were selected who were known to have polyclonal primary colorectal cancers resected for cure. All patients had multiple mutations present in exon one, codon 12 and/or 13, of the K-ras gene. Blood samples were drawn immediately before surgery and at 2-week to 6-month intervals postoperatively. Epithelial cells were isolated from peripheral blood mononuclear cells using Dynal Immunobeads coated with antiepithelial antibodies. DNA was extracted from these cells and analyzed for all K-ras mutations present in codons 12 and 13 of the patient's primary tumor using allele-specific polymerase chain reaction followed by Microwell Array Diagonal Gel Electrophoresis. Circulating tumor cells were identified in all four patients. However, in each case of positive circulating cells the only mutation identified was an aspartic acid mutation at codon 13. Once positive the circulating tumor cells persisted in subsequent multiple blood samples. These results provide further strength for the theory of polyclonal progression in primary colorectal cancers, although there may be specific mutational patterns that confer the ability to metastasize. The significance of this persistence of the glycine-to-aspartic acid mutation at codon 13 remains to be defined given that none of these patients has clinical evidence of recurrent cancer at the time of this report.

Aspartic Acid↗
PubMed1987

Moloney murine leukemia virus-induced myeloid tumors in adult BALB/c mice: requirement of c-myb activation but lack of v-abl involvement.

BALB/c mice treated with pristane and Abelson virus have been used as an animal model system for the rapid induction of plasmacytomas. Myelomonocytic tumors with helper Moloney murine leukemia virus clonally inserted into the c-myb locus were observed in about 10% of pristane-primed BALB/c mice infected with Abelson virus. However, v-abl was absent in almost all of those tumors. Since Moloney virus is thought to induce mostly T-cell lymphomas, we have carried out studies to investigate this alteration of disease specificity and to determine whether v-abl played an obligatory role in the development of these tumors. We found that, whereas lymphomas developed late (greater than 3 months) in both pristane-primed and unprinted control mice, the myelomonocytic tumors arose at a high frequency, within 3 months, but only in pristane-treated mice. Clonal Moloney virus insertion was again found in each of the seven myelomonocytic tumors examined. Northern blot analyses and S1 mapping studies revealed the presence of virally promoted chimeric mRNAs that lack the three 5'-most myb coding exons. Hence it appears that the requirement for the v-abl gene product in tumor induction is not obligatory. Our results also indicate that tumor-specific alteration at the 5' end of the myb gene plays an important role in the development of these tumors.

Abelson murine leukemia virus↗
PubMed1993

In vitro and in vivo immunopharmacological profile of Sch 40120.

Sch 40120 (10-(3-chlorophenyl) - 6,8,9,10- tetrahydrobenzo [b] [1,8] naphthyridin-5 (7H)-one) is a leukotriene inhibitor that is also a potent inhibitor of acute inflammatory responses in rodent systems. In the present study, we have evaluated the effects of this drug on immune function as well as its activity in models of immune mediated chronic inflammatory disease. Sch 40120 was particularly effective in suppressing T cell proliferative responses in vitro. Antigen-specific and poly-clonally-induced in vitro antibody responses were also inhibited by the drug. However, the in vivo potency of Sch 40120 in suppressing immune responses and in inhibiting the pathological changes seen in rodent models of autoimmune disease (EAE and adjuvant arthritis) was somewhat less than that previously observed in models of acute inflammation. Nevertheless, the spectrum of activities exhibited by Sch 40120 suggests that it will be particularly useful in the treatment of psoriasis where T lymphocytes have been implicated in the development of disease and leukotrienes appear to have a role in the persistence of psoriatic plaques.

Animals↗
PubMed2005

Distinct temporal programming of naive CD4+ T cells for cell division versus TCR-dependent death susceptibility by antigen-presenting macrophages.

Naive T cells become programmed for clonal expansion and contraction during the early hours of antigenic signaling. Recent studies support an 'autopilot' model, wherein the commitment to proliferate and the magnitude of the proliferative response are simultaneously determined during a single, brief period of antigen exposure. Here, we have examined whether the proliferation of naive CD4+ T cells must occur on 'autopilot', or whether extended periods of antigenic signaling can impact primary proliferative responses to antigen-presenting macrophages (macrophage APC). We found that a single exposure to antigen (18 h) simultaneously committed T cells to (1) up-regulate surface TCR above the level expressed on naive T cells, (2) undergo minimal cell division, and (3) acquire susceptibility to TCR-dependent activation-induced cell death. However, continued antigenic signaling between 18 and 72 h was required to amplify the number of daughter cells derived from the already committed T cells. Thus, a discrete commitment time was followed by a 'tuning' period, where extended antigenic signaling determined the volume of the proliferative response. We conclude that T cell commitment to full clonal expansion versus TCR-dependent death susceptibility represent two separate programming events whose timing can be segregated by macrophage APC.

Animals↗
PubMed2006

Aging is associated with increased clonogenic potential in rat liver in vivo.

Cancer increases with age and often arises from the selective clonal growth of altered cells. Thus, any environment favoring clonal growth per se poses a higher risk for cancer development. Using a genetically tagged animal model, we investigated whether aging is associated with increased clonogenic potential. Groups of 4-, 12-, 18-, and 24-month-old Fischer 344 rats were infused (via the portal vein) with 2x10(6) hepatocytes isolated from a normal syngenic 2-month-old donor. Animals deficient in dipeptidyl-peptidase type IV (DPP-IV-) enzyme were used as recipients, allowing for the histochemical detection of injected DPP-IV+ cells. Groups of animals were sacrificed at various times thereafter. No growth of DPP-IV+ transplanted hepatocytes was present after either 2 or 6 months in the liver of rats transplanted at young age, as expected. In striking contrast, significant expansion of donor-derived cells was seen in animals transplanted at the age of 18 months: clusters comprising 7-10 DPP-IV+ hepatocytes/cross-section were present after 2 months and were markedly enlarged after 6 months (mean of 88+/-35 cells/cluster/cross-section). These results indicate that the microenvironment of the aged liver supports the clonal expansion of transplanted normal hepatocytes. Such clonogenic environments can foster the selective growth of pre-existing altered cells, thereby increasing the overall risk for cancer development associated with aging.

Aging↗
PubMed2005

Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas.

Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.

Cell Transformation, Neoplastic↗
PubMed1999

A logical analysis of T cell activation and anergy.

Interaction of the antigen-specific receptor of T lymphocytes with its antigenic ligand can lead either to cell activation or to a state of profound unresponsiveness (anergy). Although subtle changes in the nature of the ligand or of the antigen-presenting cell have been shown to affect the outcome of T cell receptor ligation, the mechanism by which the same receptor can induce alternative cellular responses is not completely understood. A model for explaining both positive (cell proliferation and cytokine production) and negative (anergy induction) signaling of T lymphocytes is described herein. This model relies on the autophosphorylative properties of the tyrosine kinases associated with the T cell receptor. One of its basic assumptions is that the kinase activity of these receptor-associated enzymes remains above background level after ligand removal and is responsible for cellular unresponsiveness. Using a simple Boolean formalism, we show how the timing of the binding and intracellular signal-transduction events can affect the properties of receptor signaling and determine the type of cellular response. The present approach integrates into a common framework a large body of experimental observations and allows specification of conditions leading to cellular activation or to anergy.

Animals↗
PubMed2002

Neuropathology of genetically engineered mice: consensus report and recommendations from an international forum.

The Mouse Models of Cancer Consortium of the NCI sponsored a meeting of neuropathologists and veterinary pathologists in New York City in November of 2000. A rapidly growing number of genetically engineered mice (GEM) predisposed to tumors of the nervous system have led to a concomitant need for neuropathological evaluation and validation of these models. A panel of 13 pathologists reviewed material representing most of the available published and unpublished GEM models of medulloblastoma, primitive neuroectodermal tumor, astrocytoma, oligodendroglioma, mixed glioma, and tumors of the peripheral nerve. The GEM tumors were found to have many similarities and some distinct differences with respect to human disease. After review of the biology and pathology for all models presented, participants were split into groups reflective of clinical expertise in human pathology, tumor biology, neuroimaging, or treatment/intervention. Recommendations were made detailing an extensive and complete neuropathological characterization of animals. Importance was placed on including information on strains, tumor clonality, and examination for genetic mutation or altered gene expression characteristics of the corresponding human malignancy. Specific proposals were made to incorporate GEM models in emerging neuroradiological modalities. Recommendations were also made for preclinical validation of these models in cancer therapeutics, and for incorporation of surrogate markers of tumor burden to facilitate preclinical evaluation of new therapies.

Animals↗
PubMed1991

Cytogenetic evidence of clonality in a case of pigmented villonodular synovitis.

Pigmented villonodular synovitis is an uncommon benign lesion that is characterized by diffuse synovial proliferation. Based on animal models, this lesion has been conjectured previously to be reactive in nature. In this report, the authors present the histologic and cytogenetic findings for a pigmented villonodular synovitis that was excised from the right knee of a 47-year-old man. Trisomy 7 was observed in 24 of 75 (35%) metaphases obtained from short-term culture of cells from this tumor. These findings suggest that some cases of pigmented villonodular synovitis represent clonal, neoplastic proliferations.

Chromosomes, Human, Pair 7↗