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PubMed2006

Translesion synthesis in mammalian cells.

DNA damage blocks the progression of the replication fork. In order to circumvent the damaged bases, cells employ specialized low stringency DNA polymerases, which are able to carry out translesion synthesis (TLS) past different types of damage. The five polymerases used in TLS in human cells have different substrate specificities, enabling them to deal with many different types of damaged bases. PCNA plays a central role in recruiting the TLS polymerases and effecting the polymerase switch from replicative to TLS polymerase. When the fork is blocked PCNA gets ubiquitinated. This increases its affinity for the TLS polymerases, which all have novel ubiquitin-binding motifs, thereby facilitating their engagement at the stalled fork to effect TLS.

Animals↗

PubMed2002

Overview of tumor lysis syndrome.

OBJECTIVES: To provide a general overview of tumor lysis syndrome (TLS) focusing on the incidence, epidemiology, and patient outcomes associated with the syndrome; review the role of the oncology nurse in impacting patient outcomes and identify evolving issues relating to TLS. DATA SOURCES: Primary and tertiary literature related to TLS and clinical practice experience. CONCLUSIONS: Issues related to TLS continue to evolve and the oncology nurse plays a key role in patient management. As with other neoplastic disease-related complications (e.g., pain, nausea/vomiting), knowledge of TLS and attention and intervention, where appropriate, can positively impact patient outcome. IMPLICATIONS FOR NURSING PRACTICE: The oncology nurse plays a critical role in impacting patient outcomes with respect to TLS ranging from collaboration with other disciplines to identifying patients at risk, through assessments, vigilant monitoring, and implementing optimal treatment regimens.

Humans↗

PubMed1993

Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions.

A strong association exists between guttate psoriasis and group A, beta-haemolytic streptococcal infections. To demonstrate the presence of streptococcal-specific T cells in psoriatic skin, T-cell lines (TLs) were established from biopsies of lesions from five patients with guttate psoriasis, and compared with TLs from five patients with eczema, five with lichen planus, two with pityriasis rosea and three with nickel contact dermatitis. TLs from purified protein derivative (PPD)-induced delayed hypersensitivity sites in three normal individuals were also studied. All five of the psoriatic TLs responded in a proliferation assay to heat-killed isolates of group A streptococci, compared with only one eczema, two lichen planus and one pityriasis rosea. The response of one nickel contact dermatitis and two PPD TLs to group A streptococci was markedly less than to nickel and PPD, respectively. One of the psoriatic TLs was cloned in the presence of type 5 streptococcal M protein. The nine clones obtained were all CD3+, CD4+, CD45RO+, TCR alpha, beta+, gamma, delta-. However, they were all unreactive with antibodies to TCR V beta 5, 6, 8 or 12. Eight of the nine clones reacted, to a varying extent, to one or two of three preparations of group A streptococci expressing different M proteins. The streptococcal response of four consistently reactive clones from this patient was HLA-DR-restricted and inhibited by anti-HLA-DR antibody in a dose-dependent manner. On stimulation these four clones secreted high levels of gamma-interferon and detectable levels of IL-2, IL-10 and granulocyte/macrophage colony stimulating factor (GM-CSF) depending upon the nature of the stimulus, but no IL-4 or TNF-alpha production was detected. This study has demonstrated, for the first time, that T lymphocytes specific for group A streptococcal antigens can be consistently isolated from guttate psoriatic lesions. The role of streptococcal-specific T cells in the pathogenesis of psoriasis remains to be determined.

Antigens, Bacterial↗

PubMed1995

Complex partial seizures of temporal lobe origin in children of different age groups.

The semiology of complex partial seizures (CPS) of temporal lobe origin in adults is well known and is important in establishing seizure localization in patients considered for epilepsy surgery. In contrast, the behavioral features of temporal lobe seizures (TLS) in children described in the literature have not been consistent. In the present study, we investigated children with TLS to compare their attacks to TLS occurring in adults. The study was based on video recordings of 29 children with TLS aged 18 months to 16 years. Children were included, if they became seizure-free after temporal lobectomy (except 4 children with a marked reduction in seizure frequency and 1 with isolated auras), and if clear unitemporal seizure onset in ictal EEG-recordings, unilateral radiological lesions, and corresponding histopathological findings were detected. Children aged > 6 years had TLS with features similar to those of adults. In younger children, typical semiology included symmetric motor phenomena of the limbs, postures similar to frontal lobe seizures in adults, and head nodding as in infantile spasms. We concluded that the clinical features of TLS in younger children can be misleading and should therefore be considered with caution in selecting patients for surgical procedures on the temporal lobe.

Adolescent↗

PubMed1995

Association of SARFH (sarcoma-associated RNA-binding fly homolog) with regions of chromatin transcribed by RNA polymerase II.

Many oncogenes associated with human sarcomas are composed of a fusion between transcription factors and the N-terminal portions of two similar RNA-binding proteins, TLS and EWS. Though the oncogenic fusion proteins lack the RNA-binding domain and do not bind RNA, the contribution from the N-terminal portion of the RNA-binding protein is essential for their transforming activity. TLS and EWS associate in vivo with RNA polymerase II (Pol II) transcripts. To learn more about the target gene specificity of this interaction, the localization of a Drosophila melanogaster protein that has extensive sequence identity to the C-terminal RNA-binding portions of TLS and EWS was studied in preparations of Drosophila polytene nuclei. cDNA clones encoding the full-length Drosophila TLS-EWS homolog, SARFH (stands for sarcoma-associated RNA-binding fly homolog), were isolated. Functional similarity to TLS and EWS was revealed by the association of SARFH with Pol II transcripts in mammalian cells and by the ability of SARFH to elicit homologous down-regulation of the levels of the mammalian proteins. The SARFH gene is expressed in the developing Drosophila embryo from the earliest stages of cellularization and is subsequently found in many cell types. In preparations of polytene chromosomes from salivary gland nuclei, SARFH antibodies recognize their target associated with the majority of active transcription units, revealed by colocalization with the phosphorylated form of RNA Pol II. We conclude that SARFH and, by homology, EWS and TLS participate in a function common to the expression of most genes transcribed by RNA Pol II.

3T3 Cells↗

PubMed2026

Spatial habitat radiomics predicts tertiary lymphoid structure status and identifies an IDO1+ migratory dendritic cell axis in breast cancer.

BACKGROUND: Tertiary lymphoid structures (TLS) are spatially organized immune niches associated with therapeutic response and favorable outcomes in breast cancer (BC). However, TLS assessment currently relies on invasive tissue-based analyses, and the biological mechanisms underlying imaging-based TLS prediction remain poorly understood. METHODS: We developed and validated a spatial heterogeneity-based radiomic TLS signature (shTLS) using dynamic contrast-enhanced MRI to non-invasively predict TLS status across multicenter BC cohorts. Spatial habitat radiomics were used to capture intratumoral and peritumoral immune-related heterogeneity. Integrated multi-omics analyses, including transcriptomics, pathomics, genomics, single-cell RNA sequencing, immunohistochemistry, and multiplex immunofluorescence, were performed to biologically interpret shTLS-defined subgroups. Functional drug-sensitivity assays were conducted to assess therapeutic implications. RESULTS: The shTLS model achieved robust predictive performance across independent cohorts and molecular subtypes. High shTLS scores were associated with immune-inflamed tumors characterized by spatially clustered activated T cells and dendritic cells (DCs). In contrast, shTLS-low tumors exhibited an immunosuppressive spatial niche with peripheral accumulation of CD4+ PD-1+ T cells and plasma cells, increased immune-tumor separation, and enhanced inflammatory and immunoregulatory signaling. An indoleamine 2,3-dioxygenase 1 (IDO1)-associated immunoregulatory program was observed in the shTLS-low tumors, which appeared to be preferentially expressed by LAMP3+CCR7+ migratory DCs. Pharmacologic inhibition of IDO1 enhanced chemotherapy and CDK4/6 inhibitor sensitivity in vitro. CONCLUSION: This study establishes spatial radiomics as a non-invasive approach to decode TLS-associated immune ecosystems and supports the presence of an IDO1-associated immunosuppressive phenotype, providing biological insight and translational rationale for patient stratification and future combination strategies.

Humans↗

PubMed2025

Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Humans↗

PubMed2006

Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults.

Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

Adult↗

PubMed2006

Ex vivo expansion does not alter the capacity of umbilical cord blood CD34+ cells to generate functional T lymphocytes and dendritic cells.

We examined whether ex vivo expansion of umbilical cord blood progenitor cells affected their capacity to generate immune cells such as T lymphocytes (TLs) and dendritic cells (DCs). The capacity to generate TLs from cord blood CD34(+) cells expanded for 14 days (d14) was compared with that of nonexpanded CD34(+) cells (d0) using fetal thymus organ cultures or transfer into nonobese diabetic/severe combined immunodeficient mice. The cell preparations yielded comparable percentages of immature (CD4(+)CD8(-), CD4(+)CD8(+)) TLs and functional mature (CD3(+)CD4(+), CD3(+)CD8(+)) TLs with an analogous TCR (T-cell receptor)-Vbeta repertoire pattern. As regards DCs, d0 and d14 CD34(+) cells also yielded similar percentages of CD1a(+) DCs with the same expression levels of HLA-DR, costimulatory and adhesion molecules, and chemokine receptors. DCs derived from either d14 or d0 CD34(+) stimulated allogeneic TLs to the same extent, and the cytokine pattern production of these allogeneic TLs was similar with no shift toward a predominant Th1 or Th2 response. Even though the intrinsic capacity of d14 CD34(+) cells to generate DCs was 13-fold lower than that of d0 CD34(+) cells, this reduction was offset by the prior amplification of the CD34(+) cells, resulting in the overall production of 15-fold more DCs. These data indicate that ex vivo expansion of CD34(+) cells does not impair T lymphopoiesis nor DC differentiation capacity.

Animals↗

PubMed2006

Keeping mammalian mutation load in check: regulation of the activity of error-prone DNA polymerases by p53 and p21.

To overcome DNA lesions that block replication the cell employs translesion DNA synthesis (TLS) polymerases, a group of low fidelity DNA polymerases that have the capacity to bypass a wide range of DNA lesions. This TLS process is also termed error-prone repair, due to its inherent mutagenic nature. We have recently shown that the tumor suppressor p53 and the cell cycle inhibitor p21 are global regulators of TLS. When these proteins are missing or nonfunctional, TLS gets out of control: its extent increases to very high levels, and its fidelity decreases, causing an overall increase in mutation load. This may be explained by the loss of selectivity in the bypass of specific DNA lesions by their cognate specialized polymerases, such that lesion bypass continues to a maximum, regardless of the price paid in increased mutations. The p53 and p21 proteins are also required for efficient UV light-induced monoubiquitination of PCNA, which is consistent with a model in which this modification of PCNA is necessary but not sufficient for the normal activity of TLS. This regulation suggests that TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis.

Animals↗

PubMed2000

A tactile display for international space station (ISS) extravehicular activity (EVA).

BACKGROUND: A tactile display to increase an astronaut's situational awareness during an extravehicular activity (EVA) has been developed and ground tested. The Tactor Locator System (TLS) is a non-intrusive, intuitive display capable of conveying position and velocity information via a vibrotactile stimulus applied to the subject's neck and torso. In the Earth's 1 G environment, perception of position and velocity is determined by the body's individual sensory systems. Under normal sensory conditions, redundant information from these sensory systems provides humans with an accurate sense of their position and motion. However, altered environments, including exposure to weightlessness, can lead to conflicting visual and vestibular cues, resulting in decreased situational awareness. The TLS was designed to provide somatosensory cues to complement the visual system during EVA operations. METHODS: An EVA task was simulated on a computer graphics workstation with a display of the International Space Station (ISS) and a target astronaut at an unknown location. Subjects were required to move about the ISS and acquire the target astronaut using either an auditory cue at the outset, or the TLS. Subjects used a 6 degree of freedom input device to command translational and rotational motion. The TLS was configured to act as a position aid, providing target direction information to the subject through a localized stimulus. RESULTS: Results show that the TLS decreases reaction time (p = 0.001) and movement time (p = 0.001) for simulated subject (astronaut) motion around the ISS. CONCLUSION: The TLS is a useful aid in increasing an astronaut's situational awareness, and warrants further testing to explore other uses, tasks and configurations.

Aerospace Medicine↗

PubMed2002

The analysis of the risks for the development of tumour lysis syndrome in children.

BACKGROUND: Acute renal failure (ARF) during the course of cytostatic therapy is a serious complication. ARF can be isolated or became as component of tumour lysis syndrome (TLS). TLS comprises a number of metabolic abnormalities (hyperuricemia, hyperphosphatemia, hyperkalemia, azotemia and hypocalcemia) which are associated with lymphoproliferative malignancies following spontaneous or chemotherapy-induced cytolysis. There exist probably no clear prediction for the development of TLS that could enable early detection of manifestation of this severe condition. SUBJECTIVE: Conventional management with aggressive hydration, alkalization of the urine, administration of allopurinol, and the slow introduction of chemotherapy is often unable to prevent metabolic instability and ARF. Recent studies define a subgroup of patients at higher risk of renal failure during induction chemotherapy. ARF was encountered during initial therapy of patients with a lactate dehydrogenase (LDH) index greater than 3.3. METHODS AND MATERIAL: A retrospective analysis of 10 children (3 girls, 7 boys, average age 9.7 years) with LDII index greater than 3.3 has been done. All children were treated for lymphoproliferative malignancy with conventional preventive measures. RESULTS: Three children needed haemodialysis--2 boys had fully expressed TLS with ARF shortly after starting chemotherapy, in 1 boy the dialysis was indicated because of extreme hyperuricemia and high creatinine level presented before chemotherapy. We consider that LDH index is not specific criterium for prediction of TLS. In conclusion, our cases demonstrate the pathophysiologic spectrum of ARF in TLS between hyperuricemia and hyperphosphatemia. CONCLUSION: The LDH index, urine output, and hyperphosphatemia could be used to identify those paediatric patients who would benefit from the prospective use some of extracorporeal elimination methods. Further investigation of this techniques in a larger number of patients is warranted. (Tab. 5, Ref. 12.)

Acute Kidney Injury↗

PubMed1997

Enhancement of DNA synthetic activity of thymic lymphocytes by the culture supernatant of thymus epithelial cells stimulated by growth hormone.

The authors examined the effect of the culture supernatant of growth hormone (GH)-stimulated thymus epithelial cells (TECs) on DNA synthetic activity of thymic lymphocytes (TLs) and then examined TL proliferation-inducing factors released from the TECs. TEC line, IT-45R1 derived from Wistar strain rat, was used. It was revealed that the supernatant from TECs treated with GH enhanced significantly DNA synthetic activity of TLs and that the activity of the least dense subset of TLs, containing undifferentiated lymphoid cells and the most immature TLs, was significantly increased by the supernatant as compared with other subsets. Anti-insulin like growth factor-I (IGF-I) monoclonal antibody (MAb) binding specifically to C region of IGF-I molecule was added to the culture supernatant from the GH-treated TECs, and then the supernatant was treated with ultrafiltration (MW cutting off; more than 50 kDa). When TLs were incubated with the ultrafiltered supernatant, the enhancement of TL proliferation induced by the supernatant of GH-treated TECs was significantly suppressed. However, the suppression did not descend to the level of TL-proliferative response observed in the supernatant of GH non-stimulated TECs. These results suggested that IGF-I released into the supernatant from GH-stimulated TECs enhances markedly the DNA synthetic activity of TLs and that the TL-proliferation-inducing factors (PIFs) other than IGF-I possibly exist in the supernatant of GH-stimulated TECs.

Animals↗

PubMed1998

Synergistic effect of flunarizine and sodium valproate on seizure thresholds elicited by cortical stimulation in conscious rats.

The effect of flunarizine (FLU) and sodium valproate (SV) alone and in combination were examined for their effects on seizure thresholds elicited by cortical stimulation in conscious rats. Two different pharmacodynamic parameters could be distinguished viz, the threshold for localised seizures (TLS) defined as the current (mu A) required to elicit forelimb clonus and the threshold for generalised seizure (TGS), defined as the current (mu A) required to elicit vigorous clonic activity without a tonic component. In preliminary neuro-behavioral studies on rats, the most favourable combination was FLU 10 mg/kg i.p. and SV 200 mg/kg i.p., which produced anticonvulsant efficacy with minimal neurotoxicity. With FLU alone, SV alone and the combination of FLU and SV, the mean % change +/- SEM from baseline values over a period of 6 h were for TLS: 3.8 +/- 0.8, 23.9 +/- 3.7, and 29.8 +/- 2.1; and for TGS 5.5 +/- 0.7, 15.6 +/- 2.7 and 190.9 +/- 22.7 respectively, indicating that FLU alone had no effect on TLS or TGS, SV significantly elevated TLS but had no effect on TGS and the combination of FLU plus SV produced a synergistic elevation of both TLS and TGS-the intensity of effect being more on TGS than on TLS. This model provides a new dimension to the profiling of two anticonvulsant agents with different mechanisms of anticonvulsant activity and offers predictive criteria for protective effects on clinical manifestations of partial or generalised tonic clonic seizure.

Animals↗

PubMed1998

Anticonvulsant drug effects in the direct cortical ramp-stimulation model in rats: comparison with conventional seizure models.

A modified cortical ramp stimulation (CRS) model has been developed allowing repeated determinations of seizure threshold at short time intervals in individual rats without inducing postictal threshold increases. Anticonvulsant potency of the standard antiepileptic drugs carbamazepine, phenytoin, phenobarbital, valproate, diazepam and ethosuximide in the CRS model was compared with respective drug potencies in two more traditional seizure models with transcorneal stimulus application, i.e., the minimal electroshock seizure threshold (minEST) and the maximal electroshock seizure threshold (maxEST). In the CRS model, two different types of threshold were determined, the threshold for localized seizures (TLS) and the threshold for generalized seizures (TGS). When screw electrodes were implanted over the primary motor cortex, TLS was characterized by unilateral forelimb clonus, tonic abduction of contralateral forelimb, and head adversion. When ramp-shaped stimulation was continued above the TLS current, bilateral clonic forelimb seizures with loss of posture developed, which was defined as TGS. In contrast to TLS, TGS could not be repeatedly determined at short time intervals because of postictal threshold increase. TLS was dose-dependently increased by carbamazepine, phenobarbital, valproate and diazepam, although phenytoin showed a truncated dose-response, and ethosuximide was ineffective. In comparison to TLS, drug-induced increases in TGS were more marked. All drugs dose-dependently increased minEST and, except ethosuximide, maxEST. For comparison of drug potencies, doses increasing seizure thresholds by 20 or 50% were calculated from dose-response curves. Respective comparisons showed marked differences in drug potencies between models, indicating that the CRS method presents a model of another, more pharmacoresistant seizure type than seizure types induced in traditional models, such as transcorneal electroshock. Based on the location of electrodes in the frontal neocortex, the characteristic seizure pattern, and the low pharmacological sensitivity of the seizures to standard antiepileptics, the modified CRS model most likely represents a new model of localization-related seizures occurring in frontal lobe epilepsy and may thus be used in the search for novel drugs with higher efficacy against this difficult-to-treat type of epilepsy.

Animals↗

PubMed1996

Use of thin-layer preparations for gynecologic smears with emphasis on the cytomorphology of high-grade intraepithelial lesions and carcinomas.

Thin-layer (TL) technology can improve the detection rate for squamous lesions of the uterine cervix. Studies to date have under-represented high grade lesions and malignancies. The present study utilized a patient population at high risk for such lesions in order to analyze the performance of TL procedures in this group, and in addition, to assess the similarities and differences in morphologic appearances of specimens prepared by the two methods. Conventional (CS) and thin-layer smears (TLS) were made in parallel from the same specimen. Each slide was examined in a blinded fashion. Diagnoses were compared and morphologic observations made. Two hundred fifty-nine cases were included, of which 32 (12%) were high grade dysplasias (11) or carcinomas (21). Thirty five (14%) were atypical or low grade dysplasias. There was exact correlation between Bethesda classification in 231 cases (89%). Of the 21 carcinomas identified, 19 (91%) were present on each preparation. Two cases of endometrial adenocarcinoma were missed on unsatisfactory or negative TLS. One case of squamous cell carcinoma was called high grade squamous intraepithelial lesion (HGSIL) on TLS while the CS was unsatisfactory. Three cases called atypical glandular cells (AGCUS) on TLS, and negative on CS, showed HGSIL (1) or no lesion (2) on follow-up. Morphologic features of low grade lesions were virtually identical on both preparations. Distinct features were noted on TLS in the high grade lesions. These included smaller appearing nuclear areas, less distinct nuclear chromatin, thicker three-dimensional groupings, and more isolated cells. Such findings were most pronounced in the glandular lesions. With training and experience, these features were easily identified in TL preparations, further documenting the utility of this procedure for use in routine practice.

Carcinoma, Squamous Cell↗

PubMed2004

TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is characterized by recurrent chromosomal translocations resulting in fusions of the nuclear receptor gene NOR1 (also known as CHN or TEC) to various N-terminal partners, including EWS and TAF2N (or RBP56). Significant structural homology of EWS or TAF2N to TLS (or FUS) prompted us to investigate a potential novel gene fusion of NOR1 to TLS in EMCs without detectable known NOR1 fusions. In one of the EMCs examined, our reverse-transcription polymerase chain reaction using NOR1 and TLS primers unexpectedly amplified a cDNA sequence derived not from a TLS/NOR1 fusion but from a TFG/NOR1 fusion, a hitherto undescribed fusion type in EMC, probably a result of incidental misannealing by the TLS primer, which has a sequence partially identical to TFG. Encoding a protein with a putative coiled-coil structure, TFG previously was identified by a homology search in the Expressed Sequence Tag Database as having an SPYGQ-rich region similar to the N-terminal parts of EWS and TLS. TFG/NOR1 fusion appears to play an oncogenic role equivalent to those of other NOR1 fusions in EMC.

Amino Acid Sequence↗

PubMed1977

Effect of BNU treatment on leukaemogenesis in lethally irradiated AKR mice restored with bone-marrow and spleen cells.

The leukaemogenic effect of N-butyl-N-nitrosourea (BNU) was studied in normal and thymectomized AKR mice which were lethally irradiated and restored with either bone-marrow (BM) or spleen cells from (AKR X AKR/T1ALD)F1 donors. In some instances T1ALD thymic cells were added to the restorative inoculum. It was possible to determine the origin of the leukemic cells by the metacentric marker chromosomes of T1ALD. The T- or B-cell characteristics were further ascertained by the cytotoxicity test for theta antigen and the EAC rosette test. All leukaemias whether thymic (TLS) or extra-thymic (ETL), developed from donor bone-marrow or spleen cells and never from the injected thymic cells. In non-thymectomized animals BNU increased the percentage of TLS and shortened their latency. Most of TLS which occurred after BNU treatment of BM-restored mice were theta-negative whereas the majority of TLS which occurred in controls and in spleen-restored animals were theta-positive. This suggests that during their maturation process BM-derived T precursors transit through a theta-negative compartment. This compartment does not reach a similar size during the maturation process of the spleen-derived precursors. Adding thymic cells to the restorative inoculum enhanced leukaemogenesis and suppressed theta-negative TLS in BM-restored mice. Thymectomized mice, restored either by BM or spleen, had a low incidence of ETL which was not significantly increased by BNU treatment except in the case of mice restored with spleen cells. The leukaemic cells of one ETL were theta-positive whereas all the other leukaemias had no detectable T or B marker. The percentage of ETL was higher in thymectomized mice treated with BNU alone than in those previously subjected to irradiation and restoration. These results strongly suggest that a theta-negative T precursor could be involved in extra-thymic leukaemogenesis but the possible involvement of a B precursor cannot be rule out unless experiments are carried out with specific markers of T- and B-cell sub-classes.

Animals↗