{"text": "Although the bcr-abl translocation has been shown to be the causative genetic aberration in chronic myeloid leukemia (CML), there is mounting evidence that the deregulation of other genes, such as the transcription factor interferon regulatory factor 4 (IRF-4), is also implicated in the pathogenesis of CML.", "spans": [{"start": 13, "end": 16, "label": "GGP"}, {"start": 17, "end": 20, "label": "GGP"}, {"start": 222, "end": 252, "label": "GGP"}, {"start": 254, "end": 259, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "Recently, we described an impaired expression of the interferon regulatory factor 4 (IRF-4) in CML, correlating with poor response to IFN-alpha treatment (3).", "spans": [{"start": 53, "end": 83, "label": "GGP"}, {"start": 85, "end": 90, "label": "GGP"}, {"start": 134, "end": 143, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "Consistent with the restriction of expression to immunocompetent cells, mice with deletion of IRF-4 failed to develop mature and functionally active B- and T-lymphocytes (12), and the impaired expression of IRF-4 in CML was predominately found in T-cells (3).", "spans": [{"start": 94, "end": 99, "label": "GGP"}, {"start": 207, "end": 212, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "After sequencing of the IRF-4 promoter, it could be excluded that absence of IRF-4 expression in any of the above cell lines was due to genetic aberrations.", "spans": [{"start": 24, "end": 29, "label": "GGP"}, {"start": 77, "end": 82, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "It has been shown that NFkappaB elements play an important role in IRF-4 induction as IRF-4 expression depends on binding of the transactivator c-Rel to these elements in the IRF-4 promoter (31,37).", "spans": [{"start": 67, "end": 72, "label": "GGP"}, {"start": 86, "end": 91, "label": "GGP"}, {"start": 144, "end": 149, "label": "GGP"}, {"start": 175, "end": 180, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "The expression of another IRF, IFN consensus sequence binding protein (ICSBP/IRF-8), is impaired in myeloid leukemias especially CML (27,46,47).", "spans": [{"start": 31, "end": 69, "label": "GGP"}, {"start": 71, "end": 76, "label": "GGP"}, {"start": 77, "end": 82, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "In multiple myeloma (MM) a translocation on chromosome 14q was reported to lead to a fusion gene of immunoglobulin heavy-chain (IgH) and IRF-4 resulting in a subsequent overexpression of IRF-4 (48,49).", "spans": [{"start": 100, "end": 126, "label": "GGP"}, {"start": 128, "end": 131, "label": "GGP"}, {"start": 137, "end": 142, "label": "GGP"}, {"start": 187, "end": 192, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1310901"}}
{"text": "Deletion of the carboxyl-terminal forkhead (FKH) domain, critical for nuclear localization and DNA-binding activity, abrogated the ability of Foxp3 to suppress NF-kappaB activity in HEK 293T cells, but not in Jurkat or primary human CD4+ T cells.", "spans": [{"start": 142, "end": 147, "label": "GGP"}, {"start": 233, "end": 236, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "The first evidence to indicate how Foxp3 promotes the development and function of regulatory T cells came from a report by Ziegler and colleagues [16], which suggested that Foxp3 could inhibit transcriptional activation by physically interacting with forkhead binding sites located immediately adjacent to critical cis-acting NF-AT binding sites found in various cytokine promoters (e.g., IL-2 promoter).", "spans": [{"start": 35, "end": 40, "label": "GGP"}, {"start": 173, "end": 178, "label": "GGP"}, {"start": 389, "end": 393, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Extending these results from established, in vitro HEK cell lines to primary human lymphocytes, overexpression of Foxp3 in purified CD4+ T cells from three healthy donors also down-regulated the steady-state level of NF-kappaB activation (Figure 1D).", "spans": [{"start": 114, "end": 119, "label": "GGP"}, {"start": 132, "end": 135, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Although Foxp3 interaction with NF-kappaB presumably takes place in the nucleus, it may also be possible for a cytoplasmic Foxp3 protein to bind to NF-kappaB in the cytoplasm and prevent localization to the nucleus following an activation stimulus.", "spans": [{"start": 9, "end": 14, "label": "GGP"}, {"start": 123, "end": 128, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Overexpression of full-length Foxp3, but not of DeltaFKH, was able to suppress activation of a cotransfected NF-kappaB reporter vector in HEK 293T cells (Figure 2B).", "spans": [{"start": 30, "end": 35, "label": "GGP"}, {"start": 48, "end": 56, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Both Foxp3 and DeltaFKH were expressed at very high levels following transfection as detected by real-time RT-PCR (unpublished data).", "spans": [{"start": 5, "end": 10, "label": "GGP"}, {"start": 15, "end": 23, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Western blot analysis of NF-kappaB p65 expression demonstrated that Foxp3 and DeltaFKH does not block NF-kappaB activation at the level of p65 protein expression (Figure 2E).", "spans": [{"start": 35, "end": 38, "label": "GGP"}, {"start": 68, "end": 73, "label": "GGP"}, {"start": 78, "end": 86, "label": "GGP"}, {"start": 139, "end": 142, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "If Foxp3 functions as a repressor of NF-kappaB-dependent gene expression, then we hypothesized that Foxp3 overexpression could selectively down-regulate transcription from promoters previously shown to be responsive to NF-kappaB. To address this question, we examined the transcriptional activation of the HIV-1 LTR, which contains two tandem cis-acting NF-kappaB binding sites located between positions -102 and -81 with respect to the transcription initiation site [21].", "spans": [{"start": 3, "end": 8, "label": "GGP"}, {"start": 100, "end": 105, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "However, directly comparing the effect of Foxp3 overexpression on the activation of these two viral promoters demonstrated that Foxp3 was more capable of suppressing transcriptional activation of the HIV-1 LTR (Figure 3D) compared to the mutated HIV-1 LTR (Figure 3E).", "spans": [{"start": 42, "end": 47, "label": "GGP"}, {"start": 128, "end": 133, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Since the HTLV-I Tax protein can function at multiple levels in both the cytoplasm and the nucleus to stimulate activation of NF-kappaB [28,29], we hypothesized that overexpression of Foxp3 may interfere with this process.", "spans": [{"start": 17, "end": 20, "label": "GGP"}, {"start": 184, "end": 189, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "These observations further suggest that the carboxyl-terminal FKH domain is required for inhibiting activation of NF-kappaB in the presence of Tax in HEK 293T cells, strikingly similar to the requirements of Foxp3 inhibition of basal NF-kappaB activation shown in Figure 2B. Transactivation of the HTLV-I LTR was stimulated about 55-fold by overexpression of Tax (Figure 4B), while transfection of Foxp3 suppressed Tax-dependent HTLV-I LTR activation, although HTLV-I LTR activation in the presence or absence of Tax is independent of NF-kappaB or NF-AT (another transcriptional activator known to interact with Foxp3).", "spans": [{"start": 143, "end": 146, "label": "GGP"}, {"start": 208, "end": 213, "label": "GGP"}, {"start": 359, "end": 362, "label": "GGP"}, {"start": 398, "end": 403, "label": "GGP"}, {"start": 415, "end": 418, "label": "GGP"}, {"start": 513, "end": 516, "label": "GGP"}, {"start": 612, "end": 617, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Furthermore, overexpression of DeltaFKH also led to suppression of HTLV-I transactivation by Tax to a similar extent as full-length Foxp3 (Figure 4B).", "spans": [{"start": 31, "end": 39, "label": "GGP"}, {"start": 93, "end": 96, "label": "GGP"}, {"start": 132, "end": 137, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "The suppressive effects shown in Figure 4A and 4B were not the result of Foxp3 down-regulating the expression of the transfected Tax plasmid as determined by real-time RT-PCR (Figure 4C).", "spans": [{"start": 73, "end": 78, "label": "GGP"}, {"start": 129, "end": 132, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Transactivation of the Gal4-resposive promoter by Gal4-BD-Tax remained relatively unaffected by overexpression of either EGFP (control), Foxp3, or DeltaFKH, suggesting that Foxp3 does not repress Tax transactivation by directly interfacing with the HTLV-I Tax protein.", "spans": [{"start": 50, "end": 61, "label": "GGP"}, {"start": 137, "end": 142, "label": "GGP"}, {"start": 147, "end": 155, "label": "GGP"}, {"start": 173, "end": 178, "label": "GGP"}, {"start": 196, "end": 199, "label": "GGP"}, {"start": 256, "end": 259, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "As illustrated in Figure 5, the level of Tax mRNA synthesized from ACH was down-regulated in the presence of Foxp3 compared to the level produced in the presence of the control vector.", "spans": [{"start": 41, "end": 44, "label": "GGP"}, {"start": 109, "end": 114, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Although Foxp3 could down-regulate Tax-dependent transactivation of the HTLV-I LTR (Figure 4B) and inhibit Tax expression from an infectious molecular clone (Figure 5), Foxp3 failed to modulate Tax function in the absence of the viral promoter (Figure 4D).", "spans": [{"start": 9, "end": 14, "label": "GGP"}, {"start": 35, "end": 38, "label": "GGP"}, {"start": 107, "end": 110, "label": "GGP"}, {"start": 169, "end": 174, "label": "GGP"}, {"start": 194, "end": 197, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Deletion of the FKH domain of Foxp3 dampened the suppressive effect of Foxp3, but did not completely abrogate suppression, as is seen with NF-kappaB-responsive promoters in HEK 293T cells.", "spans": [{"start": 30, "end": 35, "label": "GGP"}, {"start": 71, "end": 76, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Stimulation of CREB-dependent transcription by reagents that activate adenylate cyclase and increase cAMP levels (e.g., forskolin) increase the transactivation potential of CREB through phosphorylation of serine 133 by protein kinase A, which permits binding and recruitment of coactivators CBP/p300 to the promoter [37,38].", "spans": [{"start": 291, "end": 294, "label": "GGP"}, {"start": 295, "end": 299, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "As expected, p300 overexpression stimulated transcription of the Gal4-BD-CREB-1 fusion protein.", "spans": [{"start": 13, "end": 17, "label": "GGP"}, {"start": 65, "end": 79, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Foxp3, again, repressed basal levels of Gal4-BD-CREB-1 activation by more than 2-fold, while effectively neutralizing Gal4-BD-CREB-1 activation in the presence of p300.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 40, "end": 54, "label": "GGP"}, {"start": 118, "end": 132, "label": "GGP"}, {"start": 163, "end": 167, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Overexpression of Foxp3 failed to reduce the detectable levels of CREB phosphorylation using a phosphospecific antibody for CREB-1 (unpublished data).", "spans": [{"start": 18, "end": 23, "label": "GGP"}, {"start": 124, "end": 130, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "However, when we attempted to determine whether Foxp3 could physically interact with the coactivator protein p300, we found that p300 immunoprecipitated Foxp3 when both proteins were overexpressed in HEK 293T cells (Figure 7D).", "spans": [{"start": 48, "end": 53, "label": "GGP"}, {"start": 109, "end": 113, "label": "GGP"}, {"start": 129, "end": 133, "label": "GGP"}, {"start": 153, "end": 158, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Because the pathogenesis of a number of retroviral-induced immunologic disorders such as HIV-1/AIDS and HTLV-I/HAM/TSP have been associated with dysregulation of Foxp3 expression [8,45], we also examined the role of Foxp3 in retroviral gene expression.", "spans": [{"start": 162, "end": 167, "label": "GGP"}, {"start": 216, "end": 221, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Binding of Tax enhances ATF/CREB dimerization and promotes assembly of Tax-ATF/CREB complexes onto specific sequences in the viral promoter known as Tax-responsive elements.", "spans": [{"start": 11, "end": 14, "label": "GGP"}, {"start": 71, "end": 74, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Transactivation of the NF-kappaB pathway by Tax was inhibited by overexpression of full-length Foxp3, but not DeltaFKH, as seen with basal activation of the HIV-1 LTR and a synthetic NF-kappaB reporter in HEK 293T cells.", "spans": [{"start": 44, "end": 47, "label": "GGP"}, {"start": 95, "end": 100, "label": "GGP"}, {"start": 110, "end": 118, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "Our data demonstrate that Foxp3 interferes with the latter of these two processes and that the recruitment of the coactivator protein p300, and resulting transcriptional activation are blocked by Foxp3.", "spans": [{"start": 26, "end": 31, "label": "GGP"}, {"start": 134, "end": 138, "label": "GGP"}, {"start": 196, "end": 201, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "This may be the result of the physical interaction we detected between Foxp3 and p300.", "spans": [{"start": 71, "end": 76, "label": "GGP"}, {"start": 81, "end": 85, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "However, observing that this inhibitory effect is not absolute, a low level of viral gene expression may persist in CD4+ T cells (in particular regulatory T cells, which are known reservoirs of HIV-1 and HTLV-I) and result in the accumulation of viral proteins that either stimulate NF-kappaB and/or CREB activation or directly inhibit Foxp3 expression or function.", "spans": [{"start": 116, "end": 119, "label": "GGP"}, {"start": 336, "end": 341, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-1447668"}}
{"text": "The lymphoma cells have deregulated cell cycle markers, and inhibitors of Akt, NFkappaB, and Stat3 block the enhanced viability of LMP1 transgenic lymphocytes and lymphoma cells in vitro.", "spans": [{"start": 74, "end": 77, "label": "GGP"}, {"start": 93, "end": 98, "label": "GGP"}, {"start": 131, "end": 135, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The lymphomas were also distinguished by constitutive activation of Stat3 and deregulation of the Rb cell cycle pathway.", "spans": [{"start": 68, "end": 73, "label": "GGP"}, {"start": 98, "end": 100, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "LMP1 was detectable in LMP1 transgenic B cells, but upon development of lymphoma, LMP1 expression was stronger in 5/7 lymphomas analyzed with concomitant appearance of degradation products (Figure 1A).", "spans": [{"start": 0, "end": 4, "label": "GGP"}, {"start": 23, "end": 27, "label": "GGP"}, {"start": 82, "end": 86, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "To determine whether the higher level of LMP1 detected was due to an expansion of malignant lymphocytes, expression of LMP1 in the spleen was further evaluated by immunohistochemical staining.", "spans": [{"start": 41, "end": 45, "label": "GGP"}, {"start": 119, "end": 123, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "LMP1 expression was heterogeneous with strong LMP1 staining interspersed amongst a background of cells staining weakly for LMP1.", "spans": [{"start": 0, "end": 4, "label": "GGP"}, {"start": 46, "end": 50, "label": "GGP"}, {"start": 123, "end": 127, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Upon development to lymphoma, LMP1 expression was more abundantly detected with multiple foci of intense LMP1 staining.", "spans": [{"start": 30, "end": 34, "label": "GGP"}, {"start": 105, "end": 109, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This demonstrates that the increased LMP1 detected by immunoblotting upon malignant progression reflects an increase in LMP1 expression and an accumulation of cells expressing high levels of LMP1.", "spans": [{"start": 37, "end": 41, "label": "GGP"}, {"start": 120, "end": 124, "label": "GGP"}, {"start": 191, "end": 195, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "In the MTS assay, as expected, splenocytes from wild-type mice did not survive even with the addition of IL4 due to a lack of CD40 ligation (Figure 3A).", "spans": [{"start": 105, "end": 108, "label": "GGP"}, {"start": 126, "end": 130, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "In contrast, LMP1 splenocytes had increased metabolism even in the absence of IL4, which was further enhanced upon addition of IL4.", "spans": [{"start": 13, "end": 17, "label": "GGP"}, {"start": 78, "end": 81, "label": "GGP"}, {"start": 127, "end": 130, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Wild-type and LMP1 transgenic lymphoma cells had high levels of MTS activity even in the absence of IL4 (Figure 3A).", "spans": [{"start": 14, "end": 18, "label": "GGP"}, {"start": 100, "end": 103, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Transcription of IL10, IL15, and IFNgamma were reproducibly detected in LMP1 transgenic lymphocytes and lymphoma cells and was higher than in the B cell lymphoma cell lines 967 and K46mu (Figure 5A).", "spans": [{"start": 17, "end": 21, "label": "GGP"}, {"start": 23, "end": 27, "label": "GGP"}, {"start": 33, "end": 41, "label": "GGP"}, {"start": 72, "end": 76, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "There was no significant difference in the expression of IL15 and IFNgamma between LMP1 transgenic lymphocytes and lymphoma cells, suggesting that upregulation of IL15 and IFNgamma is induced by LMP1 expression in healthy lymphocytes but is not a unique property of malignant lymphocytes.", "spans": [{"start": 57, "end": 61, "label": "GGP"}, {"start": 66, "end": 74, "label": "GGP"}, {"start": 83, "end": 87, "label": "GGP"}, {"start": 115, "end": 129, "label": "GGP"}, {"start": 163, "end": 167, "label": "GGP"}, {"start": 172, "end": 180, "label": "GGP"}, {"start": 195, "end": 199, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Strikingly, IL10, a B lymphocyte stimulatory cytokine, was increased 1.5- to 5-fold in the wild-type and LMP1 transgenic lymphoma cells compared to LMP1 transgenic lymphocytes (Figure 5A).", "spans": [{"start": 12, "end": 16, "label": "GGP"}, {"start": 105, "end": 109, "label": "GGP"}, {"start": 148, "end": 152, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "However, transformation and growth properties induced by EBV are associated with the upregulation of IL10 [35-38]; hence, the effects of IL10 upregulation on the growth properties of the lymphoma cells were further examined.", "spans": [{"start": 101, "end": 105, "label": "GGP"}, {"start": 137, "end": 141, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Immunoblot analysis indicated that LMP1 transgenic lymphocytes and wild-type and LMP1 transgenic lymphoma cells had corresponding increased levels of phosphorylated alpha and beta isoforms of activated Stat3, a target of the IL10 receptor (Figure 5B).", "spans": [{"start": 35, "end": 39, "label": "GGP"}, {"start": 81, "end": 85, "label": "GGP"}, {"start": 202, "end": 207, "label": "GGP"}, {"start": 225, "end": 229, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "However, when comparing the same lymphomas, there was no correlation between the levels of IL10 induction and the levels of Stat3 activation.", "spans": [{"start": 91, "end": 95, "label": "GGP"}, {"start": 124, "end": 129, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This suggests that the activation of Stat3 is not solely induced by IL10 or that Stat3 activation may be constitutive.", "spans": [{"start": 37, "end": 42, "label": "GGP"}, {"start": 68, "end": 72, "label": "GGP"}, {"start": 81, "end": 86, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Additionally, there was no correlation between the levels of LMP1 expression and the levels of IL10 induction (Figures 1A and 5A).", "spans": [{"start": 61, "end": 65, "label": "GGP"}, {"start": 95, "end": 99, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This indicates that the induction of IL10 is a general property associated with enhanced survival and may only be indirectly affected by LMP1.", "spans": [{"start": 37, "end": 41, "label": "GGP"}, {"start": 137, "end": 141, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Neutralizing antibodies to IL10 did not affect the survival of lymphoma cells as determined by the MTS assay (unpublished data), suggesting constitutive activation of Stat3.", "spans": [{"start": 27, "end": 31, "label": "GGP"}, {"start": 167, "end": 172, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This was confirmed by immunoblot analysis such that in the presence of anti-IL10 neutralizing antibodies, pStat3 levels remained activated in lymphoma cells isolated from wild-type and LMP1 transgenic lymphomas (Figure 5C).", "spans": [{"start": 76, "end": 80, "label": "GGP"}, {"start": 106, "end": 112, "label": "GGP"}, {"start": 185, "end": 189, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Exogenous addition of IL10 enhanced pStat3 activation above constitutive levels, indicating that lymphoma cells are responsive to IL10 treatment (Figure 5C).", "spans": [{"start": 22, "end": 26, "label": "GGP"}, {"start": 36, "end": 42, "label": "GGP"}, {"start": 130, "end": 134, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This means that although the lymphoma cells have constitutive Stat3 activation, it may be further enhanced by IL10 induction.", "spans": [{"start": 62, "end": 67, "label": "GGP"}, {"start": 110, "end": 114, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Nuclear translocation of pStat3 is a consequence of activation, and nuclear pStat3 was not detected by immunohistochemistry staining of spleen sections from control mice.", "spans": [{"start": 25, "end": 31, "label": "GGP"}, {"start": 76, "end": 82, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "LMP1 transformation of rodent fibroblasts requires activation of PI3K and Akt [5].", "spans": [{"start": 0, "end": 4, "label": "GGP"}, {"start": 74, "end": 77, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The Akt target glycogen synthase kinase 3 (GSK3) is inactivated by phosphorylation; however, increased phosphorylated GSK3 was not detected in the transgenic lymphocytes and was almost absent in the lymphoma samples (Figure 6A).", "spans": [{"start": 4, "end": 7, "label": "GGP"}, {"start": 15, "end": 41, "label": "GGP"}, {"start": 43, "end": 47, "label": "GGP"}, {"start": 118, "end": 122, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "This finding indicates that GSK3 is not a target of activated Akt in the LMP1 transgenic lymphocytes and lymphoma cells.", "spans": [{"start": 28, "end": 32, "label": "GGP"}, {"start": 62, "end": 65, "label": "GGP"}, {"start": 73, "end": 77, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Similarly, activation of Akt without phosphorylation of GSK3 has been previously shown in EBV-positive HD [40].", "spans": [{"start": 25, "end": 28, "label": "GGP"}, {"start": 56, "end": 60, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "In contrast, the wild-type lymphocytes lacked activated Akt but did have detectable phosphorylated GSK3.", "spans": [{"start": 56, "end": 59, "label": "GGP"}, {"start": 99, "end": 103, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Immunoblot analysis of splenic B cells did not consistently detect p-FoxO1 levels, a signal that targets FoxO1 for degradation.", "spans": [{"start": 69, "end": 74, "label": "GGP"}, {"start": 105, "end": 110, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Immunoblot analysis indicated that total FoxO1 levels were greatly decreased in wild-type and LMP1 transgenic lymphomas (Figure 6B), suggesting that inhibition of the Forkhead signaling pathway is an important target of Akt in lymphoma development.", "spans": [{"start": 41, "end": 46, "label": "GGP"}, {"start": 94, "end": 98, "label": "GGP"}, {"start": 220, "end": 223, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "LMP1 transgenic B cells had enhanced levels of pRb with concomitant stabilization of total Rb levels and Cdk2 compared to wild-type B lymphocytes (Figure 6C).", "spans": [{"start": 0, "end": 4, "label": "GGP"}, {"start": 47, "end": 50, "label": "GGP"}, {"start": 91, "end": 93, "label": "GGP"}, {"start": 105, "end": 109, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Progression to lymphoma in both wild-type and LMP1 transgenic lymphoma cells led to increased levels of Rb, correspondingly high levels of Cdk2, and decreased levels of p27 (Figure 6C).", "spans": [{"start": 46, "end": 50, "label": "GGP"}, {"start": 104, "end": 106, "label": "GGP"}, {"start": 139, "end": 143, "label": "GGP"}, {"start": 169, "end": 172, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Triciribine inhibits the activation of Akt and at 20 muM has been shown to induce growth arrest in cancer cells with aberrant Akt activity [46].", "spans": [{"start": 39, "end": 42, "label": "GGP"}, {"start": 126, "end": 129, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The effects of triciribine on cell growth of the transgenic lymphocytes and lymphomas were apparent as low as 1 muM, suggesting that activation of Akt is required for the survival and growth of LMP1 transgenic lymphocytes and lymphoma cells (Figure 7).", "spans": [{"start": 147, "end": 150, "label": "GGP"}, {"start": 194, "end": 198, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Treatment with triciribine effectively blocked phosphorylation of Akt, and phosphorylated Akt was no longer detected past 5 muM.", "spans": [{"start": 66, "end": 69, "label": "GGP"}, {"start": 90, "end": 93, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "I inhibits activation of Stat3 by suppressing the activation of its kinase JAK2.", "spans": [{"start": 25, "end": 30, "label": "GGP"}, {"start": 75, "end": 79, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "A second reported inhibitor of Stat3, AG490, had no effect on growth (Figure 7), but activation of Akt, Stat3, or levels of IkappaBalpha were also not affected (Figure 8).", "spans": [{"start": 31, "end": 36, "label": "GGP"}, {"start": 99, "end": 102, "label": "GGP"}, {"start": 104, "end": 109, "label": "GGP"}, {"start": 124, "end": 136, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The lymphomas were marked by the upregulation of IL10, constitutive activation of Stat3 signaling, and a requirement for activation of Akt, NFkappaB, and Stat3 pathways (Figures 5 and 7).", "spans": [{"start": 49, "end": 53, "label": "GGP"}, {"start": 82, "end": 87, "label": "GGP"}, {"start": 135, "end": 138, "label": "GGP"}, {"start": 154, "end": 159, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "In addition, LMP1 has been shown to stimulate IL10 expression in Burkitt lymphoma cell lines [61,62].", "spans": [{"start": 13, "end": 17, "label": "GGP"}, {"start": 46, "end": 50, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "We have previously shown that cRel is specifically activated in both wild-type and LMP1 transgenic lymphomas, suggesting that activation of cRel is associated with B cell transformation [27].", "spans": [{"start": 30, "end": 34, "label": "GGP"}, {"start": 83, "end": 87, "label": "GGP"}, {"start": 140, "end": 144, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The requirement for Akt activation was confirmed by the striking inhibition of lymphoma viability by triciribine, an Akt inhibitor.", "spans": [{"start": 20, "end": 23, "label": "GGP"}, {"start": 117, "end": 120, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "However, the activated pAkt did not lead to phosphorylation and inactivation of the downstream target GSK3 (Figure 6A).", "spans": [{"start": 23, "end": 27, "label": "GGP"}, {"start": 102, "end": 106, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Repression of the pro-apoptotic transcription factor FoxO1 in a PI3K-dependent manner can inhibit expression of bcl6, a transcription factor necessary for GC formation [49,70].", "spans": [{"start": 53, "end": 58, "label": "GGP"}, {"start": 112, "end": 116, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The constitutive signaling by LMP1 likely blocks GC formation through downregulation of bcl6.", "spans": [{"start": 30, "end": 34, "label": "GGP"}, {"start": 88, "end": 92, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Interestingly, clinical studies indicate that expression of LMP1 and bcl6 are mutually exclusive in non-HD and classical HD [72,73].", "spans": [{"start": 60, "end": 64, "label": "GGP"}, {"start": 69, "end": 73, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Although the activation of Akt and the lack of Fox01 in the lymphoma cells suggest that LMP1 affects bcl6 and GC formation through this pathway, regulation of other Forkhead targets involved in cell cycle progression, such as p27 and CyclinD2, likely contribute to malignant transformation.", "spans": [{"start": 27, "end": 30, "label": "GGP"}, {"start": 47, "end": 52, "label": "GGP"}, {"start": 88, "end": 92, "label": "GGP"}, {"start": 101, "end": 105, "label": "GGP"}, {"start": 226, "end": 229, "label": "GGP"}, {"start": 234, "end": 242, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Indeed, loss of FoxO1 expression in lymphoma cells correlated with a loss of p27 (Figure 6B and 6C).", "spans": [{"start": 16, "end": 21, "label": "GGP"}, {"start": 77, "end": 80, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "The malignant lymphocytes were distinguished by constitutively active Stat3 signaling, decreased p27, and activated Akt and NFkappaB pathways, properties that are associated with promoting the growth and survival of B lymphocytes.", "spans": [{"start": 70, "end": 75, "label": "GGP"}, {"start": 97, "end": 100, "label": "GGP"}, {"start": 116, "end": 119, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Immunohistochemistry detection of activated nuclear pStat3 in the spleens of WT and LMP1 transgenic mice.", "spans": [{"start": 52, "end": 58, "label": "GGP"}, {"start": 84, "end": 88, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "Immunoblot analysis for cell cycle proteins regulating the Rb pathway, probing for activated pRb, and total levels of Cdk2 and the Cdk inhibitor p27.", "spans": [{"start": 59, "end": 61, "label": "GGP"}, {"start": 93, "end": 96, "label": "GGP"}, {"start": 118, "end": 122, "label": "GGP"}, {"start": 145, "end": 148, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2065877"}}
{"text": "We show that effector CTL differentiation occurs in two sequential phases in vitro, characterized by early induction of T-bet and late induction of Eomesodermin (Eomes), T-box transcription factors that regulate the early and late phases of interferon (IFN) gamma expression, respectively.", "spans": [{"start": 120, "end": 125, "label": "GGP"}, {"start": 148, "end": 160, "label": "GGP"}, {"start": 162, "end": 167, "label": "GGP"}, {"start": 241, "end": 263, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "In uninfected mice, compound deletion of the Tbx21 (encoding T-bet) and eomesodermin genes is associated with a selective loss of CD8+ T cells with an IL-2Rbeta-high, memory phenotype (8).", "spans": [{"start": 45, "end": 50, "label": "GGP"}, {"start": 61, "end": 66, "label": "GGP"}, {"start": 72, "end": 84, "label": "GGP"}, {"start": 130, "end": 133, "label": "GGP"}, {"start": 151, "end": 160, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Although Runx3 is not expressed in naive CD4+ T cells, its expression is up-regulated during Th1 cell differentiation, and Runx3 influences Th1 cell differentiation and function through direct regulation of the Il4 and Ifng cytokine genes (15, 16).", "spans": [{"start": 9, "end": 14, "label": "GGP"}, {"start": 41, "end": 44, "label": "GGP"}, {"start": 123, "end": 128, "label": "GGP"}, {"start": 211, "end": 214, "label": "GGP"}, {"start": 219, "end": 223, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "T-bet is induced quickly upon TCR stimulation and is required for early programming of cytokine production (17), whereas Eomes is induced later during differentiation and sustains IFN-gamma expression.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 121, "end": 126, "label": "GGP"}, {"start": 180, "end": 189, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Runx3 is required for Eomes and perforin expression, and both Eomes and Runx3 bind at the Prf1 locus; in contrast, perforin expression is unaffected in T-bet-deficient cells.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 22, "end": 27, "label": "GGP"}, {"start": 32, "end": 40, "label": "GGP"}, {"start": 62, "end": 67, "label": "GGP"}, {"start": 72, "end": 77, "label": "GGP"}, {"start": 90, "end": 94, "label": "GGP"}, {"start": 115, "end": 123, "label": "GGP"}, {"start": 152, "end": 157, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "T cells lacking Runx3 show decreased expression of IFN-gamma and granzyme B, and Runx3 also binds the promoter regions of the Ifng and Gzmb genes.", "spans": [{"start": 16, "end": 21, "label": "GGP"}, {"start": 51, "end": 60, "label": "GGP"}, {"start": 65, "end": 75, "label": "GGP"}, {"start": 81, "end": 86, "label": "GGP"}, {"start": 126, "end": 130, "label": "GGP"}, {"start": 135, "end": 139, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "As expected, a small fraction of naive T cells expressed the cytokines IFN-gamma and TNF in response to stimulation, and this capacity increased significantly in differentiated cells (Fig.", "spans": [{"start": 71, "end": 80, "label": "GGP"}, {"start": 85, "end": 88, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "These results show that after a strong priming stimulus through TCRs and co-stimulatory receptors in vitro, granzyme B expression and the ability to produce effector cytokines are programmed early, whereas perforin expression and cytolytic function are induced later, during the phase of clonal expansion in IL-2.", "spans": [{"start": 108, "end": 118, "label": "GGP"}, {"start": 206, "end": 214, "label": "GGP"}, {"start": 308, "end": 312, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "T-bet is required early for IFN-gamma production, and our data suggested that Eomes might not function during this early period but rather might contribute later to the control of perforin expression.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 28, "end": 37, "label": "GGP"}, {"start": 78, "end": 83, "label": "GGP"}, {"start": 180, "end": 188, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "In contrast, T-bet-deficient T cells cultured for 6 d showed no defect in perforin mRNA expression (Fig. 2 B, compare lanes 1 and 4).", "spans": [{"start": 13, "end": 18, "label": "GGP"}, {"start": 74, "end": 82, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "As expected, Eo-VP16 also rescued the early defect in IFN-gamma production observed in T-bet-deficient CD8+ T cells (Fig.", "spans": [{"start": 13, "end": 20, "label": "GGP"}, {"start": 54, "end": 63, "label": "GGP"}, {"start": 87, "end": 92, "label": "GGP"}, {"start": 103, "end": 106, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "We previously reported that Th1 cell differentiation was regulated through a feed-forward loop in which T-bet is up-regulated early and induces Runx3, after which T-bet and Runx3 cooperate to induce IFN-gamma and silence IL-4, thus promoting stable differentiation toward the Th1 lineage (15, 22).", "spans": [{"start": 104, "end": 109, "label": "GGP"}, {"start": 144, "end": 149, "label": "GGP"}, {"start": 163, "end": 168, "label": "GGP"}, {"start": 173, "end": 178, "label": "GGP"}, {"start": 199, "end": 208, "label": "GGP"}, {"start": 221, "end": 225, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Because (a) Runx3 appeared necessary for Eomes induction (Fig.", "spans": [{"start": 12, "end": 17, "label": "GGP"}, {"start": 41, "end": 46, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "It represses Runx1 and has a positive role in the induction of Eomes, granzyme B, perforin, and IFN-gamma.", "spans": [{"start": 13, "end": 18, "label": "GGP"}, {"start": 63, "end": 68, "label": "GGP"}, {"start": 70, "end": 80, "label": "GGP"}, {"start": 82, "end": 90, "label": "GGP"}, {"start": 96, "end": 105, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "An unexpected finding was that the two T-box transcription factors, T-bet and Eomes, are up-regulated with very different kinetics in CD8+ T cells under our culture conditions and have nonredundant roles in the subsequent expression of key effector proteins (Fig. 4 C).", "spans": [{"start": 68, "end": 73, "label": "GGP"}, {"start": 78, "end": 83, "label": "GGP"}, {"start": 134, "end": 137, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Eomes, which is induced late and functions downstream of Runx3, may substitute for T-bet in promoting the acute expression of IFN-gamma in restimulated CTLs (8).", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 57, "end": 62, "label": "GGP"}, {"start": 83, "end": 88, "label": "GGP"}, {"start": 126, "end": 135, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Surprisingly, however, Eomes and T-bet appeared nonredundant in their ability to induce two other markers of CTL function, Prf1 and Gzmb (Fig.", "spans": [{"start": 23, "end": 28, "label": "GGP"}, {"start": 33, "end": 38, "label": "GGP"}, {"start": 123, "end": 127, "label": "GGP"}, {"start": 132, "end": 136, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Rather, T-bet and Eomes were involved in regulating granzyme B and perforin expression, respectively: up-regulation of T-bet and Eomes mRNA and protein closely preceded up-regulation of Gzmb and Prf1 mRNA and protein, respectively.", "spans": [{"start": 8, "end": 13, "label": "GGP"}, {"start": 18, "end": 23, "label": "GGP"}, {"start": 52, "end": 62, "label": "GGP"}, {"start": 67, "end": 75, "label": "GGP"}, {"start": 119, "end": 124, "label": "GGP"}, {"start": 129, "end": 134, "label": "GGP"}, {"start": 186, "end": 190, "label": "GGP"}, {"start": 195, "end": 199, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Collectively, our data are consistent with a transcriptional network in which preexisting Runx3 cooperates with the induced T-box factors T-bet and Eomes and IL-2Rbeta signals (unpublished data) to orchestrate CTL differentiation (Fig.", "spans": [{"start": 90, "end": 95, "label": "GGP"}, {"start": 138, "end": 143, "label": "GGP"}, {"start": 148, "end": 153, "label": "GGP"}, {"start": 158, "end": 167, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "T cells, preexisting Runx3 is required to induce the T-box transcription factor Eomes.", "spans": [{"start": 21, "end": 26, "label": "GGP"}, {"start": 80, "end": 85, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Regulation of perforin, granzyme B, and IFN-gamma expression by T-bet and Eomes in differentiating CTLs.", "spans": [{"start": 14, "end": 22, "label": "GGP"}, {"start": 24, "end": 34, "label": "GGP"}, {"start": 40, "end": 49, "label": "GGP"}, {"start": 64, "end": 69, "label": "GGP"}, {"start": 74, "end": 79, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Runx3 controls Eomes, perforin, granzyme B, and IFN-gamma expression in effector CTLs.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 15, "end": 20, "label": "GGP"}, {"start": 22, "end": 30, "label": "GGP"}, {"start": 32, "end": 42, "label": "GGP"}, {"start": 48, "end": 57, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Overexpression of Eomes-VP16 cannot be detected with the Eomes antibody, as the C-terminal epitope is within the region that has been replaced with the VP16 transactivation domain.", "spans": [{"start": 18, "end": 28, "label": "GGP"}, {"start": 57, "end": 62, "label": "GGP"}, {"start": 152, "end": 156, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "T-bet is induced by TCR signals and is essential for early IFN-gamma expression.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 59, "end": 68, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Runx3 is present in naive CD8+ T cells and represses Runx1 and induces Eomes, perforin, granzyme B, and IFN-gamma expression.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 26, "end": 29, "label": "GGP"}, {"start": 53, "end": 58, "label": "GGP"}, {"start": 71, "end": 76, "label": "GGP"}, {"start": 78, "end": 86, "label": "GGP"}, {"start": 88, "end": 98, "label": "GGP"}, {"start": 104, "end": 113, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Eomes may participate in sustaining late IFN-gamma expression, whereas Runx3 and Eomes (but not T-bet) may cooperate to activate perforin expression.", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 41, "end": 50, "label": "GGP"}, {"start": 71, "end": 76, "label": "GGP"}, {"start": 81, "end": 86, "label": "GGP"}, {"start": 96, "end": 101, "label": "GGP"}, {"start": 129, "end": 137, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2626671"}}
{"text": "Although Th1, Th2, and Th17 cells require the activation of distinct STATs for their differentiation, activation of ERK1 and ERK2 wasa common requirement for production of IL-10 by all Th cell subsets.", "spans": [{"start": 116, "end": 120, "label": "GGP"}, {"start": 125, "end": 129, "label": "GGP"}, {"start": 172, "end": 177, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Th2 cell development, with expression of IL-4, IL-5, and IL-13, requires IL-4, STAT6, and the transcription factor GATA binding protein (GATA)-3 (Glimcher and Murphy, 2000).", "spans": [{"start": 41, "end": 45, "label": "GGP"}, {"start": 47, "end": 51, "label": "GGP"}, {"start": 57, "end": 62, "label": "GGP"}, {"start": 73, "end": 77, "label": "GGP"}, {"start": 79, "end": 84, "label": "GGP"}, {"start": 115, "end": 144, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Furthermore, we showed that activation of ERK1 and ERK2 is a requirement for production of IL-10 by Th1, Th2, and Th17 cell subsets.", "spans": [{"start": 42, "end": 46, "label": "GGP"}, {"start": 51, "end": 55, "label": "GGP"}, {"start": 91, "end": 96, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Culture with high doses of antigen for 7 days gave rise to Th1 cells expressing IFN-gamma upon restimulation (Constant etal., 1995; Hosken etal., 1995), but not IL-10 (FigureS1A available online).", "spans": [{"start": 80, "end": 89, "label": "GGP"}, {"start": 161, "end": 166, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "To investigate whether the lack of IL-10 produced by Th1 cells resulted from inhibition of IL-10 production by DCs and high antigen dose or alternatively required IL-12, we cultured naive CD4+ Tcells with increasing doses of antigen presented by DC in the presence of IL-12.", "spans": [{"start": 35, "end": 40, "label": "GGP"}, {"start": 91, "end": 96, "label": "GGP"}, {"start": 163, "end": 168, "label": "GGP"}, {"start": 188, "end": 191, "label": "GGP"}, {"start": 268, "end": 273, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "At low doses of antigen, IL-12 abrogated the development of Th2 cells and induced IFN-gamma expression but only low levels of IL-10 expression, suggesting that IL-12 per se was not sufficient to induce significant IL-10 production in Th1 cells (Figure1A).", "spans": [{"start": 25, "end": 30, "label": "GGP"}, {"start": 82, "end": 91, "label": "GGP"}, {"start": 126, "end": 131, "label": "GGP"}, {"start": 160, "end": 165, "label": "GGP"}, {"start": 214, "end": 219, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Thus, the development of Th1 cells producing IL-10 required both IL-12 and high doses of antigen.", "spans": [{"start": 45, "end": 50, "label": "GGP"}, {"start": 65, "end": 70, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Th1 cells differentiated to produce large amounts of IL-10 and IFN-gamma and lost theircapacity to produce IL-2 (Figure1B).", "spans": [{"start": 53, "end": 58, "label": "GGP"}, {"start": 63, "end": 72, "label": "GGP"}, {"start": 107, "end": 111, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "In fact, neutralization of TGF-beta led to increased IL-10 production by both Tcell subsets (FigureS3).", "spans": [{"start": 27, "end": 35, "label": "GGP"}, {"start": 53, "end": 58, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "IL-10 Production by Th1 Cells Is Dependent on STAT4 but Not on STAT6, IFN-gamma, or IL-4 Signaling\nTo further elucidate the mechanisms required for the development of Th1 cells producing IL-10, we investigated the role of STAT4, one of the signaling pathways activated by IL-12 (Murphy etal., 2000).", "spans": [{"start": 0, "end": 5, "label": "GGP"}, {"start": 46, "end": 51, "label": "GGP"}, {"start": 63, "end": 68, "label": "GGP"}, {"start": 70, "end": 79, "label": "GGP"}, {"start": 84, "end": 88, "label": "GGP"}, {"start": 187, "end": 192, "label": "GGP"}, {"start": 222, "end": 227, "label": "GGP"}, {"start": 272, "end": 277, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "As expected, lack of STAT6 abrogated both IL-4 and IL-10 production by Tcells developed with IL-4 or with low antigen dose (Figures 2B and 2C).", "spans": [{"start": 21, "end": 26, "label": "GGP"}, {"start": 42, "end": 46, "label": "GGP"}, {"start": 51, "end": 56, "label": "GGP"}, {"start": 93, "end": 97, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "However, in the absence of STAT4 signaling, IL-10 and IL-4 production by Th2 cells was if anything increased (Figures 2B and 2C).", "spans": [{"start": 27, "end": 32, "label": "GGP"}, {"start": 44, "end": 49, "label": "GGP"}, {"start": 54, "end": 58, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "As observed in the absence of STAT6 (Figure2A), IL-4 deficiency had no effect on the development of Th1 cells producing IL-10 (Figure2E), but compromised the development of Th2 cells producing IL-10 (Figure2F).", "spans": [{"start": 30, "end": 35, "label": "GGP"}, {"start": 48, "end": 52, "label": "GGP"}, {"start": 120, "end": 125, "label": "GGP"}, {"start": 193, "end": 198, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "In vivo expression of both IL-10 and IFN-gamma was markedly reduced but not completely abrogated in the absence of STAT4 signaling (Figures 3B and 3C), suggesting the existence of compensatory mechanisms that were absent in the invitro system.", "spans": [{"start": 27, "end": 32, "label": "GGP"}, {"start": 37, "end": 46, "label": "GGP"}, {"start": 115, "end": 120, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Repeated high antigen dose stimulation in the absence of exogenously added IL-12 resulted in the production of IL-10 by Th1 cells, suggesting that repeated strong TCR triggering may overcome the need for IL-12 for IL-10 induction (Figures 4C and 4D).", "spans": [{"start": 75, "end": 80, "label": "GGP"}, {"start": 111, "end": 116, "label": "GGP"}, {"start": 204, "end": 209, "label": "GGP"}, {"start": 214, "end": 219, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Th1 cells induced in the first week to produce IL-10 by culture with high antigen doses and IL-12 lost their ability to express IL-10 when recultured with low doses of OVA, which could be compensated for, to some extent, by addition of IL-12 to the secondary cultures (Figure4F), again suggesting that antigen dose and IL-12 signals cooperate for the induction of IL-10.", "spans": [{"start": 47, "end": 52, "label": "GGP"}, {"start": 92, "end": 97, "label": "GGP"}, {"start": 128, "end": 133, "label": "GGP"}, {"start": 168, "end": 171, "label": "GGP"}, {"start": 236, "end": 241, "label": "GGP"}, {"start": 319, "end": 324, "label": "GGP"}, {"start": 364, "end": 369, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}
{"text": "Finally, DO11.10 CD4+ cells that were exposed to low doses of antigen and IL-12 during the primary differentiation phase produced high amounts of IFN-gamma but little IL-10, but they could be induced to produce IL-10 when both high antigen dose and IL-12 were present during the recall phase (FigureS4).", "spans": [{"start": 17, "end": 20, "label": "GGP"}, {"start": 74, "end": 79, "label": "GGP"}, {"start": 146, "end": 155, "label": "GGP"}, {"start": 167, "end": 172, "label": "GGP"}, {"start": 211, "end": 216, "label": "GGP"}, {"start": 249, "end": 254, "label": "GGP"}], "meta": {"source": "BioNLP 2011 Genia Shared Task, PMC-2791889"}}