Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-... more Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-lysosomal accumulation of immunoglobulin (Ig) as crystals, reported in patients with plasmacytic/ lymphoplasmacytic neoplasms. We report the clinicopathologic features of 13 patients with CSH and describe the proteomic composition of the crystals in 3 cases analyzed by mass spectrometry (MS). There were 7 men and 6 women with a median age of 60 years (range, 33-79). CSH was generalized in 1 (8%) and localized in 12 (92%) patients involving various sites. CSH was associated with a low-grade B-cell lymphoma with plasmacytoid differentiation or a plasma cell neoplasm in all cases. In 10 (77%) cases, CSH represented more than 50% of the neoplastic infiltrate. By immunohistochemical studies, histiocytes were positive for monotypic kappa in 5 (50%), lambda in 4 (40%) cases; in 1 (10%) case, results were equivocal. MS analysis of the histiocyte contents in all 3 tested cases showed predominance of variable-region fragments of Ig light and/or heavy chains. CSH is frequently associated with an underlying lymphoplasmacytic neoplasm. MS findings suggest that Ig alterations and/ or possibly defects in the ability of histiocytes to process Ig play a role in pathogenesis. This article is protected by copyright. All rights reserved.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 26, 2015
Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study f... more Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-κB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-κB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-κB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free surviv...
Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a mole... more Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are ≤50 years of age and compared this patient group to patients who are >50 years. In patients who are ≤50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG≥2). Comparing EBV+ DLBCL patients in ≤50 years ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 23, 2015
Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on ... more Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis o...
CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBC... more CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5+ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5+ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell-like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5- DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression aboli...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014
Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, inva... more Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited. We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations. pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified accordi...
Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemi... more Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 s...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 6, 2015
Follicular lymphoma is a low-grade B-cell lymphoma of germinal center B-cell origin that typicall... more Follicular lymphoma is a low-grade B-cell lymphoma of germinal center B-cell origin that typically lacks CD5 expression. We describe the clinicopathologic features of 88 cases of CD5+ follicular lymphoma (53 men, 35 women; median age, 60 years; range, 31-86). Follicular lymphoma was diagnosed initially in lymph nodes in 66 and extranodal sites in 22 patients. Eighty-one patients had lymphadenopathy, 66 had more than one involved site, 46 had bone marrow involvement, and 7 had splenomegaly. Staging information was available for 84 patients: 52 stage IV, 18 stage III, 12 stage II, and 2 stage I. Sixty-one cases were grade 1 or 2 and 27 were grade 3. The median proliferation index (Ki-67) was 30%. CD5 expression was detected by flow cytometry in 69, immunohistochemistry in 8, and both methods in 11 cases. The presence of t(14;18)(q32;q21)/IGH-BCL2 or other BCL2 translocation was detected in 28/44 (64%) cases. A total of 38 (43%) patients also had diffuse large B-cell lymphoma, concurre...
The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress... more The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress has been made to discern the importance of p53 in coordinating cellular responses to DNA damage, oncogene activation, and other stresses. Noncoding RNAs are RNA molecules functioning without being translated into proteins. In this work, we discuss the dichotomy of p53 regulation by noncoding RNAs with four unconventional questions. First, is overexpression of microRNAs responsible for p53 inactivation in the absence of p53 mutation? Second, are there somatic mutations in the noncoding regions of the p53 gene? Third, is there a germline mutant in the noncoding regions of the p53 gene that predisposes carriers to cancer? Fourth, can p53 activation mediated by a noncoding RNA mutation cause cancer? This work highlights the prominence of noncoding RNAs in p53 dysregulation and tumorigenesis.
Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficien... more Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficiency that may influence the capacity of T cells to extract an efficient antitumor immune response. It has been confirmed that the B7-CD28 pathway may promote tumor immune evasion by providing a negative regulatory signal. The current study analyzed the expression of programmed death 1 (PD-1)/programmed death ligand (PD-L) in ENKL cell lines and tissues. The functional studies were performed to analyze the functional activity of PD-L1 interacting with effective T cells in ENKL. PD-L1 and PD-L2 mRNA levels in ENKL cell lines were markedly upregulated compared with those in normal natural killer cells. The proteins constitutively expressed in the 30 ENKL specimens were significantly higher than in the 20 rhinitis specimens. In addition, PD-L1 and PD-L2 expression were found to closely correlate with certain clinical histopathological parameters. Furthermore, the count of PD-1(+) tumor-infiltr...
Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections t... more Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.
Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal ... more Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis.
Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediat... more Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation. LIF is overexpressed in a large percentage of CRCs. LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured CRC cells and colorectal xenograft tumours in a largely p53-dependent manner. Overexpression of LIF is associated with a poor prognosis in CRC patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which pr...
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. ... more Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recen...
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) ... more Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells; their distinction is critical as MCL is a more aggressive neoplasm. Rarely, cases of composite MCL and CLL/SLL have been reported. Little is known about the nature of these cases and, in particular, the clonal relationship of the 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the ☆ SH is an honorable pathology scholar supported Human Pathology (2013) 44, 110-121 following growth patterns: in situ (n = 1), mantle zone (n = 3), nodular and diffuse (n = 3), diffuse (n = 3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n = 1); 6 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (n = 9) or diffuse (n = 2). All MCL were CD5 + and cyclin D1 + with t(11;14) translocation. All CLL/SLL were CD5 + , CD23 + and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell.
In this study we used a next generation sequencing-based approach to profile gene mutations in th... more In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de nov...
Using the partially completed Submillimeter Array with five antennas, we have observed the CO J=2... more Using the partially completed Submillimeter Array with five antennas, we have observed the CO J=2-1 and 3-2 emission from the envelope surrounding the carbon star V Hya. The high-angular resolution (2 ′′ -4 ′′ ) maps show that V Hya is powering a bipolar molecular jet having an extreme velocity of 70-185 km s −1 . The axis of this high velocity jet is perpendicular to the major axis of the flattened disk-like envelope, which is expanding with a velocity of ∼16 km s −1 . There is a third kinematic component, a medium-velocity wind having a deprojected velocity of 40-120 km s −1 moving along the disk plane. Both the high velocity jet and the medium velocity wind have a dynamical time scale of a few hundred years. The flattened structure and the collimated jet observed in V Hya suggests that the formation of asymmetrical structure proceeds while the central star is still in the AGB phase.
may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and ... more may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD). #
The absolute inclusive semileptonic branching fraction of the D s meson has been measured based o... more The absolute inclusive semileptonic branching fraction of the D s meson has been measured based on 22.3 pb -1 of e + e - collision data collected with the Beijing Spectrometer at sqrt[s]=4.03 GeV. At this energy, the D s are produced in pairs: e + e - →D s + D s - . We ...
Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-... more Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intra-lysosomal accumulation of immunoglobulin (Ig) as crystals, reported in patients with plasmacytic/ lymphoplasmacytic neoplasms. We report the clinicopathologic features of 13 patients with CSH and describe the proteomic composition of the crystals in 3 cases analyzed by mass spectrometry (MS). There were 7 men and 6 women with a median age of 60 years (range, 33-79). CSH was generalized in 1 (8%) and localized in 12 (92%) patients involving various sites. CSH was associated with a low-grade B-cell lymphoma with plasmacytoid differentiation or a plasma cell neoplasm in all cases. In 10 (77%) cases, CSH represented more than 50% of the neoplastic infiltrate. By immunohistochemical studies, histiocytes were positive for monotypic kappa in 5 (50%), lambda in 4 (40%) cases; in 1 (10%) case, results were equivocal. MS analysis of the histiocyte contents in all 3 tested cases showed predominance of variable-region fragments of Ig light and/or heavy chains. CSH is frequently associated with an underlying lymphoplasmacytic neoplasm. MS findings suggest that Ig alterations and/ or possibly defects in the ability of histiocytes to process Ig play a role in pathogenesis. This article is protected by copyright. All rights reserved.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 26, 2015
Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study f... more Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-κB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-κB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-κB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free surviv...
Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a mole... more Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are ≤50 years of age and compared this patient group to patients who are >50 years. In patients who are ≤50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG≥2). Comparing EBV+ DLBCL patients in ≤50 years ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 23, 2015
Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on ... more Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis o...
CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBC... more CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5+ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5+ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell-like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5- DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression aboli...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014
Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, inva... more Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited. We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations. pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified accordi...
Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemi... more Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 s...
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jan 6, 2015
Follicular lymphoma is a low-grade B-cell lymphoma of germinal center B-cell origin that typicall... more Follicular lymphoma is a low-grade B-cell lymphoma of germinal center B-cell origin that typically lacks CD5 expression. We describe the clinicopathologic features of 88 cases of CD5+ follicular lymphoma (53 men, 35 women; median age, 60 years; range, 31-86). Follicular lymphoma was diagnosed initially in lymph nodes in 66 and extranodal sites in 22 patients. Eighty-one patients had lymphadenopathy, 66 had more than one involved site, 46 had bone marrow involvement, and 7 had splenomegaly. Staging information was available for 84 patients: 52 stage IV, 18 stage III, 12 stage II, and 2 stage I. Sixty-one cases were grade 1 or 2 and 27 were grade 3. The median proliferation index (Ki-67) was 30%. CD5 expression was detected by flow cytometry in 69, immunohistochemistry in 8, and both methods in 11 cases. The presence of t(14;18)(q32;q21)/IGH-BCL2 or other BCL2 translocation was detected in 28/44 (64%) cases. A total of 38 (43%) patients also had diffuse large B-cell lymphoma, concurre...
The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress... more The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress has been made to discern the importance of p53 in coordinating cellular responses to DNA damage, oncogene activation, and other stresses. Noncoding RNAs are RNA molecules functioning without being translated into proteins. In this work, we discuss the dichotomy of p53 regulation by noncoding RNAs with four unconventional questions. First, is overexpression of microRNAs responsible for p53 inactivation in the absence of p53 mutation? Second, are there somatic mutations in the noncoding regions of the p53 gene? Third, is there a germline mutant in the noncoding regions of the p53 gene that predisposes carriers to cancer? Fourth, can p53 activation mediated by a noncoding RNA mutation cause cancer? This work highlights the prominence of noncoding RNAs in p53 dysregulation and tumorigenesis.
Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficien... more Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficiency that may influence the capacity of T cells to extract an efficient antitumor immune response. It has been confirmed that the B7-CD28 pathway may promote tumor immune evasion by providing a negative regulatory signal. The current study analyzed the expression of programmed death 1 (PD-1)/programmed death ligand (PD-L) in ENKL cell lines and tissues. The functional studies were performed to analyze the functional activity of PD-L1 interacting with effective T cells in ENKL. PD-L1 and PD-L2 mRNA levels in ENKL cell lines were markedly upregulated compared with those in normal natural killer cells. The proteins constitutively expressed in the 30 ENKL specimens were significantly higher than in the 20 rhinitis specimens. In addition, PD-L1 and PD-L2 expression were found to closely correlate with certain clinical histopathological parameters. Furthermore, the count of PD-1(+) tumor-infiltr...
Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections t... more Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.
Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal ... more Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis.
Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediat... more Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation. LIF is overexpressed in a large percentage of CRCs. LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured CRC cells and colorectal xenograft tumours in a largely p53-dependent manner. Overexpression of LIF is associated with a poor prognosis in CRC patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which pr...
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. ... more Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recen...
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) ... more Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells; their distinction is critical as MCL is a more aggressive neoplasm. Rarely, cases of composite MCL and CLL/SLL have been reported. Little is known about the nature of these cases and, in particular, the clonal relationship of the 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the ☆ SH is an honorable pathology scholar supported Human Pathology (2013) 44, 110-121 following growth patterns: in situ (n = 1), mantle zone (n = 3), nodular and diffuse (n = 3), diffuse (n = 3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n = 1); 6 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (n = 9) or diffuse (n = 2). All MCL were CD5 + and cyclin D1 + with t(11;14) translocation. All CLL/SLL were CD5 + , CD23 + and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell.
In this study we used a next generation sequencing-based approach to profile gene mutations in th... more In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de nov...
Using the partially completed Submillimeter Array with five antennas, we have observed the CO J=2... more Using the partially completed Submillimeter Array with five antennas, we have observed the CO J=2-1 and 3-2 emission from the envelope surrounding the carbon star V Hya. The high-angular resolution (2 ′′ -4 ′′ ) maps show that V Hya is powering a bipolar molecular jet having an extreme velocity of 70-185 km s −1 . The axis of this high velocity jet is perpendicular to the major axis of the flattened disk-like envelope, which is expanding with a velocity of ∼16 km s −1 . There is a third kinematic component, a medium-velocity wind having a deprojected velocity of 40-120 km s −1 moving along the disk plane. Both the high velocity jet and the medium velocity wind have a dynamical time scale of a few hundred years. The flattened structure and the collimated jet observed in V Hya suggests that the formation of asymmetrical structure proceeds while the central star is still in the AGB phase.
may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and ... more may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD). #
The absolute inclusive semileptonic branching fraction of the D s meson has been measured based o... more The absolute inclusive semileptonic branching fraction of the D s meson has been measured based on 22.3 pb -1 of e + e - collision data collected with the Beijing Spectrometer at sqrt[s]=4.03 GeV. At this energy, the D s are produced in pairs: e + e - →D s + D s - . We ...
Uploads
Papers by Ken Young