CD3-positive plasmablastic B-cell neoplasms: a diagnostic pitfall.

Rare B-cell neoplasms with plasmablastic differentiation may aberrantly express CD3 by immunohistochemical staining, which places a great challenge for diagnosis. We here studied 17 cases of CD3+ plasmablastic B-cell neoplasms, including 12 plasmablastic lymphomas and 5 plasmablastic plasma cell myelomas. All 17 cases occurred in the extranodal sites with a male predominance (13/17). Four cases were initially misinterpreted by outside institutions, among which three were diagnosed as 'peripheral T-cell lymphoma, not otherwise specified' and one was classified as 'poorly differentiated neuroendocrine carcinoma'. The plasmablastic cells were present in all 17 cases diffusely or in a subset of tumor cells. CD3 expression was mostly diffuse (12/17) and moderate to strong (11/16) with a cytoplasmic staining pattern (14/16). Other T-cell markers were nearly absent, including CD2 (0/10), CD4 (1/13), CD5 (0/14), CD7 (0/11), and CD8 (0/13). CD138 was positive in all 17 cases and CD79a was variably positive in 8 of 14 cases. Only one case had immunoreactivity to CD20 (1/17) and PAX5 (1/12). CD56 expression and EBV infection were detected in 8/15 and 6/17, respectively. No HHV8 infection was noted in all 11 cases tested. Most cases (11/13) revealed either kappa or lambda light chain restriction. Of the nine cases studied, six had clonal IGH rearrangements but no clonal TRG rearrangements. Our study further emphasizes that the accurate classification of CD3+ plasmablastic neoplasms requires thorough morphologic examination, incorporation of more B-cell and T-cell markers in addition to CD3 and CD20, frequent addition of CD138 staining, and utilization of necessary molecular and genetic studies.

Distinct GATA1 Point Mutations in Monozygotic Twins With Down Syndrome and Transient Abnormal Myelopoiesis From a Triplet Pregnancy: A Case Report and Review of Literature.

OBJECTIVES: Down syndrome (DS)-associated transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL) in monozygotic twins is exceedingly rare and has not been well characterized. METHODS: We describe a unique case of monozygotic twins with simultaneous TAM from a triplet pregnancy at 34 weeks' gestation. Previously reported cases of TAM and DS-AMKL in monozygotic twins have been reviewed to compare with our cases. The current concept of a sequential multistep process in leukemogenesis and disease evolution of TAM into DS-AMKL through the collaboration among trisomy 21, GATA1, and other gene mutations is also reviewed. RESULTS: Distinct GATA1 mutations are identified in our neonate twins with TAM from a triplet pregnancy, whereas precisely identical GATA1 mutations have been detected in all three monozygotic DS twins reported in the literature. CONCLUSIONS: Identical GATA1 mutations in cases of monozygotic twins are likely derived from twin-twin transmission. Distinct GATA1 mutations identified in our neonate twins with TAM provide unequivocal evidence of independent intra-utero GATA1 mutations, a completely different mechanism of development of TAM in monozygotic twins from previously reported cases. Interaction of trisomy 21 and GATA1 mutation produces TAM, but additional gene mutations are required for TAM to transform into DS-AMKL.

Oct2 and Bob1 are sensitive and specific markers in lineage determination of B cell lymphomas with no expression of conventional B cell markers.

AIMS: Rare cases of B cell lymphomas do not express conventional B cell markers (CD20, CD79a and PAX5), and these types of lymphomas include anaplastic lymphoma kinase (ALK)-positive large B cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma and the solid variant of primary effusion lymphoma, extracavitary human herpesvirus 8 (HHV8)-positive large B cell lymphoma. Establishing accurate diagnoses of these B cell lymphomas can be challenging, and often requires a large panel of immunohistochemical stains, molecular assays and cytogenetic studies. B cell-specific transcription factors, Oct2 and Bob1, have been shown to be expressed consistently in most, if not all, B cell lymphomas, and therefore we investigated the utility of Oct2 and Bob1 immunohistochemistry in lineage determination of the aforementioned B cell lymphomas. METHODS AND RESULTS: We selected 34 cases of previously diagnosed B cell lymphomas with no or weak expression of CD20, CD79a and PAX5. Oct2 and Bob1 were positive in 74% (25 of 34) and 85% (29 of 34) of the cases, respectively. When we combined the results of these two immunostains, 94% (32 of 34) cases expressed at least one of these two markers. We also included 51 control cases of non-B cell neoplasms, and none of them expressed either Oct2 or Bob1. CONCLUSIONS: Oct2 and Bob1 are very reliable in determining B cell lineage in the absence of expression of other pan-B cell markers, and it should provide great diagnostic benefit to include them both in a panel of immunohistochemistry to assess undifferentiated malignant neoplasms.

Development and Preliminary Validation of the Questionnaire (the First Edition) Based on TCM for Detecting Health Status in China.

Background. More and more people come to realize the importance of healthcare and early detecting of health status before becoming much more serious. Self-perceived health is an easy, economic, and effective indicator of health, which has been widely applied in measuring health. In this paper, the development and preliminary validation of the questionnaire (the First Edition) based on TCM theory were described and combined with Manual Mental Health Pattern for detecting health status in community of Tianjin, China. Methods. Questionnaire validity and reliability were evaluated in a small sample as a pilot study. Analyses included tests for reliability and internal consistency, exploratory factor analysis, and tests for discriminative ability and convergent validity. Results. Overall, 294 of 303 participants completed the questionnaire (97.3%). The questionnaire included 49 items. Cronbach's α was 0.83. Factor analysis established 10 distinct domains. The Pearson's rho correlation between the total scores and MHP (SCL) was statistically significant (r = 0.43, P < 0.001). t-test revealed significant differences (P < 0.05) in total scores between the healthy and unhealthy results distinguished by physical examination. Conclusions. Questionnaire reliability and validity were acceptable. Further work and larger sample would be warranted to refine items that measure the health status, to improve the reliability and discriminated validity of the questionnaire.

Relationship between Hyperuricemia and Haar-Like Features on Tongue Images.

OBJECTIVE: To investigate differences in tongue images of subjects with and without hyperuricemia. MATERIALS AND METHODS: This population-based case-control study was performed in 2012-2013. We collected data from 46 case subjects with hyperuricemia and 46 control subjects, including results of biochemical examinations and tongue images. Symmetrical Haar-like features based on integral images were extracted from tongue images. T-tests were performed to determine the ability of extracted features to distinguish between the case and control groups. We first selected features using the common criterion P < 0.05, then conducted further examination of feature characteristics and feature selection using means and standard deviations of distributions in the case and control groups. RESULTS: A total of 115,683 features were selected using the criterion P < 0.05. The maximum area under the receiver operating characteristic curve (AUC) of these features was 0.877. The sensitivity of the feature with the maximum AUC value was 0.800 and specificity was 0.826 when the Youden index was maximized. Features that performed well were concentrated in the tongue root region. CONCLUSIONS: Symmetrical Haar-like features enabled discrimination of subjects with and without hyperuricemia in our sample. The locations of these discriminative features were in agreement with the interpretation of tongue appearance in traditional Chinese and Western medicine.

The association between gene polymorphism of TCF7L2 and type 2 diabetes in Chinese Han population: a meta-analysis.

In recent years, it has been widely accepted that transcription factor 7-like 2 (TCF7L2) is associated with type 2 diabetes mellitus (T2DM) in multiple ethnic groups, especially its single nucleotide polymorphisms of rs7903146C/T, rs12255372G/T and rs290487T/C. However, the results previously obtained in Chinese Han population are often inconsistent. For clearing this issue, herein we performed meta-analysis based on the reports that can be found to assess the association. In the meta-analysis, Odds ratio (OR) and 95% confidence interval (95% CI) were calculated with random-effect model or fixed-effect model based on the heterogeneity analysis. The quality of included studies was evaluated by using the Newcastle-Ottawa Scale. The sensitivity analysis was used to confirm the reliability and stability of the meta-analysis. In total, 20 case-control studies with 9122 cases of T2DM and 8017 controls were included. Among these case-control studies, we selected 13 ones on rs7903146 C/T, 5 ones on rs12255372 G/T, 8 ones on rs290487 T/C. The results indicated that rs7903146C/T polymorphism was significantly associated with T2DM (T vs. C, OR = 1.73, 95% CI = 1.39-2.16). There was no evidence that rs12255372G/T and rs290487T/C polymorphisms increased T2DM risk (T vs. G, OR = 1.77, 95% CI = 0.88-3.56; C vs. T, OR = 1.08, 95% CI = 0.93-1.25). Subgroup analysis of different regions proved the relationship between rs7903146C/T polymorphism and T2DM risk in both the northern and the southern China. The association of rs290487 with T2DM was affected by body mass index, whereas the association of rs7903146 and rs290487 with T2DM was influenced neither by age nor by sex. In conclusion, this study indicated that the rs7903146C/T polymorphism of the TCF7L2 gene had a significant effect on T2DM risk in Chinese Han population, with rs12255372G/T and rs290487T/C polymorphisms showing no significant effect.

Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening.

BACKGROUND: A number of adhesion-mediated signaling pathways and cell-cycle events have been identified that regulate cell proliferation, yet studies to date have been unable to determine which of these pathways control mitogenesis in response to physiologically relevant changes in tissue elasticity. In this report, we use hydrogel-based substrata matched to biological tissue stiffness to investigate the effects of matrix elasticity on the cell cycle. RESULTS: We find that physiological tissue stiffness acts as a cell-cycle inhibitor in mammary epithelial cells and vascular smooth muscle cells; subcellular analysis in these cells, mouse embryonic fibroblasts, and osteoblasts shows that cell-cycle control by matrix stiffness is widely conserved. Remarkably, most mitogenic events previously documented as extracellular matrix (ECM)/integrin-dependent proceed normally when matrix stiffness is altered in the range that controls mitogenesis. These include ERK activity, immediate-early gene expression, and cdk inhibitor expression. In contrast, FAK-dependent Rac activation, Rac-dependent cyclin D1 gene induction, and cyclin D1-dependent Rb phosphorylation are strongly inhibited at physiological tissue stiffness and rescued when the matrix is stiffened in vitro. Importantly, the combined use of atomic force microscopy and fluorescence imaging in mice shows that comparable increases in tissue stiffness occur at sites of cell proliferation in vivo. CONCLUSIONS: Matrix remodeling associated with pathogenesis is in itself a positive regulator of the cell cycle through a highly selective effect on integrin-dependent signaling to FAK, Rac, and cyclin D1.

ABCG2 expression and side population abundance regulated by a transforming growth factor beta-directed epithelial-mesenchymal transition.

We describe here the regulation of ABCG2 expression and side population (SP) abundance in MCF7 human breast cancer cells. The level of ABCG2 mRNA and protein were increased in purified MCF7 SP relative to non-SP cells, and incubation with an ABCG2-specific inhibitor or ABCG2 short interfering RNA eliminated the MCF7 SP. The purified MCF7 SP could generate a heterogeneous population containing both SP and non-SP cells in culture. In vivo tumorigenicity experiments showed that the purified MCF7 SP has an increased ability to colonize the mouse mammary gland. Importantly, the MCF7 SP was depleted by a transforming growth factor-beta (TGFbeta)-directed epithelial-mesenchymal transition (EMT), and this effect was associated with a strong down-regulation of ABCG2 gene expression, and an increased sensitivity to mitoxantrone. ABCG2 expression and SP abundance were restored upon the removal of transforming growth factor-beta and reversion of the cells to an epithelial phenotype. Knock-down of E-cadherin also reduced SP abundance, but this effect was not accompanied by the loss of ABCG2 mRNA or protein. We conclude that ABCG2 expression in MCF7 cells is regulated during an EMT, and that the EMT effect reflects posttranslational regulation of ABCG2 function by E-cadherin as well as transcriptional repression of the ABCG2 gene.

Restoration of NK T cell development in fyn-mutant mice by a TCR reveals a requirement for Fyn during early NK T cell ontogeny.

NK T cells are a unique lymphocyte population that have developmental requirements distinct from conventional T cells. Mice lacking the tyrosine kinase Fyn have 5- to 10-fold fewer mature NK T cells. This study shows that Fyn-deficient mice have decreased numbers of NK1.1(-) NK T cell progenitors as well. 5-Bromo-2'-deoxyuridine-labeling studies indicate that the NK T cells remaining in fyn(-/-) mice exhibit a similar turnover rate as wild-type cells. The fyn(-/-) NK T cells respond to alpha-galactosylceramide, a ligand recognized by NK T cells, and produce cytokines, but have depressed proliferative capacity. Transgenic expression of the NK T cell-specific TCR alpha-chain Valpha14Jalpha18 leads to a complete restoration of NK T cell numbers in fyn(-/-) mice. Together, these results suggest that Fyn may have a role before alpha-chain rearrangement rather than for positive selection or the peripheral upkeep of cell number. NK T cells can activate other lymphoid lineages via cytokine secretion. These secondary responses are impaired in Fyn-deficient mice, but occur normally in fyn mutants expressing the Valpha14Jalpha18 transgene. Because this transgene restores NK T cell numbers, the lack of secondary lymphocyte activation in the fyn-mutant mice is due to the decreased numbers of NK T cells present in the mutant, rather than an intrinsic defect in the ability of the other fyn(-/-) lymphoid populations to respond.