Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)–induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11^+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL

Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study

PURPOSE: The differential diagnosis among the commonest peripheral T-cell lymphomas (PTCLs; ie, PTCL not otherwise specified [NOS], angioimmunoblastic T-cell lymphoma [AITL], and anaplastic large-cell lymphoma [ALCL]) is difficult, with the morphologic and phenotypic features largely overlapping. We performed a phase III diagnostic accuracy study to test the ability of gene expression profiles (GEPs; index test) to identify PTCL subtype. METHODS: We studied 244 PTCLs, including 158 PTCLs NOS, 63 AITLs, and 23 ALK-negative ALCLs. The GEP-based classification method was established on a support vector machine algorithm, and the reference standard was an expert pathologic diagnosis according to WHO classification. RESULTS: First, we identified molecular signatures (molecular classifier [MC]) discriminating either AITL and ALK-negative ALCL from PTCL NOS in a training set. Of note, the MC was developed in formalin-fixed paraffin-embedded (FFPE) samples and validated in both FFPE and frozen tissues. Second, we found that the overall accuracy of the MC was remarkable: 98% to 77% for AITL and 98% to 93% for ALK-negative ALCL in test and validation sets of patient cases, respectively. Furthermore, we found that the MC significantly improved the prognostic stratification of patients with PTCL. Particularly, it enhanced the distinction of ALK-negative ALCL from PTCL NOS, especially from some CD30+ PTCL NOS with uncertain morphology. Finally, MC discriminated some T-follicular helper (Tfh) PTCL NOS from AITL, providing further evidence that a group of PTCLs NOS shares a Tfh derivation with but is distinct from AITL. CONCLUSION: Our findings support the usage of an MC as additional tool in the diagnostic workup of nodal PTCL

An Activity–Rotation Relationship and Kinematic Analysis of Nearby Mid-to-Late-Type M Dwarfs

Using spectroscopic observations and photometric light curves of 238 nearby M dwarfs from the MEarth exoplanet transit survey, we examine the relationships between magnetic activity (quantified by Hα emission), rotation period, and stellar age. Previous attempts to investigate the relationship between magnetic activity and rotation in these stars were hampered by the limited number of M dwarfs with measured rotation periods (and the fact that v sin i measurements probe only rapid rotation). However, the photometric data from MEarth allows us to probe a wide range of rotation periods for hundreds of M dwarf stars (from shorter than one to longer than 100 days). Over all M spectral types that we probe, we find that the presence of magnetic activity is tied to rotation, including for late-type, fully convective M dwarfs. We also find evidence that the fraction of late-type M dwarfs that are active may be higher at longer rotation periods compared to their early-type counterparts, with several active, late-type, slowly rotating stars present in our sample. Additionally, we find that all M dwarfs with rotation periods shorter than 26 days (early-type; M1–M4) and 86 days (late-type; M5–M8) are magnetically active. This potential mismatch suggests that the physical mechanisms that connect stellar rotation to chromospheric heating may be different in fully convective stars. A kinematic analysis suggests that the magnetically active, rapidly rotating stars are consistent with a kinematically young population, while slow-rotators are less active or inactive and appear to belong to an older, dynamically heated stellar population

The dynamics of university units as a multi-level process. Credibility cycles and resource dependencies

This paper presents an analysis of resource acquisition and profile development of institutional units within universities. We conceptualize resource acquisition as a two level nested process, where units compete for external resources based on their credibility, but at the same time are granted faculty positions from the larger units (department) to which they belong. Our model implies that the growth of university units is constrained by the decisions of their parent department on the allocation of professorial positions, which represent the critical resource for most units’ activities. In our field of study this allocation is largely based on educational activities, and therefore, units with high scientific credibility are not necessarily able to grow, despite an increasing reliance on external funds. Our paper therefore sheds light on the implications that the dual funding system of European universities has for the development of units, while taking into account the interaction between institutional funding and third-party funding

Plan, execute, and discuss vibration measurements and correlations to evaluate a NASTRAN finite element model of the AH-64 helicopter airframe

A ground vibration test was performed on the AH-64 (Apache) helicopter to determine the frequency response of the airframe. The structure was excited at both the main and tail rotor hubs, separately, and response measurements were taken at 102 locations throughout the fuselage structure. Frequency responses were compared and correlated with results from a NASTRAN finite element model of AH-64. In addition, natural frequencies and mode shapes were estimated from the frequency response data and were correlated with analytical results

PRE-binding sites in the MDR of CLL: Potential Tumor Suppressor Regulation

Chronic lymphocytic leukemia [CLL] is the most common adult leukemia and is heterogeneous in clinical presentation. CLL cases present with various chromosomal aberrations, including 11q23, 14q32, 17p, and trisomy 12, with the most common abnormality being deletion of 13q14 [1]. Although monoallelic deletion of 13q14 is common, there is a subset of patients who have complete nullisomy at 13q14, a locus that has been hypothesized to contribute to CLL pa thogenesis [2] due to loss of tumor suppressors [DLEU and miR-15a/16-1].We hypothesized that deletion of both copies of 13q14 would lead to uncontrollable proliferation of CLL cells and a poor prognosis. We examined our 13q14 nullisomy for survival, treatment-free survival, lymphocyte doubling time, and the presence of lymphadenopathy. Furthermore, we compared the gene expression profiles between patients with 13q14 monosomy, nullisomy, or normal karyotype. Our results suggest that patients with 13q nullisomy have a higher incidence of bulky lymphadenopathy [16.6% compared to 10% of monosomy patients], a higher frequency of lymphocyte doubling time [27.7% compared to 7.4% of monosomy patients], and a higher rate of needing treatment [50% compared to 18.5% of monosomy patients]. We observed deletion of DLEU1 and HTR2A, consistent with a gene dosage effect, and observed PRE-binding sites on DLEU1. Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes. Lastly, the DLEU1 locus is a possible “second hit” loss for CLL progression

Agricultural Pesticide Use and Risk of t(14;18)-Defined Subtypes of Non-Hodgkin Lymphoma

Pesticides have been specifically associated with the t(14;18)(q32;q21) chromosomal translocation. To investigate whether the association between pesticides and risk of non-Hodgkin lymphoma (NHL) differs for molecular subtypes of NHL defined by t(14; 18) status, we obtained 175 tumor blocks from case subjects in a population-based case-control study conducted in Nebraska between 1983 and 1986. The t(14;18) was determined by interphase fluorescence in situ hybridization in 172 of 175 tumor blocks. We compared exposures to insecticides, herbicides, fungicides, and fumigants in 65 t(14;18)-positive and 107 t(14;18)-negative case subjects with those among 1432 control subjects. Multivariate polytomous logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared with farmers who never used pesticides, the risk of t(14;18)-positive NHL was significantly elevated among farmers who used animal insecticides (OR = 2.6; 95%CI, 1.0-6.9), crop insecticides (OR = 3.0; 95% CI, 1.1-8.2), herbicides (OR = 2.9; 95% CI, 1.1-7.9), and fumigants (OR = 5.0; 95% CI, 1.7-14.5). None of these pesticides were associated with t(14;18)-negative NHL. The risk of t(14;18)-positive NHL associated with insecticides and herbicides increased with longer duration of use. We conclude that insecticides, herbicides, and fumigants were associated with risk of t(14;18)-positive NHL but not t(14;18)-negative NHL. These results suggest that defining subsets of NHL according to t(14;18) status is a useful approach for etiologic research. (Blood. 2006; 108:1363-1369