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Supplementary Table 5 shows the results of NSD2-MASPEC in KMS11 cells.

Supplementary Table 2 shows 26 SE-associated genes commonly acquired in both t(4:14)-positive HMCLs and patient-derived MM sample.

Supplementary Table 1 shows the list of 4C primers applied in the Circular Chromosome Conformation Capture assay.

Supplementary Materials and Methods shows detailed descriptions of methodology or materials and methods used in this manuscript.

Supplementary Figures, including Figures S1-6, and each figure legends.

Supplementary Table 4 shows the sequences of SE fragments inserted into pGL3 vector

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma.Significance:A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets.

Supplementary Table 3 Uni- and multivariate Cox survival analysis using HJURP and NSD2 expression in myeloma dataset

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. Published version The work was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (to W.J. Chng), the NMRC Clinician Scientist Investigator award (to W.J. Chng), the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3–1-006 (to W.J. Chng), the National Natural Science Foundation of China (grant no. 82000212 to Y. Jia), Natural Science Foundation of Zhejiang Province (grant no. LQ21H160022 to Y. Jia), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant no. 2021RC003 to Y. Jia). Y. Jia also thanks the China Scholarship Council (grant no. 201706320167) for financial support to visit National University of Singapore.

Breast cancer remains the first cause of death in women worldwide even if the average 10-year survival rate is 83%. It remains difficult to accurately evaluate the risk of recurrence, and consequently the need of chemotherapy, in estrogen receptor (ER)-positive, HER2-negative early breast cancers, at the individual level, leading to overtreatment for some patients. In that context, multigene prognostic scores are proposed in combination with clinicopathological parameters, to guide adjuvant treatment decisions. In our study, patients diagnosed with ER-positive, Her2-negative breast cancer, analyzed with the 12-gene EndoPredictTM test are prospectively included in the national SiMosein registry. The decision for Endopredict testing is determined by an oncological tumor board in expert breast cancer centers. The test is locally performed (10 national laboratories, evaluated by a national quality control exchange program). Clinicopathological parameters are recorded and the treatment decision before and after the genomic test is requested. The aim of the study is to prospectively evaluate the real-life use of the EndopredictTM test and the impact of the recurrence risk on the adjuvant treatment decision. A total of 3153 patients were included between May 2016 and December 2018. Patients are 75.6% post-menopausal (median age: 57.55y) and are mostly diagnosed as invasive ductal carcinoma not otherwise specified (81.2%) with SBR grade 2 (74.02%) and positive Ki67 staining (>14%, 66.4%). Tumor sizes are pT1ab, pT1c or pT2 in respectively 12.1%, 54.7% and 31.4% of the cases. Lymph node involvement is negative (pN0) in 70.5% of the cases. However, 29.5% of cases are pN1-3 with 5.2% of pN1mi. All cases are ER-positive, HER2-negative early breast cancers and 74.8% are progesterone receptor (PR)-positive (PR>10%) and 76.43% of the cases are of luminal B-like subtype. The population evaluated in this prospective study is in accordance to the intermediate prognostic subpopulation of luminal breast cancers where genomic signatures could contribute to guide the adjuvant treatment decision. The risk of relapse at 10 years, as reflected by the EPclin score, is of 13.16% on average, with 55.18% of high risk (positive threshold 10%). Treatment decisions before and after the test were recorded for 599 patients. The decision remains unmodified after the test in 54.59% of the cases. Conversely, change in adjuvant treatment decision was made from hormone therapy (HT) to adjunction of chemotherapy (HT+CT) in 18.20% of the cases and from (HT+CT) to (HT) leading to chemotherapy withdrawn in 27.21%. Finally, the national SiMosein registry, evaluated the utility of the test. The use of EndopredictTM is mostly restricted to the intermediate prognostic subgroup of the early luminal breast subtype as requested by the French health authority (HAS). The test is routinely used in France and clinicians need mainly the test for treatment decision. The EPclin score leads to 45.41% of modification of treatment with a majority of avoidance of chemotherapy (59.93%). Citation Format: Jacqueline Lehmann-Che, Jennifer Wong, Lucie Tixier, Ludovic Lacroix, Magali Triki-Lacroix, Pierre-Jean Lamy, Agnes Garnier, Véronique Quillien, Florence Godey, Isabelle Soubeyran, Gaëtan MacGrogan, Laurent Arnould, Juliette Haudebourg, Anne Tallet, Linda Dainese, Caroline Hugonin, Frédérique Penault-Llorca. Simosein registry, the French national real-life prospective evaluation of the impact of Endopredict® (EPclin) on treatment decision in ER-positive, HER2-negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-25.

Introduction Breast-conserving surgery (BCS) with radiation therapy is the procedure of choice for early-stage breast cancer. Survival and locoregional recurrence is non-inferior to mastectomy, with superior cosmetic and psycho-social outcomes. Differing health systems have demonstrated a wide variation in the rate of BCS. Little is known about the rate of BCS and factors influencing its practice in middle resource countries. This study aims to examine the BCS rates in Malaysia and to identify factors influencing its uptake. Methodology This is a multi-centre, cross-sectional study involving the University of Malaya Medical Centre (UMMC), Queen Elizabeth II Hospital (QEH), and Tengku Ampuan Rahimah Hospital (TARH). Patients diagnosed with invasive breast cancer from January 2014 to December 2015 were included, excluding stromal cancers and lymphomas. Univariate and multivariate analyses identified factors influencing BCS. Results A total of 1005 patients were diagnosed with breast cancer in the allocated time frame. Excluding incomplete records and those who did not have surgery, 730 patients were analysed. Overall BCS rate was 32.9%. The BCS rate was highest at QEH (54.1%), followed by UMMC (29.5%), and TARH (17.4%). 16.9% had BCS after neoadjuvant therapy. Factors influencing BCS uptake included age, ethnic group, breast-surgeon led services, AJCC Stage, tumour size, HER-2 expression, and tumour grade. Conclusions The rate of BCS in Malaysia is low. A wide variation of rate exists among the studied hospitals. Younger age, earlier AJCC stage, and the presence of a Breast sub-specialist surgeon, would make it more likely that the patient has her breast conserved.

Knee joint-position sensitivity has been shown to decline with increasing age, with much of the research reported in the literature investigating this age effect in non-weight-bearing (NWB) conditions. However, little data is available in the more functional position of weight-bearing conditions. The objective of this study was to identify the influence of age on the accuracy and nature of knee joint-position sense (JPS) in both full weight-bearing (FWB) and partial weight-bearing (PWB) conditions and to determine the effect of lower-extremity dominance on knee JPS. Sixty healthy subjects from three age groups (young: 20-35 years old, middle-aged: 40-55 years, and older: 60-75 years) were assessed. Tests were conducted on both the right and left legs to examine the ability of subjects to correctly reproduce knee angles in an active criterion-active repositioning paradigm. Knee angles were measured in degrees using an electromagnetic tracking device, Polhemus 3Space Fastrak, that detected positions of sensors placed on the test limb. Errors in FWB knee joint repositioning did not increase with age, but significant age-related increases in knee joint-repositioning error were found in PWB. It was found that elderly subjects tended to overshoot the criterion angle more often than subjects from the young and middle-aged groups. Subjects in all three age groups performed better in FWB than in PWB. Differences between the stance-dominant (STD) and skill-dominant (SKD) legs did not reach significance. Results demonstrated that for, normal pain-free individuals, there is no age-related decline in knee JPS in FWB, although an age effect does exist in PWB. This outcome challenges the current view that a generalised decline in knee joint proprioception occurs with age. In addition, lower-limb dominance is not a factor in acuity of knee JPS.

The PHENIX [Photon Electron New Heavy Ion Experiment] Detector is one of two large detectors presently under construction for RHIC (Relativistic Heavy Ion Collider) located at Brookhaven National Laboratory. Its primary goal is to detect a new phase of matter; the quark-gluon plasma. In order to achieve this objective, the PHENIX Detector utilizes a complex magnet subsystem which is comprised of two large magnets identified as the Central Magnet and the Muon Magnet. Muon Identifier steel is also included as part of this package. The entire magnet subsystem stands over 10 meters tall and weighs in excess of 1900 tons. Magnet size alone provided many technical challenges throughout the design and fabrication of the project. In addition, interaction with foreign collaborators provided the authors with new areas to address and problems to solve. Russian collaborators would fabricate a large fraction of the steel required and Japanese collaborators would supply the first coil. This paper describes the overall design of the PHENIX magnet subsystem and discusses its present fabrication status.

MicroRNAs (miRNAs) are a class of small, noncoding RNAs (∼22–25 nt in length) that were originally discovered in Caenorhabditis elegans ([Lagos-Quintana et al., 2003][1]). Since this discovery, over ∼4500 miRNAs have been identified in worms, plants, vertebrates, and viruses ([Lagos-Quintana

Following spinal cord injury, spared axonal projections undergo spontaneous compensatory sprouting in an attempt to reinnervate synaptic targets that were deinnervated as a result of injury. However, compensatory sprouting is hindered by the expression of a myriad of inhibitory molecules throughout the adult central nervous system, including chondroitin sulfate proteoglycans (CSPGs) and myelin associated inhibitory proteins (MAIPs). In this study, we have identified a diketopiperazine designated DKP101516 that can overcome the inhibitory effects of MAIPs and CSPGs on neurite outgrowth and branching. In vivo analysis demonstrates that DKP101516 enhances the plasticity of various axonal populations following septuple dorsal rhizotomy by overcoming the inhibitory effects of CSPGs and MAIPs. Our results suggest that DKP101516 may encourage spinal cord repair by stimulating compensatory sprouting of intact axonal projections.

Following spinal cord injury, a variety of inhibitory molecules hinder the success of axon regeneration. The motile tip of the axon, the growth cone, shares a similar cytoskeletal array as a migrating cell, and in general the cytoskeleton is regulated by a conserved set of signaling pathways that act downstream of guidance cue and growth factor receptors. We exploit these similarities by using migrating cells as a model system to screen for extracts that promote axon outgrowth. The screen is a high-throughput wound-healing assay performed by a 96-pin tool Biogrid robot where positive candidates are identified as extracts that stimulate complete wound healing. Testing of positive candidates on chick DRG explants has lead to the identification of extracts that promote neurite outgrowth on permissive and inhibitory substrates. Extracts can be fractionated to purity, identifying novel compounds that promote neurite outgrowth on inhibitory substrates.

Summary This study aimed to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF) measurements in our laboratory for patients with node-negative breast cancer. Frozen tumors from axillary node-negative breast cancer patients (n = 50) treated at Westmead Hospital, NSW, between 1988 and 1991 were analysed by flow cytometry. The median duration of follow-up for all patients was 8.4 years. Forty-six specimens provided evaluable DNA histograms with 43% (n = 20) diploid and 56% (n = 26) aneuploid tumors identified. Comparisons of DNA ploidy status and SPF were made with traditional prognostic variables, which included age, menopausal status, tumor size, histologic grade and hormone receptor status. Our results showed that there was no significant difference in disease-free or overall survival between patients with diploid and aneuploid tumors. Histologic grade 3 tumors were more likely to be aneuploid and had higher SPF than grade 1 or 2 tumors. Patients with grade 3 tumors and a high SPF were four times more likely to relapse than the rest of the population. These results indicate that DNA flow cytometric analysis in our laboratory provides additional prognostic data that could be utilised alongside traditional clinical and histopathologic indicators for predicting outcome for patients.

The failure of axon regeneration after spinal cord injury is attributed in part to the upregulation of chondroitin sulfate proteoglycans (CSPGs) in the astroglial scar. CSPGs are a diverse class of complex macromolecules that consist of a protein core covalently attached to sulfated carbohydrate

Herpes Simplex Virus 1 (HSV1) is an oncolytic virus that is often engineered with viral gene manipulations to selectively destroy cancer cells through its lytic replication cycle. The engineered HSV1 features effective tumor cell killing and low toxicity in clinical applications, making it an ideal therapeutic option for gliomas and other cancers. However, there are many examples where HSV1 demonstrates poor killing efficacy in highly malignant rat glioblastoma multiforme (GBM) models as well as in clinical samples of high grade human GBM. Further vitro evidence revealed the problem may not be simply physical obstacles in the tumor mass, but rather the resistance of glioma cells themselves to HSV1 infection. A good example is the stem-like BTUC (BTUCsph) rat glioma cell line, which we find to be completely resistant to HSV1 entry. Unlike other glioma cell lines, the BTUCsph cells are derived from an aggressive rat GBM model that strongly mimics the histological features of a malignant and highly infiltrative form of human GBM known as gliosarcoma. BTUCsph shares many features with brain tumor initiating cells including: 1) the expression of neural stem cell markers such as CD133 and nestin; 2) their ability to grow as self-renewing spheres; and 3) their remarkable tumor initiating abilities, where as few as 100 cells are sufficient to generate a tumor in vivo. Further molecular characterization of the BTUCsph cell line revealed that it expresses very low levels of the MEOX2, a tumor suppressor that not only inhibits cell proliferation, but also suppresses epithelial-mesenchymal transition (EMT) - a hallmark of malignant progression in GBMs. Interestingly, we find that many HSV1-permissive glioma cell lines (U87, SF188, 9L) express significantly higher MEOX2 compared to the HSV1-resistant BTUCsph cell line. Hypothesis and Rationale: Based on our characterization of BTUCsph, we suggest that low MEOX2 is a feature of the HSV1-resistant BTUCsph cell line that sets it apart from HSV1-permissive glioma cell lines. We further suggest that low MEOX2 expression profile may contribute to their resistance to HSV1 entry. Experiments and Key Findings: Using a defective HSV1 virus UL53-RTK-UL54 (ICP27 deleted virus expressing GFP reporter) to infect a panel of glioma cell lines (BTUCsph, 9L, U87, SF188) and BTUCsph derived tumors in vivo, we find that cells permissive to HSV1 infection strongly correlates with MEOX2 positivity. In our functional studies, we further revealed that MEOX2 knockdown in the HSV1-permissive 9L glioma cell line resulted in marked decline in HSV1 entry, while MEOX2 overexpression in the HSV1-resistant BTUCsph glioma cell line resulted in significant increase in HSV1 entry. Conclusion: Low MEOX2 expression is a feature of the highly malignant BTUCsph glioma cells that contributes to their resistance to HSV1 entry. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5648. doi:1538-7445.AM2012-5648

If G is the special orthogonal group O+(V) of a quadratic space V over a finite field of characteristic p, and r is a positive integer, we determine the abelian p-subgroups of largest order in G whose fixed subspaces in V have dimension at least r. In particular, we determine the abelian subgroups of largest order in a Sylow p-subgroup of G, extending some results obtained with different methods by Barry (1979).

A filtration is constructed for each dual Weyl module of a connected reductive group in prime characteristic p, and the quotients of the filtration are identified when the highest weight is far enough from the walls of the dominant chamber. The existence of certain composition factors is deduced.

Presentation in terms of generators and relations for the classical finite simple groups of Lie type have been given by Steinberg and Curtis [2,4]. These presentations are useful in proving characterzation theorems for these groups, as in the author's work on the projective symplectic groups [5]. However, in some cases, the application is not quite instantaneous, and an intermediate result is needed to provide a presentation more suitable for the situation in hand. In this paper we prove such a result, for the orthogonal simple groups over finite fields of odd characteristic. In a subsequent article we shall use this to give a characterization of these groups in terms of the structure of the centralizer of an involution.

If Sp(V) is the symplectic group of a vector space V over a finite field of characteristic p, and r is a positive integer, the abelian p-subgroups of largest order in Sp(V) whose fixed subspaces in V have dimension at least r were determined in the preceding paper, in the case p ≠ 2. Here we deal with the case p = 2. Our results also complete earlier work on the orthogonal groups.

The class of finite groups having a subgroup of order 4 which is its own centralizer has been studied by Suzuki [9], Gorenstein and Walter [6], and the present author [11]. The main purpose of this paper is to strengthen Theorem 5 of [11] by using an early result of Zassenhaus [12]. In particular, we find all groups of the class which are core-free, i.e. which have no nontrivial normal subgroup of odd order. As an application, we make a determination of a certain class of primitive permutation groups.

Suppose that G is the projective symplectic groupPSp(4, q), the Dickson groupG2(q)>or the Steinberg “triality-twisted” groupwhereqis an odd prime power. Then G is a finite simple group, andGcontains an involutionjsuch that the centralizerC(j)inGhas a subgroup of index 2 which containsjand which is the central product of two groups isomorphic withSL(2,q1)andSL(2,q2)for suitableqlq2.We wish to show that conversely the only finite simple groups containing an involution with this property are the groupsPSp(4,q), G2(q)9.In this first paper we shall prove the following result.

This study investigated the relationship between conversational behaviour and sex-role self concept as measured by the Bem Sex Role Inventory (BSRI) and the Personal Attributes Questionnaire (PAQ). More seconds of silence were found in incompatible dyads (as determined by sex-role orientation) than in compatible dyads, but generally sex-role self concept did not predict behaviour very well. We also found that the PAQ femininity scale correlates with self-reported self-esteem and assertiveness whereas the BSRI F-scale does not.

Publisher Summary This chapter presents a characterization of orthogonal simple groups PΩ(2n, q). The centralizer of an involution PΩ α (2n, q) in corresponding to an involution of Ω α (2n, q), which fixes the vectors of a (2n – 2)-dimensional subspace.