Browsing by Author "Biostatistics, IU School of Medicine"

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    An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer
    (American Association for Cancer Research, 2018-07-15) Lu, Xin; Pan, Xiaolu; Wu, Chang-Jiun; Zhao, Di; Feng, Shan; Zang, Yong; Lee, Rumi; Khadka, Sunada; Amin, Samirkumar B.; Jin, Eun-Jung; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Morgenlander, William R.; Weinrich, Jacqueline; Lu, Xuemin; Jiang, Shan; Chang, Qing; Navone, Nora M.; Troncoso, Patricia; DePinho, Ronald A.; Wang, Y. Alan; Biostatistics, IU School of Medicine
    Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823-33. ©2018 AACR.
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    Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection
    (Springer Nature, 2019-02) Zhou, Wenjun; He, Yanlin; Rehman, Atteeq U.; Kong, Yan; Hong, Sungguan; Ding, Guolian; Yalamanchili, Hari Krishna; Wan, Ying-Wooi; Paul, Basil; Wang, Chuhan; Gong, Yingyun; Zhou, Wenxian; Liu, Hao; Dean, John; Scalais, Emmanuel; O’Driscoll, Mary; Morton, Jenny E.V.; Hou, Xinguo; Wu, Qi; Tong, Qingchun; Liu, Zhandong; Liu, Pengfei; Xu, Yong; Sun, Zheng; Biostatistics, IU School of Medicine
    Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.
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    Safety and feasibility of virus-specific T cells derived from umbilical cord blood in cord blood transplant recipients
    (American Society of Hematology, 2019-07-23) Abraham, Allistair A.; John, Tami D.; Keller, Michael D.; Cruz, C. Russell N.; Salem, Baheyeldin; Roesch, Lauren; Liu, Hao; Hoq, Fahmida; Grilley, Bambi J.; Gee, Adrian P.; Dave, Hema; Jacobsohn, David A.; Krance, Robert A.; Shpall, Elizabeth. J.; Martinez, Caridad A.; Hanley, Patrick J.; Bollard, Catherine M.; Biostatistics, IU School of Medicine
    Adoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vβ clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.
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    Verbal Learning and Memory After Cochlear Implantation in Postlingually Deaf Adults: Some New Findings with the CVLT-II
    (Wolters Kluwer, 2018) Pisoni, David B.; Broadstock, Arthur; Wucinich, Taylor; Safdar, Natalie; Miller, Kelly; Hernandez, Luis R.; Vasil, Kara; Boyce, Lauren; Davies, Alexandra; Harris, Michael S.; Castellanos, Irina; Xu, Huiping; Kronenberger, William G.; Moberly, Aaron C.; Biostatistics, IU School of Medicine
    OBJECTIVES: Despite the importance of verbal learning and memory in speech and language processing, this domain of cognitive functioning has been virtually ignored in clinical studies of hearing loss and cochlear implants in both adults and children. In this article, we report the results of two studies that used a newly developed visually based version of the California Verbal Learning Test-Second Edition (CVLT-II), a well-known normed neuropsychological measure of verbal learning and memory. DESIGN: The first study established the validity and feasibility of a computer-controlled visual version of the CVLT-II, which eliminates the effects of audibility of spoken stimuli, in groups of young normal-hearing and older normal-hearing (ONH) adults. A second study was then carried out using the visual CVLT-II format with a group of older postlingually deaf experienced cochlear implant (ECI) users (N = 25) and a group of ONH controls (N = 25) who were matched to ECI users for age, socioeconomic status, and nonverbal IQ. In addition to the visual CVLT-II, subjects provided data on demographics, hearing history, nonverbal IQ, reading fluency, vocabulary, and short-term memory span for visually presented digits. ECI participants were also tested for speech recognition in quiet. RESULTS: The ECI and ONH groups did not differ on most measures of verbal learning and memory obtained with the visual CVLT-II, but deficits were identified in ECI participants that were related to recency recall, the buildup of proactive interference, and retrieval-induced forgetting. Within the ECI group, nonverbal fluid IQ, reading fluency, and resistance to the buildup of proactive interference from the CVLT-II consistently predicted better speech recognition outcomes. CONCLUSIONS: Results from this study suggest that several underlying foundational neurocognitive abilities are related to core speech perception outcomes after implantation in older adults. Implications of these findings for explaining individual differences and variability and predicting speech recognition outcomes after implantation are discussed.