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Molecular and immunohistochemical profiling of invasive micropapillary carcinoma of the breast

Deqin Ma, Alexandra Thomas, Ryan Askeland, Natalya Guseva, Ramakrishna Sompallae
2014 Pathology and Laboratory Medicine International  
Pathology and Laboratory Medicine International Dovepress submit your manuscript | www.dovepress.com Dovepress 33 O r I g I n a L r e s e a r c h open access to scientific and medical research Open access Full Text article http://dx.
doi:10.2147/plmi.s67836 fatcat:mliedr7fczgtlpnm75lro642ra

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

Chunyan Gu, Xuefang Jing, Carol Holman, Ramakrishna Sompallae, Fenghuang Zhan, Guido Tricot, Ye Yang, Siegfried Janz
2018 BMC Cancer  
Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as
more » ... the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.
doi:10.1186/s12885-018-5015-0 pmid:30463534 pmcid:PMC6249818 fatcat:cv4uo3idgraavovbx7hliqgchm

Diverse CD8 T Cell Responses to Viral Infection Revealed by the Collaborative Cross

Matthew D. Martin, Ramakrishna Sompallae, Christina S. Winborn, John T. Harty, Vladimir P. Badovinac
2020 Cell Reports  
Enhanced host protection against re-infection requires generation of memory T cells of sufficient quantity and functional quality. Unlike well-studied inbred mice, T cell responses of diverse size and quality are generated following infection of humans and outbred mice. Thus, additional models are needed that accurately reflect variation in immune outcomes in genetically diverse populations and to uncover underlying genetic causes. The Collaborative Cross (CC), a large recombinant inbred panel
more » ... f mice, is an ideal model in this pursuit for the high degree of genetic variation present, because it allows for assessment of genetic factors underlying unique phenotypes. Here, we advance the utility of the CC as a tool to analyze the immune response to viral infection. We describe variability in resting immune cell composition and adaptive immune responses generated among CC strains following systemic virus infection and reveal quantitative trait loci responsible for generation of CD62L+ memory CD8 T cells.
doi:10.1016/j.celrep.2020.03.072 pmid:32294433 pmcid:PMC7212788 fatcat:hra372ww3nbndhgt7s3yvfsfwu

Correction to: Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

Chunyan Gu, Xuefang Jing, Carol Holman, Ramakrishna Sompallae, Fenghuang Zhan, Guido Tricot, Ye Yang, Siegfried Janz
2019 BMC Cancer  
As a result of an author oversight in the original article [1], the legend of Figure 5A and C is inaccurate and one panel in Figure 5C (FOXM1N H929 cells shown in the top row, left) is wrong.
doi:10.1186/s12885-019-6443-1 pmid:31862002 fatcat:u55tau4tjrezraevvz4k44cfkm

Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations

Carole Grasso, Matthew Anaka, Oliver Hofmann, Ramakrishna Sompallae, Kate Broadley, Winston Hide, Michael V. Berridge, Jonathan Cebon, Andreas Behren, Melanie J. McConnell
2016 BMC Cancer  
The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial. Methods: We iteratively sorted CD133+ and CD133-cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice. Results: We demonstrate that iterative
more » ... ting is required to make highly pure populations of CD133+ and CD133-cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133-cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133-tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133-cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133-cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment. Conclusion: We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma. Background The heterogeneity and tumourigenicity of metastatic melanoma has been widely debated. Originally attributed to a stochastic model of clonal evolution [1], in recent years it has been proposed to follow a cancer stem cell model [2] [3] [4] [5] [6] . This model suggests tumour initiation, growth and recurrence is driven by a subpopulation of tumourigenic cells that undergo stem cell-like asymmetric division to self-renew and produce hierarchical lineages of phenotypically differentiated, non-tumourigenic cells. However, the evidence that melanoma follows a cancer stem cell model is disputed [7] [8] [9] [10] . Variations in methodology, from the reliability of xenografting melanoma cells taken directly from the patient, to how immuno-compromised mice need to be to accurately assess tumourigenicity, have raised doubts of the validity of a cancer stem cell model for melanoma [11, 12] . Key evidence supporting a melanoma cancer stem cell model has come from isolating cells that differentially express stem and progenitor cell markers, or chemo-resistance markers, and comparing their tumourigenic ability. In the case of melanoma, cells expressing the surface markers CD133 [4, 13] and ABCG2 [4], ABCB5 [14] and CD271 [15] [16] [17] have been examined, as well as
doi:10.1186/s12885-016-2759-2 pmid:27613604 pmcid:PMC5017126 fatcat:tnaktxjisng6xnhegp44zf7heq

Transcription Profiling of Epstein-Barr Virus Nuclear Antigen (EBNA)-1 Expressing Cells Suggests Targeting of Chromatin Remodeling Complexes

Ramakrishna Sompallae, Simone Callegari, Siamak Akbari Kamranvar, Maria G. Masucci, Thomas F. Schulz
2010 PLoS ONE  
Interestingly, increased protein levels of several of H2B variants were detected by quantitative mass spectrometry in short-term EBNA-1 expressing cells (Sompallae et al. unpublished observation).  ... 
doi:10.1371/journal.pone.0012052 pmid:20706582 pmcid:PMC2919392 fatcat:vpdxsfc72jf6hpprle57utdzmm

The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates

Gerco C Hassink, Bin Zhao, Ramakrishna Sompallae, Mikael Altun, Stefano Gastaldello, Nikolay V Zinin, Maria G Masucci, Kristina Lindsten
2009 EMBO Reports  
Deconjugase activity was investigated in bacterial co-transformation assays as described earlier (Sompallae et al, 2008) .  ... 
doi:10.1038/embor.2009.69 pmid:19465887 pmcid:PMC2727442 fatcat:opqqhgvewvhfxdy4pil3ovza3a

TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF

Hannah E. Seberg, Eric Van Otterloo, Stacie K. Loftus, Huan Liu, Greg Bonde, Ramakrishna Sompallae, Derek E. Gildea, Juan F. Santana, J. Robert Manak, William J. Pavan, Trevor Williams, Robert A. Cornell (+1 others)
2017 PLoS Genetics  
Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent
more » ... xpression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the "master regulator" of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific PLOS Genetics | transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells. Author summary Identifying the elements and structure of the gene regulatory network governing melanocyte differentiation may yield insight into the mechanisms of pigmentation diseases and melanoma progression. Pigmentation is abnormal in Tfap2a mutants, but deciphering the exact role of TFAP2A in the network has been complicated by pleiotropic requirements for TFAP2A during development and the redundant function of TFAP2 paralogs in melanocytes. In this study, we find that TFAP2A directly regulates genes involved in melanocyte differentiation and melanin synthesis by binding at both promoters and enhancers associated with these genes. Furthermore, we report evidence that TFAP2A shares many targets with the melanocyte "master regulator" MITF. These findings indicate that TFAP2A drives melanocyte differentiation in parallel with MITF and affects the net prodifferentiation activity that is lost in melanoma. TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF PLOS Genetics |
doi:10.1371/journal.pgen.1006636 pmid:28249010 pmcid:PMC5352137 fatcat:ks2wyvx645el7hfwao3k2lwl3m

Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection

Matthew D. Martin, Marie T. Kim, Qiang Shan, Ramakrishna Sompallae, Hai-Hui Xue, John T. Harty, Vladimir P. Badovinac, Paul G. Thomas
2015 PLoS Pathogens  
PLOS Pathogens | Following infection or vaccination, memory CD8 T cells persist at higher numbers and have enhanced functional abilities compared to naïve cells, providing immune hosts with increased protection from viral, bacterial, or parasitic infection. Protection provided by memory CD8 T cells depends on the numbers, quality (functional abilities), and location of cells present at the time of re-infection. While memory CD8 T cells can be maintained for great lengths of time, how time
more » ... nces qualitative properties of these cells remains largely unknown. We show that the phenotype and functions of circulating memory CD8 T cells, including cytokine production, proliferation, and mitochondrial function following re-infection improves with time after infection. We also show that changes in function are not due solely to changes in subset composition of the memory pool. Importantly, due to enhanced proliferative and metabolic abilities, memory CD8 T cells analyzed late after infection were more protective against a chronic viral infection. Our study shows that the properties of memory CD8 T cells continue to change with time, and that the protective outcome of vaccination may depend on the timing of re-infection relative to the initial immunization. Changes in CD8 T Cell Memory with Time after Infection PLOS Pathogens | Results Changes occur in memory CD8 T cell location, phenotype, function, and maintenance with time after infection Heterogeneous populations of Ag-specific CD8 T cells can be analyzed on the level of the population (every CD8 T cell in the host), the subset level (CD8 T cells expressing a marker or combination of phenotypic markers), or the level of single cells. T cm and T em subsets differ in anatomical location and functionality [5, 6] . Thus, differences in function between memory populations could be due to alterations in subset composition that occur with time after primary antigen recognition. Additionally, individual cells within the population and within subsets can differ in phenotype and function from one another. However, because the level of protection is determined by the quality of all memory CD8 T cells present at the time of re-infection, we first Changes in CD8 T Cell Memory with Time after Infection PLOS Pathogens |
doi:10.1371/journal.ppat.1005219 pmid:26485703 pmcid:PMC4618693 fatcat:daw5clvczfgkrbl5s4riwr7bki

The Epstein–Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins

Giuseppe Coppotelli, Nouman Mughal, Simone Callegari, Ramakrishna Sompallae, Laia Caja, Martijn S. Luijsterburg, Nico P. Dantuma, Aristidis Moustakas, Maria G. Masucci
2013 Nucleic Acids Research  
Viral proteins reprogram their host cells by hijacking regulatory components of protein networks. Here we describe a novel property of the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) that may underlie the capacity of the virus to promote a global remodeling of chromatin architecture and cellular transcription. We found that the expression of EBNA1 in transfected human and mouse cells is associated with decreased prevalence of heterochromatin foci, enhanced accessibility of cellular DNA
more » ... micrococcal nuclease digestion and decreased average length of nucleosome repeats, suggesting de-protection of the nucleosome linker regions. This is a direct effect of EBNA1 because targeting the viral protein to heterochromatin promotes large-scale chromatin decondensation with slow kinetics and independent of the recruitment of adenosine triphosphate-dependent chromatin remodelers. The remodeling function is mediated by a bipartite Gly-Arg rich domain of EBNA1 that resembles the AT-hook of High Mobility Group A (HMGA) architectural transcription factors. Similar to HMGAs, EBNA1 is highly mobile in interphase nuclei and promotes the mobility of linker histone H1, which counteracts chromatin condensation and alters the transcription of numerous cellular genes. Thus, by regulating chromatin compaction, EBNA1 may reset cellular transcription during infection and prime the infected cells for malignant transformation.
doi:10.1093/nar/gkt032 pmid:23358825 pmcid:PMC3597695 fatcat:ecipdhiiindorkasmuqqwuo6xe

IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Rudragouda Channappanavar, Anthony R. Fehr, Jian Zheng, Christine Wohlford-Lenane, Juan E. Abrahante, Matthias Mack, Ramakrishna Sompallae, Paul B. McCray, David K. Meyerholz, Stanley Perlman
2019 Journal of Clinical Investigation  
Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling
more » ... ulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.
doi:10.1172/jci126363 pmid:31355779 pmcid:PMC6715373 fatcat:r3prw5smizdlpherbio3kw2nca

The MAPK Signaling Cascade is a Central Hub in the Regulation of Cell Cycle, Apoptosis and Cytoskeleton Remodeling by Tripeptidyl-Peptidase II

Ramakrishna Sompallae, Vaia Stavropoulou, Mathieu Houde, Maria G. Masucci
2008 Gene Regulation and Systems Biology  
Tripeptidyl-peptidase II (TPPII) is a serine peptidase highly expressed in malignant Burkitt's lymphoma cells (BL). We have previously shown that overexpression of TPPII correlates with chromosomal instability, centrosomal and mitotic spindle abnormalities and resistance to apoptosis induced by spindle poisons. Furthermore, TPPII knockdown by RNAi was associated with endoreplication and the accumulation of polynucleated cells that failed to complete cell division, indicating a role of TPPII in
more » ... he cell cycle. Here we have applied a global approach of gene expression analysis to gain insights on the mechanism by which TPPII regulates this phenotype. mRNA profi ling of control and TPPII knockdown BL cells identifi ed one hundred and eighty fi ve differentially expressed genes. Functional categorization of these genes highlighted major physiological functions such as apoptosis, cell cycle progression, cytoskeleton remodeling, proteolysis, and signal transduction. Pathways and protein interactome analysis revealed a signifi cant enrichment in components of MAP kinases signaling. These fi ndings suggest that TPPII infl uences a wide network of signaling pathways that are regulated by MAPKs and exerts thereby a pleiotropic effect on biological processes associated with cell survival, proliferation and genomic instability.
doi:10.4137/grsb.s882 fatcat:byym6mew35eglnkomxdhuvmqqy

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease

Ashutosh Mangalam, Shailesh K. Shahi, David Luckey, Melissa Karau, Eric Marietta, Ningling Luo, Rok Seon Choung, Josephine Ju, Ramakrishna Sompallae, Katherine Gibson-Corley, Robin Patel, Moses Rodriguez (+3 others)
2017 Cell Reports  
Graphical Abstract Highlights d A human gut bacterium has potential as a therapy for multiple sclerosis (MS) d P. histicola can suppress disease in a preclinical animal model of MS d P. histicola suppresses disease by inducing CD4 + FoxP3 + regulatory T cells In Brief Mangalam et al. show that P. histicola can suppress autoimmune disease in a preclinical model of multiple sclerosis. Thus, gut bacteria have the potential to be used as a therapy in human diseases.
doi:10.1016/j.celrep.2017.07.031 pmid:28793252 pmcid:PMC5763484 fatcat:g7jlefknwbhptljx7srwzikbzq

Prevotella histicola, A Human Gut Commensal, Is as Potent as COPAXONE® in an Animal Model of Multiple Sclerosis

Shailesh K. Shahi, Samantha N. Freedman, Alexandra C. Murra, Kasra Zarei, Ramakrishna Sompallae, Katherine N. Gibson-Corley, Nitin J. Karandikar, Joseph A. Murray, Ashutosh K. Mangalam
2019 Frontiers in Immunology  
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis. Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease. In particular, we and others have shown that MS patients have a lower
more » ... ance of Prevotella compared to HC, whereas the abundance of Prevotella is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA). This inverse correlation between the severity of MS disease and the abundance of Prevotella suggests its potential for use as a therapeutic option to treat MS. Notably we have previously identified a specific strain, Prevotella histicola (P. histicola), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment. In the present study we analyzed whether the disease suppressing effects of P. histicola synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone. Treatment with P. histicola was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of P. histicola plus Copaxone® was not more effective than either individual treatment. P. histicola-treated mice had an increased frequency and number of CD4+FoxP3+ regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 T cells in the CNS, suggesting P. histicola suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients.
doi:10.3389/fimmu.2019.00462 pmid:30984162 pmcid:PMC6448018 fatcat:d5ftfj77eraftjbsabuij47ece

A comprehensive promoter landscape identifies a novel promoter for CD133 in restricted tissues, cancers, and stem cells

Ramakrishna Sompallae, Oliver Hofmann, Christopher A. Maher, Craig Gedye, Andreas Behren, Morana Vitezic, Carsten O. Daub, Sylvie Devalle, Otavia L. Caballero, Piero Carninci, Yoshihide Hayashizaki, Elizabeth R. Lawlor (+2 others)
2013 Frontiers in Genetics  
AUTHOR CONTRIBUTIONS Ramakrishna Sompallae: Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing; Oliver Hofmann: Collection and/or assembly of data, Data analysis and  ... 
doi:10.3389/fgene.2013.00209 pmid:24194746 pmcid:PMC3810939 fatcat:c2ezxpcmvjcghin6qmqqewisfa
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