The Impact of Time Post Cardiac Transplant on Gene Expression Profile Scores, an Analysis of 32,043 Tests

BackgroundTumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development.MethodsMicroarrays were used to analyze the gene expression profile of macrophages (MΦs) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects MΦ gene expression and function. Mouse studies were carried out to investigate the impact of MΦ TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes.ResultsTAM-mimic MΦs display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor γ (PPARγ) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1α mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1β, IL-6 and prostaglandin E2. MΦ-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPARγ are positive prognostic markers, while HIF-1α is a negative prognostic marker of breast cancer.ConclusionsOur study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.

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Prognostic Significance of Expression of a Single MicroRNA,miR-181a, in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.2953 ◽

2010 ◽

Vol 28 (36) ◽

pp. 5257-5264 ◽

Cited By ~ 137

Author(s):

Sebastian Schwind ◽

Kati Maharry ◽

Michael D. Radmacher ◽

Krzysztof Mrózek ◽

Kelsi B. Holland ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Gene Expression Profile ◽

Expression Profile ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Comprehensive Cancer Center ◽

Wild Type ◽

The Impact ◽

Acute Myeloid

PurposeTo evaluate the prognostic significance of expression levels of a single microRNA, miR-181a, in the context of established molecular markers in cytogenetically normal acute myeloid leukemia (CN-AML), and to gain insight into the leukemogenic role of miR-181a.Patients and MethodsmiR-181a expression was measured in pretreatment marrow using Ohio State University Comprehensive Cancer Center version 3.0 arrays in 187 younger (< 60 years) adults with CN-AML. Presence of other molecular prognosticators was assessed centrally. A gene-expression profile associated with miR-181a expression was derived using microarrays and evaluated by Gene-Ontology analysis.ResultsHigher miR-181a expression associated with a higher complete remission (CR) rate (P = .04), longer overall survival (OS; P = .01) and a trend for longer disease-free survival (DFS; P = .09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P = .009), and longer DFS (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥ 60 years) patients with CN-AML. A miR-181a-associated gene-expression profile was characterized by enrichment of genes usually involved in innate immunity.ConclusionTo our knowledge, we provide the first evidence that the expression of a single microRNA, miR-181a, is associated with clinical outcome of patients with CN-AML and may refine their molecular risk classification. Targeted treatments that increase endogenous levels of miR-181a might represent novel therapeutic strategies.

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Effects of histamine and various histamine receptor antagonists on gene expression profiles of macrophages during compressive strain

Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie ◽

10.1007/s00056-021-00318-x ◽

2021 ◽

Author(s):

Agnes Schröder ◽

Catharina Petring ◽

Anna Damanaki ◽

Jonathan Jantsch ◽

Peter Proff ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

Periodontal Ligament ◽

Tooth Movement ◽

Expression Profiles ◽

Quantitative Polymerase Chain Reaction ◽

Compressive Strain ◽

Orthodontic Tooth Movement ◽

The Impact

Abstract Purpose Tissue hormone histamine can accumulate locally within the periodontal ligament via nutrition or may be released during allergic reactions by mast cells, which may have an impact on orthodontic tooth movement. In addition to periodontal ligament fibroblasts, cells of the immune system such as macrophages are exposed to compressive strain. The aim of this study was thus to investigate the impact of histamine on the gene expression profile of macrophages in the context of simulated orthodontic compressive strain. Methods Macrophages were incubated with different histamine concentrations (50, 100, 200 µM) for 24 h and then either left untreated or compressed for another 4 h. To assess the role of different histamine receptors, we performed experiments with antagonists for histamine 1 receptor (cetirizine), histamine 2 receptor (ranitidine) and histamine 4 receptor (JNJ7777120) under control and pressure conditions. We tested for lactate dehydrogenase release and analyzed the expression of genes involved in inflammation and bone remodeling by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results Histamine elevated gene expression of tumor necrosis factor under control conditions and in combination with pressure application. Increased prostaglandin-endoperoxide synthase‑2 mRNA was observed when histamine was combined with compressive force. Interleukin‑6 gene expression was not affected by histamine treatment. In macrophages, compressive strain increased osteoprotegerin gene expression. Histamine further elevated this effect. Most of the observed histamine effects were blocked by the histamine 1 receptor antagonist cetirizine. Conclusions Histamine has an impact on the gene expression profile of macrophages during compressive strain in vitro, most likely having an impairing effect on orthodontic tooth movement by upregulation of osteoprotegerin expression.

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MON-031 A Gene Expression Profile of the Adolescent Breast and the Impact of Obesity

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.538 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Dennis Y Akrobetu ◽

Adam B Burkholder ◽

Thai-Vu T Ton ◽

Susan Kim ◽

Arun Pandiri ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

Ethinyl Estradiol ◽

Breast Development ◽

Aromatase Activity ◽

Adult Women ◽

Extracellular Matrix Components ◽

The Impact ◽

Upstream Regulators

Abstract Environmental exposures that occur early in life affect breast development and breast cancer (BC) risk in adulthood. Puberty is one such developmental ‘window of susceptibility’ when estrogen (E) stimulates breast adipocytes and stromal and epithelial cells to proliferate at an exponential rate, making them vulnerable to carcinogens. Excess adiposity during adulthood may increase BC risk through obesity-associated inflammation and/or aromatase activity, which increases local E levels. While obesity during puberty might be expected to also increase future BC risk, epidemiological studies suggest that pediatric obesity may actually be protective. The current studies investigated the gene expression profile of the normal adolescent breast and how early life factors such as obesity may influence these profiles. We performed RNA-seq in 62 histologically-normal breast tissue samples from adolescent girls and young women (mean age 17.8 yrs) who underwent breast reduction surgery. Twenty-nine patients were normal weight (NW; mean BMI 23.2 kg/m2) and 33 were overweight/obese (OB; BMI 31.7). Comparison of our adolescent dataset with published mammary RNAseq datasets from pubertal mice, rats, macaques, and adult women (mean age 38 yrs) revealed relatively poor (~ 30%) overlap with other species, but 88% overlap with adults for the 500 most highly expressed genes in each dataset. The small gene set (n=43) common to all groups was enriched for extracellular matrix components. We used DESeq2 to identify differentially-expressed (DE) genes in NW vs OB samples. To avoid confounding due to differences in the cellular composition of NW and OB samples, we first used CIBERSORT to computationally estimate the adipocyte fraction of each sample and included this estimate as a covariate. We identified 74 up-regulated and 73 down-regulated genes in NW vs. OB (padj < 0.05). We used Ingenuity Pathway Analysis (IPA) to determine whether the DE genes might reflect activation or inhibition of upstream transcriptional regulators in OB samples. IPA identified the cytokines CSF1 and CSF2 and the chemokine receptor CCR2 as the most highly activated upstream regulators, suggesting a signature of increased inflammation in OB samples. While classical E receptor (ER) targets (e.g., PR, AREG) were not DE’d, IPA identified ESR1, 17-α-ethinyl estradiol, genistein, and PR, as well as growth factors/receptors (EGF, IGF-1, HGF, HER3) and kinases (AKT1, ERK) involved in hormone-independent ER activation, as activated upstream regulators in OB samples. These studies represent the first investigation of the human breast transcriptome during late puberty and demonstrate that in adolescents, as in adults, OB is associated with increased inflammation which may augment E action in the breast microenvironment.

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Exploratory study of the subcutaneous fat gene expression profile in patients with metastatic pancreatic carcinoma treated with standard gemcitabine chemotherapy regimen

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22220 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22220-e22220

Author(s):

D. E. Castellano ◽

C. Gomez-Martin ◽

R. Cubedo Cervera ◽

J. Garcia Lopez ◽

R. Gomez-Sanz ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Gene Expression Profile ◽

Expression Profile ◽

Clinical Benefit ◽

Evaluation System ◽

Subcutaneous Fat ◽

Serum Cytokines ◽

Number Of Patients ◽

The Impact

e22220 Background: Most clinical trials are designed to assess the antitumor effect of the chemoterapeutic intervention. There are few examples where the endpoint is to assess the biology of the host response to the treatment of the tumor. A large number of patients with pancreatic cancer present features of the cachexia syndrome and specially a marked weight loss. It has been postulated that a “cytokine storm” is the cause of the profound effect that this cancer has on distant tissues. This trial analyzed changes in the subcutaneous fat gene expression profile in relation with the clinical benefit variable with standard gemcitabine (G) treatment. Methods: Patients with histology confirmed advanced pancreatic cancer, adequate organ function and written informed consent. Eligible pts were intended for a subcutaneous fat biopsy pretreatment and after 7 weeks of gemcitabine 1000 mg/m2 together with response assessment. Clinical benefit (CB) (pain, analgesic consumption, Karnofsky and weight), QLQ-C30, serum cytokines and tumor markers were evaluated pretreatment, at 4 and 8 weeks. Fat gene expression profile was analyzed using Affimetrix U133Plus2.0 with the corresponding bioinformatic software. Serum cytokines where analyzed with xMAP technology with the Luminex 200 platform. Results: 16 pts [8 m, 8 f, median age 62 yrs (range 47–72)]. Median weight change -0.75 kg (range -4.5 to 2). Nine pts had pre and post treatment biopsies and 7 only pretreatment. Three pts achieved CB at 8 weeks. Objective responses: 0 CR, 0 PR, 31% SD and 68%PD. Toxicity was similar to the one reported in gemcitabine's label. It was possible to extract quality RNA for microarray from subcutaneous fat use from all samples but 1. The limited number of samples precluded to obtain genes clearly involved in cachexia, however the IL-8 expression (p0.03) was significantly correlated with CB response either to gene and serum profile. Conclusions: It is feasible to study prospectively the impact of cancer treatment on different tissue biomarkers and correlated with standard antitumor evaluation system. The reduced number of samples in this exploratory trial precludes producing significant biological conclusions. No significant financial relationships to disclose.

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Impact of PD-L1 and T-cell inflamed gene expression profile on survival in advanced ovarian cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-001109 ◽

2020 ◽

Vol 30 (7) ◽

pp. 1034-1042

Author(s):

Estrid Høgdall ◽

Claus Høgdall ◽

Thao Vo ◽

Wei Zhou ◽

Lingkang Huang ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Overall Survival ◽

T Cell ◽

Gene Expression Profile ◽

Expression Profile ◽

Advanced Ovarian Cancer ◽

Free Interval ◽

Positive Expression ◽

The Impact

ObjectiveProgrammed death ligand 1 (PD-L1) expression affects tumor evasion of immune surveillance. The prognostic value and relationship of PD-L1 expression to T-cell–inflamed immune signatures in ovarian cancer are unclear. The purpose of this study is to evaluate the impact of PD-L1 on overall survival and its correlation with an immune-mediated gene expression profile in patients with advanced ovarian cancer.MethodsPD-L1 expression in tumor and immune cells was assessed by immunohistochemistry, and PD-L1–positive expression was defined as a combined positive score ≥1; a T-cell–inflamed gene expression profile containing interferon γ response genes was evaluated using extracted RNA from surgical samples. Associations between PD-L1 expression, gene expression profile status, and overall survival were analyzed using the Kaplan-Meier method, log-rank test, and multivariate Cox proportional hazards regression models.ResultsA total of 376 patients with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer treated by cytoreductive surgery and platinum-based therapy were included. PD-L1–positive expression was observed in 50.5% of patients and associated with more advanced stage (p=0.047), more aggressive histologic subtype (p=0.001), and platinum sensitivity defined by increasing treatment-free interval from first platinum-based chemotherapy to next systemic treatment (p=0.027). PD-L1–positive expression was associated with longer overall survival in multivariate analyses (adjusted HR 0.72, 95% CI 0.56 to 0.93). In subgroup analyses, this association was most pronounced in patients with partially platinum-sensitive disease (treatment-free interval ≥6 to <12 months). T-cell–inflamed gene expression profile status correlated with PD-L1 expression (Spearman, ρ=0.712) but was not an independent predictor of overall survival.ConclusionPD-L1 expression is associated with longer overall survival among advanced ovarian cancer patients. PD-L1 expression may be an independent prognostic biomarker.

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The impact of gene expression profile testing on confidence in chemotherapy decisions and prognostic expectations

Breast Cancer Research and Treatment ◽

10.1007/s10549-018-4988-3 ◽

2018 ◽

Vol 173 (2) ◽

pp. 417-427 ◽

Cited By ~ 3

Author(s):

Laura Panattoni ◽

Tracy A. Lieu ◽

Jinani Jayasekera ◽

Suzanne O’Neill ◽

Jeanne S. Mandelblatt ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

The Impact

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Gene Expression Profile in Patients with Classical Hodgkin Lymphoma in Brazil: Results from a Pilot Study

Blood ◽

10.1182/blood.v128.22.5294.5294 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5294-5294

Author(s):

Priscilla Brito Silva ◽

Juliana Monte Real ◽

Ludmila Rodrigues Pinto Ferreira ◽

Gustavo Henrique Esteves ◽

Joao Garibaldi Junior ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Gene Expression Profile ◽

Expression Profile ◽

Immune Gene ◽

Healthy Controls ◽

Classical Hodgkin Lymphoma ◽

Immune Gene Expression ◽

Effective Immune Response ◽

The Impact

Abstract Introduction: Although immunosuppression has long been recognized in classical Hodgkin lymphoma (cHL), the underlying basis for this lack of an effective immune response against tumor remains unclear. Recently, our group showed increased frequencies levels of pro and anti-inflammatory cytokines, such as interleukins IL-6, IL-10, TNF-alpha and sCD25 in cHL patients and the impact of treatment on these cytokines. These cytokines participate in the Hodgkin and Reed-Sternberg (HRS) cells survival and immunological escape. Objectives: In this study we aimed to evaluate the immune gene expression profile in cHL patients at diagnosis and the impact of treatment on this profile. Patient and Methods: This is an open multicenter study and, so far, we included 51 patients consecutively from February 2011 to November 2015. Twenty consecutively diagnosed cHL patients, with whole blood RNA extracted at diagnosis and after treatment, were recruited for this study and prospectively evaluated. The general expression of 96 messengers RNAs present in the peripheral blood and involved in immune response was performed by a customized quantitative real-time PCR array (TaqMan¨Low Density Array). We also included 7 healthy controls. The data was normalized with B2M mRNAs levels and relative gene expression was calculated by the 2^DDCt method, considering Wilcoxon test and Benjamini-Hochberg adjustment to correct p-values. In this study, only cHL patients whose histology could be confirmed were studied. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results: From the 20 patients included for this study, 12 (60%) were male, 5 (31%) had Epstein Barr virus related cHL, 18 (90%) patients presented with B symptoms, 19 (95%) patients had advanced diseases at diagnosis (stage IIBX, III and IV) and 10% of patients relapsed. Results of immune gene expression profile in patients before (pre) treatment, after (post) treatment and healthy subjects (controls) are summarized in the following table: We observed that 4 mRNAs were altered in cHL patients before therapy (IL-10, CCL2, CD40 and HLA-DRA). After treatment, gene expression profile was similar to healthy controls. When we considered paired samples from 15 patients, 10 mRNAs were differently expressed after therapy, although the adjusted p value showed no different expression. We found no association between clinical and epidemiological characteristics with immune gene expression profile. Conclusions: In this study we showed that, in comparison with healthy donors, cHL patients presented higher expression of inflammatory genes in peripheral blood at diagnosis. After treatment, gene expression profile was comparable to healthy controls. Furthermore, treatment seems to restore a more effective immune response; particularly, IL-10, CD274 (PD-L1) and CTLA4 which were downregulated after therapy. Understanding cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new prognostic factors and treatment strategies. Table Table. Disclosures No relevant conflicts of interest to declare.

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