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

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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Abstract 2911: Immune related melanoma gene expression profile predicts neoadjuvant ipilimumab clinical benefit

10.1158/1538-7445.am2014-2911 ◽

2014 ◽

Cited By ~ 1

Author(s):

Ahmad A. Tarhini ◽

Yan Lin ◽

Hui-Min Lin ◽

Cindy Sander ◽

William A. La Framboise ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

Clinical Benefit

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TFEB is a master regulator of tumor-associated macrophages in breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000543 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000543 ◽

Cited By ~ 3

Author(s):

Yong Li ◽

Johnie Hodge ◽

Qing Liu ◽

Junfeng Wang ◽

Yuzhen Wang ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Tumor Growth ◽

Gene Expression Profile ◽

Expression Profile ◽

Breast Tumor ◽

Tumor Development ◽

Tumor Associated Macrophages ◽

And Function ◽

The Impact

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

Journal of Cardiovascular Diseases & Diagnosis ◽

10.4172/2329-9517.1000114 ◽

2013 ◽

Vol 01 (04) ◽

Cited By ~ 1

Author(s):

Bethany A Austin PJ Arnold

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Expression Profile ◽

Cardiac Transplant ◽

The Impact

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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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261 Association of T-cell–inflamed gene expression profile and PD-L1 status with efficacy of pembrolizumab in patients with esophageal cancer from KEYNOTE-180

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0261 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A285-A285

Author(s):

Manish Shah ◽

Takashi Kojima ◽

Daniel Hochhauser ◽

Peter Enzinger ◽

Judith Raimbourg ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Sample Size ◽

Gene Expression Profile ◽

Expression Profile ◽

Small Sample Size ◽

Gastroesophageal Junction ◽

Small Sample ◽

Link Type ◽

Number Of Patients

BackgroundKey biomarkers under investigation for the ability to predict response to monotherapy PD-1 inhibitors such as pembrolizumab include PD-L1, TMB, MSI, and T-cell–inflamed gene expression profile (GEP). The KEYNOTE-180 trial (NCT02559687) was a single-arm phase 2 study of pembrolizumab as third-line or greater therapy in advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma (SCC). ORR was 9.9% and median DOR was NR at the primary analysis. We investigated the relationship in KEYNOTE-180 between response to pembrolizumab and T-cell–inflamed GEP or PD-L1 expression by histology.MethodsPatients received pembrolizumab 200 mg Q3W for ≤2 years until disease progression, toxicity, or withdrawal. The end points for this analysis were ORR, DOR, and PFS per RECIST v1.1 by central review and OS in the SCC and adenocarcinoma populations by GEP (non-low [≥–1.540] or low [<–1.540]; cutoff prespecified) and PD-L1 (CPS ≥10 or <10). Tumor GEP was determined using the NanoString nCounter Analysis System. PD-L1 expression was characterized using PD-L1 IHC 22C3 pharmDx. Data cutoff date was July 30, 2018.ResultsOf 121 total patients, 118 had an evaluable GEP score and 121 had an evaluable PD-L1 CPS. Fifty-one patients (42.1%) had GEPnon-lowtumors, 58 (48.0%) had CPS ≥10 tumors, and 31 (25.6%) had GEPnon-low/CPS ≥10 tumors; 63 patients (52.1%) had SCC and 58 (47.9%) had adenocarcinoma. ORR was 15.4% with GEPnon-low and 13.5% with GEPlow among patients with SCC and 12% and 0% among patients with adenocarcinoma, respectively (table 1). ORR was 20% with CPS ≥10 and 7.1% with CPS <10 among patients with SCC and 4.3% and 5.7%, respectively, among patients with adenocarcinoma (table 2). Median OS was slightly higher among patients with SCC in the GEPnon-low subgroup and the CPS ≥10 subgroup versus GEPlow and CPS <10 subgroups, respectively (tables 1, 2); this trend was reversed among patients with adenocarcinoma (tables 1, 2). Median PFS ranged from 1.9 to 2.1 across histology/biomarker subgroups. Median DOR was NR regardless of GEP or CPS status (tables 1, 2).Abstract 261 Table 1Response by GEP status and histologyaAnalysis by biomarker status was not possible because of the small sample size.Abstract 261 Table 2Response by PD-L1 status and histologyaAnalysis by biomarker status was not possible because of the small sample size.ConclusionsIn KEYNOTE-180, data in a small number of patients suggested that measures of inflammation, like PD-L1 and GEP, may enrich for responses to pembrolizumab. In SCC, some trends toward enrichment were observed for both biomarkers, although the trend was stronger for PD-L1 CPS ≥10. In adenocarcinoma, a trend was observed for GEP but not for PD-L1; the small number of responders is limiting, and further studies are needed to understand molecular correlates in adenocarcinoma.AcknowledgementsMedical writing and/or editorial assistance was provided by Tim Peoples, MA, ELS, and Holly C. Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrials. gov, NCT02559687Ethics ApprovalThe study and the protocol were approved by the institutional review board or ethics committee at each site.ConsentAll patients provided written informed consent to participate in the clinical trial.

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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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54: Development of a Gene Expression Profile for Predicting Gemcitabine Response in Pancreatic Cancer

Journal of Surgical Research ◽

10.1016/j.jss.2008.11.064 ◽

2009 ◽

Vol 151 (2) ◽

pp. 195

Author(s):

R. White ◽

S. Singh ◽

S. Hsu ◽

K. Viles ◽

A. Potti ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Gene Expression Profile ◽

Expression Profile

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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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