Effects Of ICI Research Articles

Phase 2 study of cabozantinib (Cabo) and pembrolizumab (Pembro) in metastatic gastric/gastroesophageal adenocarcinoma (mGEA) resistant or refractory to immune checkpoint inhibitors (ICI).

315 Background: Most mGEA patients (pt) progress on therapy including ICI, with about 5% progression-free at 6 mo (PFS-6) with single agent ICI in later lines of therapy. Alternative therapeutic approaches are needed. Cabo is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study reports on safety and efficacy of the combination of Cabo+Pembro in mGEA resistant or refractory to ICI. Methods: Investigator-initiated, single‐arm, single institution, phase 2 study in pts with mGEA after ≥1L of fluoropyrimidine and platinum-containing regimens. Pts with a PD-L1 CPS score ≥10% had also progressed on ICI. Cabo dose was 40mg p.o. daily on days 1 through 21 of a 21‐day cycle, with Pembro 200 mg i.v. on day 1. The primary endpoint was PFS-6, with H0=5%, Ha≥20%, requiring n=27 evaluable pts and n≥4 pts with PFS-6 to reject H0 in favor of Ha. Results: 27 pts were enrolled. Median age 58 years (24-87), female (n=14), ECOG 0/1= 13/14, GC/GEJ= 16/11, Non-Hispanic White/Hispanic/Asian= 12/8/7. The primary endpoint was met with n=6 pts having PFS>6mo. After a median follow-up of 31.4mo (range 3.3-42.5), PFS-6 is 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3mo (95% CI 1.7-4.1) and 5.5mo (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). In exploratory analyses, 5/7 (71.4%) pts in the top quartile for PFS had alterations in the cMET-PI3K-AKT pathway. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension and muscle cramps (14.8% each). G3-4 TRAE were seen in n=3 pts (Hypertension, Thromboembolic event, esophageal perforation; each n=1). No G5 were observed. Conclusions: The addition of Cabo to Pembro shows clinical benefit in ICI resistant or refractory mGEA with an observed PFS-6 of 22.2%. The regimen appears tolerable with no new safety signals. An exploratory association of alterations in the cMET-PI3K-AKT pathway with prolonged PFS needs to be confirmed in a larger cohort. Clinical trial information: NCT04164979 .

Blocking of oestrogen signals improves anti-tumour effect regardless of oestrogen receptor alpha expression in cancer cells.

Anti-oestrogenic therapy has been used for breast cancer patients with oestrogen susceptibility cancer cells. However, little has been known about its potential role for immune cell biology within TME, particularly in cancer patients without oestrogen sensitivity of tumour cells. Therefore, we aimed to study the effect of oestrogen on immunity within TME. Using a clinical dataset, immune cells of humans and mice, female mice with and without ovaries, and several murine ERα-negative cancer cell lines, we evaluated the effect of oestrogen on immunity in TME. Clinical data analysis suggested oestrogen's suppressive efficacy against CTLs. Additionally, in vitro and in vivo experiments revealed intra-tumoural CTLs' direct repressive action by oestrogen in both mice and humans; blockade of oestrogen signals cancelled its immunosuppression resulting in tumour growth reduction in vivo. Most notably, immunotherapy (immune checkpoint inhibitor; ICI) combined with anti-oestrogenic therapy exhibited a dramatic anti-tumour effect. This study provides novel insights into how oestrogen contributes to tumour progression and a therapeutic rationale for blocking oestrogen signalling to boost the anti-tumour effect of ICI, regardless of tumour cells' ERα expression.

T-cell tolerant fraction as a predictor of immune-related adverse events

BackgroundImmune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight...

Norepinephrine as the Intrinsic Contributor to Contact Lens-Induced Pseudomonas aeruginosa Keratitis.

Contact lens wear (CLW) is one of the leading risk factors for Pseudomonas aeruginosa keratitis (PAK). However, the intrinsic factors that contribute to the high susceptibility to keratitis during CLW remain to be elucidated. CLW over an extended period can elevate corneal norepinephrine (NE) concentration. In this study, we investigated the role of NE in promoting PAK. We constructed an injury-induced PAK model and a CLW-induced PAK model to confirm the impact of NE during corneal infection. Pharmacological blockage of NE and gene knockdown mouse were used to investigate the downstream effector of NE. RNA sequencing was performed to explore the cellular alterations during NE treatment. Non-parametric Mann-Whitney U test or Kruskal-Wallis test were used to ascertain the significance (P < 0.05). Supplementation of NE led to PAK even without artificial corneal injury during CLW. The effect was mediated by the β2-adrenergic receptor (β2-AR) in the corneal epithelium. The β2-AR blockage by the NE antagonist ICI118,551 (ICI) or by deleting of its encoding gene Adrb2 significantly alleviated infection during CLW. Conversely, β2-AR activation compromised the integrity of the epithelium and significantly increased the cortical plaque marker ezrin. Transcriptome analysis identified that the protective effect of ICI on the keratitis was mediated by dual-specificity phosphatases. Suramin, a Dusp5 antagonist, abrogated the protective effect of ICI. These data reveal a new mechanism by which NE acts as an intrinsic factor that promotes CLW-induced PAK and provide novel therapeutic targets for treating keratitis by targeting NE-β2-AR.

Abstract P3-11-08: Inhibition of Sirtuin 3 Sensitizes Breast Cancer Cells to Fulvestrant

Abstract Endocrine therapy can lead to nutrient deprivation by reducing glucose and glutamine uptake and total cellular ATP production. The ability of cells to bypass this metabolic stress is fundamental to how they regulate BC growth and acquire endocrine resistance. Sirtuins (SIRTs) are NAD+-dependent deacylases and regulate a widerange of intracellular processes including metabolism. SIRT3, activated by calorie restriction, modulates mitochondrial adaptation to low energy input. It has a key role in mitochondrial integrity and function, regulating cell survival, death and metabolic pathways, regulating the shift to amino-acid and fatty-acid catabolism. SIRT3 can maintain ROS levels at the appropriate levels for sustaining a proliferative phenotype, preventing apoptosis and promoting carcinogenesis. A role of SIRT3 in epigenetic regulation has also been reported. We used Differential Dependency Network analysis to compare the wiring of the SIRTs and key metabolism-related genes in matched antiestrogen- sensitive vs. resistant breast cancer (BC) cells, which identified several novel signaling hubs including CDKN2A (p16), linking SIRT3 to cell proliferation. The ability of SIRTs to sense and respond to changes in energy, coupled with their deacetylase/deacylase functions, could provide a mechanism for the cell to rewire signaling and maintain a newly acquired drug-resistant phenotype. Using endocrine sensitive (LCC1) and resistant (LCC9) BC cells, we confirmed the higher expression of SIRT3 in LCC9, compared to LCC1 cells. Upregulation of SIRT3 expression within 24 hrs of Fulvestrant (ICI 1 µM) treatment (p=0.0176) in LCC1 was shown, but no effect was observed in LCC9 cells. Conversely, treatment with 17β-estradiol (E2- 10 nM) did not significantly affect SIRT3 expression in either LCC1 or LCC9 cells. Inhibition of SIRT3 acitivity, using the LC0296 inhibitor (15 µM), reduced growth rate in LCC1 and SIRT3-silenced LCC9 cells under treatment with ICI (1 nM and 1 µM, respectively) (p&amp;lt; 0.0001, p&amp;lt; 0.001 respectively). Treatment with SIRTUIN 3 inhibitor and ICI induced apoptosis in LCC1 and SIRT3-silenced LCC9 cells compared to the untreated control and ICI only treated cells (p&amp;lt; 0.001). The combination SIRT3 inhibitor (15 µM) plus ICI (0.5 µM) increased ROS production in LCC9-SIRT3 silenced cells in 24 hours of treatment compared to the untreated control and ICI only treated cells (p&amp;lt; 0.001). SIRT3 inhibitor (15 µM) decreased LCC1 cell spheroid formation (p&amp;lt; 0.05), however it didn’t show additive effect to the effect of ICI (0.5 µM) in the same conditions. The combination of SIRT3 inhibitor (15 µM) and ICI (1 µM) reduced the growth of LCC9 SIRT3-silenced cells in detached condition compared to untreated control and ICI only treated cells (p&amp;lt; 0.001). The results show that SIRT3 may have a role in Fulvestrant response in BC cells; the mechanism is under investigation in our laboratory. Citation Format: Karla Andrade de Oliveira, Surojeet Sengupta, Lu Jin, Fabia de Oliveira Andrade, Melike Ozgu-Onal, Anil Yadav, Robert Clarke. Inhibition of Sirtuin 3 Sensitizes Breast Cancer Cells to Fulvestrant [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-08.

Severe drug eruption after antibiotic administration in patients receiving immune checkpoint inhibitors: A monocentric case series

AbstractImmune checkpoint inhibitor (ICI) therapy is often associated with cutaneous immune‐related adverse events (irAEs). Drug eruptions stemming from concomitantly or consecutively administered medications are also frequent and tend to be severe. We herein present three cases of severe drug eruption in patients receiving antibiotics during ICI therapy in which hypotensive shock occurring during antibiotic administration was followed by generalized erythema and prolonged organ damage. Three patients received tazobactam/piperacillin (TAZ/PIPC) for an infection during ICI treatment. A high fever developed in all the patients after a switch was made to other antibiotics (Figures 2–4). Since no skin rash was observed at fever onset, a flare‐up of the infection was suspected, and TAZ/PIPC administration was resumed. Thereafter, the patients suddenly experienced hypotensive shock and respiratory failure requiring ICU management for generalized erythema and organ damage. Since anaphylaxis caused by TAZ/PIPC is rare, the patients’ clinical findings might be a manifestation of synergistic, complementary, immunomodulatory effects of ICI. In patients receiving ICI therapy, a fever occurring during antibiotic administration may indicate the onset of an immune hypersensitivity reaction to the drug. Resumption of antibiotic administration, especially TAZ/PIPC, during such a period may trigger an excessive inflammatory response, leading to an anaphylaxis‐like reaction and organ damage.

DNA methylation-based patterns for early diagnostic prediction and prognostic evaluation in colorectal cancer patients with high tumor mutation burden.

Immune checkpoint inhibitor (ICI) therapy has proven to be a promising treatment for colorectal cancer (CRC). We aim to investigate the relationship between DNA methylation and tumor mutation burden (TMB) by integrating genomic and epigenetic profiles to precisely identify clinical benefit populations and to evaluate the effect of ICI therapy. A total of 536 CRC tissues from the Cancer Genome Atlas (TCGA) with mutation data were collected and subjected to calculate TMB. 80 CRC patients with high TMB and paired normal tissues were selected as training sets and developed the diagnostic and prognostic methylation models, respectively. In the validation set, the diagnostic model was validated in our in-house 47 CRC tissues and 122 CRC tissues from the Gene Expression Omnibus (GEO) datasets, respectively. And a total of 38 CRC tissues with high TMB from the COLONOMICS dataset verified the prognostic model. A positive correlation between differential methylation positions and TMB level was observed in TCGA CRC cohort (r=0.45). The diagnostic score that consisted of methylation levels of four genes (ADHFE1, DOK6, GPR75, and MAP3K14-AS1) showed high diagnostic performance in the discovery (AUC=1.000) and two independent validation (AUC=0.946, AUC=0.857) datasets. Additionally, these four genes showed significant positive correlations with NK cells. The prognostic score containing three genes (POU3F3, SYN2, and TMEM178A) had significantly poorer survival in the high-risk TMB samples than those in the low-risk TMB samples (P=0.016). CRC patients with low-risk scores combined with TMB levels represent a favorable survival. By integrating analyses of methylation and mutation data, it is suggested that DNA methylation patterns combined with TMB serve as a novel potential biomarker for early screening in more high-TMB populations and for evaluating the prognostic effect of CRC patients with ICI therapy.

ODP159 A Rare Case of Pembrolizumab Induced Diabetic Ketoacidosis

Abstract Introduction Immune checkpoint inhibitors (ICI), such as Pembrolizumab, have demonstrated excellent clinical outcomes in numerous solid organ malignancies. However, this new drug comes with unpredictable adverse reactions which are still under review in the medical literature. We are showcasing a cancer patient treated with an ICI and presenting to the hospital in diabetic ketoacidosis (DKA), despite no significant history of a formal diagnosis of Diabetes Mellitus. Case description The patient is a 69 year old male who presented to the hospital with generalized weakness. His past medical history was significant but not limited to, Hypothyroidism, Tobacco use disorder, Stage IV Siewert type 2 gastroesophageal junction adenocarcinoma (cT4N2M1, HER2/FGFR negative, PD-L1 positive) after completion of one year of chemotherapy. He was now undergoing immunotherapy with Pembrolizumab, with his first dose three weeks ago. Reviews of systems including fever, abdominal pain, nausea, vomiting, polyuria, polydipsia were negative. Vital signs were grossly normal. He gave no personal or family history of diabetes. On admission venous blood gas demonstrated a high anion gap metabolic acidosis (pH 7. 096, Blood glucose 762 mg/dL, Anion Gap 29 mmol/L, bicarbonate 9 mmol/L, Plasma osmolality 337 mOsm/kg). Serum Lipase was 23 U/L. HbA1c was found to be 5.9%. Urinalysis was significant for glucose &amp;gt;500 mg/dl and &amp;gt;80 mg/dl of ketones. The physical exam was only remarkable for dry mucous membranes. Given the presentation and lab findings, he was subsequently diagnosed with DKA. The patient was treated with standard guideline therapy for DKA including bolus fluids, maintenance fluids and intravenous (IV) Insulin. The Anion gap closed and glucose decreased to under 200. He was transitioned to a subcutaneous insulin regimen, and discharged on the same. Discussion Based on diagnostic workup and exclusion of probable aetiologies, the patient was diagnosed with pembrolizumab-induced DKA. In the acute care setting, an autoimmune workup was not done in our patient. A meta analysis review of 71 such cases from 56 publications showed the average HbA1c concentration was 7.84% + 1. 0% at presentation. The A1c finding of 5.9%, defined at pre-diabetes, in represents an outlier. Another meta-analysis of such patients demonstrated DKA as the first sign of diabetes in 30 out of 35. The pathophysiology of this side effect of ICI's remains unknown, however several mouse studies have shown PD-1/PD L1 blockade precipitating diabetes in prediabetic non-obese mice. Anti -PD-1 drugs might have the same effect, and the reduction of PD-1 might activate autoreactive T cells, resulting in an autoimmune response against pancreatic islet cells. As the use of immunotherapy is expected to increase, it is essential that clinicians become aware of DKA as a rare and life threatening side effects of immunotherapy and that blood glucose monitoring is strongly considered as a method of prevention. Presentation: No date and time listed

INCIDENCE OF POSTCHECKPOINT INHIBITOR SARCOIDOSIS: A SINGLE-CENTER OBSERVATIONAL STUDY

INCIDENCE OF POSTCHECKPOINT INHIBITOR SARCOIDOSIS: A SINGLE-CENTER OBSERVATIONAL STUDY

Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients

BackgroundImmune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival.MethodsPatients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary’s Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction.ResultsAmong the 191 patients, 64 (33.5%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (25 months vs. 18 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.480 (p = 0.006). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for mortality of 0.324 (p = 0.002). Patients with thyrotoxicosis showed a worse hazard ratio for mortality than those without thyroid irAE, although the difference was not statistically significant.ConclusionsIt was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

Gene mutation analysis and immune checkpoint therapy in head and neck squamous cell carcinoma*

Abstract Immune checkpoint inhibitors (ICI), represented by blocked programmed cell death-1 (PD-1), is a group of novel medicines for anti-tumor immunotherapy. It has been approved by the U.S. Food and Drug Administration (FDA) in recent years for relapsed or metastatic head and neck squamous cell carcinoma (HNSCC), and brings promising treatment prospects. However, the instability caused by tumor gene mutations significantly compromises the therapeutic effect of ICI. Therefore, the identification and analysis of HNSCC gene mutations can further guide and optimize the application of ICIs in HNSCC. In this study, we preliminarily described the clinical research progress of ICI therapy and the potential immune escape mechanism in HNSCC. An overview of complete HNSCC gene mutation results was generated from the bioinformatics study of TCGA database to further explain and analyze the relevant molecular mechanisms, which may aid in designing future personalized therapeutic strategies for HNSCC patients.

Effects of ICI 182,780, an ERα and ERβ antagonist, and G-1, a GPER agonist, on autophagy in breast cancer cells

ABSTRACTObjectiveTo investigate if ICI 182,780 (fulvestrant), a selective estrogen receptor alpha/beta (ERα/ERβ) antagonist, and G-1, a selective G-protein-coupled receptor (GPER) agonist, can potentially induce autophagy in breast cancer cell lines MCF-7 and SKBr3, and how G-1 affects cell viability.MethodsCell viability in MCF-7 and SKBr3 cells was assessed by the MTT assay. To investigate the autophagy flux, MCF-7 cells were transfected with GFP-LC3, a marker of autophagosomes, and analyzed by real-time fluorescence microscopy. MCF-7 and SKBr3 cells were incubated with acridine orange for staining of acidic vesicular organelles and analyzed by flow cytometry as an indicator of autophagy.ResultsRegarding cell viability in MCF-7 cells, ICI 182,780 and rapamycin, after 48 hours, led to decreased cell proliferation whereas G-1 did not change viability over the same period. The data showed that neither ICI 182,780 nor G-1 led to increased GFP-LC3 puncta in MCF-7 cells over the 4-hour observation period. The cytometry assay showed that ICI 182,780 led to a higher number of acidic vesicular organelles in MCF-7 cells. G-1, in turn, did not have this effect in any of the cell lines. In contrast, ICI 182,780 and G-1 did not decrease cell viability of SKBr3 cells or induce formation of acidic vesicular organelles, which corresponds to the final step of the autophagy process in this cell line.ConclusionThe effect of ICI 182,780 on increasing acidic vesicular organelles in estrogen receptor-positive breast cancer cells appears to be associated with its inhibitory effect on estrogen receptors, and GPER does notseem to be involved. Understanding these mechanisms may guide further investigations of these receptors’ involvement in cellular processes of breast cancer resistance.

Effects of Alcohol and Estrogen Receptor Blockade Using ICI 182,780 on Bone in Ovariectomized Rats.

Estrogen signaling is essential for the sexual dimorphism of the skeleton, is required for normal bone remodeling balance in adults, and may influence the skeletal response to alcohol. High levels of alcohol consumption lower bone mass in ovary-intact but not ovariectomized (ovx) rats. However, the extremely rapid rate of bone loss immediately following ovx may obscure the effects of alcohol. We therefore determined (i) whether heavy alcohol consumption (35% caloric intake) influences bone in sexually mature ovx rats with established cancellous osteopenia and (ii) whether ICI 182,780 (ICI), a potent estrogen receptor signaling antagonist, alters the skeletal response to alcohol. Three weeks following ovx, rats were randomized into 5 groups, (i) baseline, (ii) control+vehicle, (iii) control+ICI, (iv) ethanol (EtOH)+vehicle, or (v) EtOH+ICI, and treated accordingly for 4weeks. Dual-energy X-ray absorptiometry, microcomputed tomography, blood measurements of markers of bone turnover, and gene expression in femur and uterus were used to evaluate response to alcohol and ICI. Rats consuming alcohol had lower bone mass and increased fat mass. Bone microarchitecture of the tibia and gene expression in femur were altered; specifically, there was reduced accrual of cortical bone, net loss of cancellous bone, and differential expression of 19/84 genes related to bone turnover. Furthermore, osteocalcin, a marker of bone turnover, was lower in alcohol-fed rats. ICI had no effect on weight gain, body composition, or cortical bone. ICI reduced cancellous bone loss and serum CTX-1, a biochemical marker of bone resorption; alcohol antagonized the latter 2 responses. Neither alcohol nor ICI affected uterine weight or gene expression. Alcohol exaggerated bone loss in ovx rats in the presence or absence of estrogen receptor blockade with ICI. The negligible effect of alcohol on uterus and limited effects of ICI on bone in alcohol-fed ovx rats suggest that estrogen receptor signaling plays a limited role in the action of alcohol on bone in a rat model for chronic alcohol abuse.

Performance Analysis of OFDM System with CP-Free STBC by using the Oblique Projection Technique

Background and Objective: This paper considers the model in which the digital feedback equalizer (DFE) together with oblique projection (OB) has been used to minimize the effect of Inter symbol Interference and Inter carrier Interference in multiple input multiple output orthogonal frequency division multiplexing system. The conventional MIMO-OFDM system uses cyclic prefix (CP) to remove ISI in received signals & this cyclic prefix is just an overhead on the transmitted data. In the proposed model CP has been removed and placed with Oblique Projection for saving the bandwidth. Usually by eliminating the CP in the system, the effect of ISI and ICI is not sufficiently removed. The frequency- domain block based decision feedback equalizer with oblique projection technique is proposing to dealing with this problem. This will also improve the spectral efficiency of the system. The proposed system has been able to give improvement of 12dB SNR at BER of 26dB in MMSE equalization and 27dB in zero forcing (ZF) decoding as compared to CP based conventional MIMO-OFDM system. Result and Conclusion: Further the proposed system has been able to increase the achievable rate at 0dB SNR the rate is 1.8 bits/sec/Hz. Keywords: MIMO, CP-OFDM, Decision Feedback Equalizer, Oblique Projection, STBC, ICI, ISI.

MP65-12 TARGETING ESTROGEN/ESTROGEN RECEPTOR SIGNAL PATHWAYS TO ENHANCE THE EFFICACY OF BACILLUS CALMETTE-GUÉRIN TREATMENT IN BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III1 Apr 2017MP65-12 TARGETING ESTROGEN/ESTROGEN RECEPTOR SIGNAL PATHWAYS TO ENHANCE THE EFFICACY OF BACILLUS CALMETTE-GUÉRIN TREATMENT IN BLADDER CANCER Zhiqun Shang, Yang Yang, Matthew Truong, Yanjun Li, Iawen Hsu, Jing Tian, Simeng Wen, Ruifa Han, Edward M. Messing, Chawnshang Chang, Yuanjie Niu, and Shuyuan Yeh Zhiqun ShangZhiqun Shang More articles by this author , Yang YangYang Yang More articles by this author , Matthew TruongMatthew Truong More articles by this author , Yanjun LiYanjun Li More articles by this author , Iawen HsuIawen Hsu More articles by this author , Jing TianJing Tian More articles by this author , Simeng WenSimeng Wen More articles by this author , Ruifa HanRuifa Han More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Chawnshang ChangChawnshang Chang More articles by this author , Yuanjie NiuYuanjie Niu More articles by this author , and Shuyuan YehShuyuan Yeh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2006AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although Bacillus Calmette-Guerin (BCG) is the most effective agent for non-muscle-invasive bladder cancers, approximately 30% of patients treated with intravesical BCG fail to respond to this agent. Previous studies from our lab showed the potential linkage of estrogen/estrogen receptor signaling with the efficacy of BCG, yet the detailed mechanisms remain unclear. Our new data showed the combination of BCG and the anti-estrogen ICI 182,780 (ICI) or tamoxifen could lead to a better suppression of bladder cancer (BCa) than BCG alone. METHODS We first applied PCR to detect BCG internalization in two ERα positive BCa cell lines to investigate the potential effect of anti-estrogen ICI. Then, we used Q-PCR and western blot and examined the E2/ER effects on the integrin-α5β1 expression and the BCG attachment/internalization to BCa cells. To examine whether ICI can help the recruitment of macrophages toward BCa cells, we applied the transwell migration assay and in vivo mouse BCG model. Q-PCR, Elisa assay and MTT assay were used to detect the cytokine profile changes and BCa cell viability. For our in vivo studies, we applied the BBN-induced mouse BCa model, HE staining, BrdU and F4/80 staining to show the changes of macrophage infiltration and to prove the better efficacy of combining BCG plus anti-estrogen. RESULTS We found treatment with either 1 μM ICI or tamoxifen significantly increased the BCG attachment/internalization, and the neutralization of integrin-α5β1 could reduce the ability of the ICI enhanced BCG attachment/internalization to BCa cells (Figure 1). Mechanism dissection revealed ICI could promote BCG attachment/internalization to the BCa cells through targeting ERα and increased the integrin-α5β1 expression and IL-6 secretion. The increased cytokine production may enhance BCG-mediated suppression of BCa cell growth and TNF-α production via recruiting more monocytes/macrophages to BCa cells (Figure 2-3). Consistently, in vivo studies found ICI could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models (Figure 4). CONCLUSIONS Taken together, these in vitro and in vivo results suggest that combining BCG with the anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e858 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Zhiqun Shang More articles by this author Yang Yang More articles by this author Matthew Truong More articles by this author Yanjun Li More articles by this author Iawen Hsu More articles by this author Jing Tian More articles by this author Simeng Wen More articles by this author Ruifa Han More articles by this author Edward M. Messing More articles by this author Chawnshang Chang More articles by this author Yuanjie Niu More articles by this author Shuyuan Yeh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

New approach to wireless data communication in a propagation environment

This paper presents a new idea of perfect signal reconstruction in multivariable wireless communications systems including a different number of transmitting and receiving antennas. The proposed approach is based on the polynomial matrix S -inverse associated with Smith factorization. Crucially, the above mentioned inverse implements the so-called degrees of freedom. It has been confirmed by simulation study that the degrees of freedom allow to minimalize the negative impact of the propagation environment in terms of increasing the robustness of whole signal reconstruction process. Now, the parasitic drawbacks in form of dynamic ISI and ICI effects can be eliminated in framework described by polynomial calculus. Therefore, the new method guarantees not only reducing the financial impact but, more importantly, provides potentially the lower consumption energy systems than other classical ones. In order to show the potential of new approach, the simulation studies were performed by author's simulator based on well-known OFDM technique.

Short-term effects of β2-AR blocker ICI 118,551 on sarcoplasmic reticulum SERCA2a and cardiac function of rats with heart failure.

The study was conducted to examine the effects of ICI 118,551 on the systolic function of cardiac muscle cells of rats in heart failure and determine the molecular mechanism of selective β2-adrenergic receptor (β2-AR) antagonist on these cells. The chronic heart failure model for rats was prepared through abdominal aortic constriction and separate cardiac muscle cells using the collagenase digestion method. The rats were then divided into Sham, HF and HF+ICI 50 nM goups and cultivated for 48 h. β2-AR, Gi/Gs and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) protein expression levels in the cardiac muscle cells were evaluated by western blotting and changes in the systolic function of cardiac muscle cells based on the boundary detection system of contraction dynamics for individual cells was measured. The results showed that compared with the Sham group, the survival rate, percentage of basic contraction and maximum contraction amplitude percentage of cardiac muscle cells with heart failure decreased, Gi protein expression increased while Gs and SERCA2a protein expression decreased. Compared with the HF group, the maximum contraction amplitude percentage of cardiac muscle cells in group HF+ICI 50 nM decreased, the Gi protein expression level increased while the SERCA2a protein expression level decreased. Following the stimulation of Ca2+ and ISO, the maximum contraction amplitude percentage of cardiac muscle cells in the HF+ICI 50 nM group was lower than that in group HF. This indicated that ICI 118,551 has negative inotropic effects on cardiac muscle cells with heart failure, which may be related to Gi protein. Systolic function of cardiac muscle cells with heart failure can therefore be reduced by increasing Gi protein expression and lowering SERCA2a protein expression.

β1 Adrenoceptor Antagonistic Effects of ICI 118,551 on the Positive Inotropic Effect of Adrenaline in Murine Hearts

β1 Adrenoceptor Antagonistic Effects of ICI 118,551 on the Positive Inotropic Effect of Adrenaline in Murine Hearts

Mitigating ICI at cell edges in cognitive-femtocell networks through fractional frequency reuse

In this paper, we consider a situation where femtocells are deployed over the existing macrocell network and share the same frequency spectrum with macrocells where we focus only on downlink situation. It is essential to implant femtocell at cell edges due to the fact that the number of outage user is large because of their position which is far away from macrocell base station MBS located at macrocell centre, more precisely at 0, 0 coordinates. In general, the uncoordinated deployment of femtocell creates the potential for severe interference to co-located femtocells, especially in dense deployment, resulting in large inter cell interference ICI effect on the users located at cell edges. Here, we propose dynamic FFR algorithm at cell edges to overcome all possible difficulties in the networks. Frequency reuse is an approach to increase the signal to interference plus noise ratio SINR and channel capacity Bits/s/Hz. The bit error rate BER is also evaluated by maximal ratio combining MRC diversity technique for accurate transmission over multipath fading dispersive channels. The simulation results conclusively validate the superior performance of the network model in interference mitigation, precisely in high density FAP scenarios.

Regulation of cyclooxygenase-2 expression in rat oviductal epithelial cells: Evidence for involvement of GPR30/Src kinase-mediated EGFR signaling

The oviduct plays a crucial role in female reproduction by regulating gamete transport, providing a specific microenvironment for fertilization and early embryonic development. Cyclooxygenase (COX)-derived prostaglandins play essential role in carrying out these oviduct-specific functions. Estrogen upregulates COX-2 expression in rat oviduct; however, the mechanisms responsible for regulation of COX-2 expression in rat oviductal epithelial cells (OECs) remain unclear. In the present study, we proposed that estrogen induces COX-2 expression via G-protein coupled receptor i.e., GPR30 in OECs. To investigate this hypothesis, we examined the effects of E2-BSA, ICI 182,780, GPR30 agonist and GPR30 antagonist on COX-2 expression and explored potential signaling pathway leading to COX-2 expression. Co-localization experiments revealed GPR30 to be primarily located in the peri-nuclear space, which was also the site of E2-BSA-fluorescein isothiocyanate (E2-BSA-FITC) binding. The E2-BSA induced-COX-2 and prostaglandin release were subjected to regulation by both EGFR and PI3K signaling as inhibitors of c-Src kinase (PP2), EGFR (EGFR inhibitor) and PI-3 kinase (LY294002) attenuated E2-BSA mediated effect. These results suggest that EGFR transactivation leading to activation of PI-3K/Akt pathway participates in COX-2 expression in rat OECs. Interestingly, E2-BSA induced COX-2 expression and subsequent prostaglandin release were abolished by NF-κB inhibitor. In addition, E2-BSA induced the nuclear translocation of p65-NF-κB and up-regulated the NF-κB promoter activity in rat OECs. Taken together, results demonstrated that E2-BSA induced the COX-2 expression and consequent PGE2 and PGF2α release in rat OECs. These effects are mediated through GPR30-derived EGFR transactivation and PI-3K/Akt cascade leading to NF-κB activation.