Predictive markers in metastatic transitional cell carcinoma (mTCC) patients treated with carboplatin plus pemetrexed regimen.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15558-e15558
Author(s):  
Guadalupe Aparicio ◽  
Vanessa Medina Villaamil ◽  
Miquel Taron ◽  
Rafael Rosell ◽  
Luis M. Antón Aparicio
Keyword(s):  
Transitional Cell ◽  
Predictive Markers ◽  
Moderate Activity ◽  
Mrna Levels ◽  
Nucleotide Synthesis ◽  
Real Time Quantitative Pcr ◽  
Response To Chemotherapy ◽  
Total Treatment ◽  
Pre Treatment ◽  
A Prospective Study

e15558 Background: Treatment with platinum derivatives plus pemetrexed has shown a benefit in metastatic transitional cell bladder carcinoma (mTCC); however, the subset of patients most likely to benefit has not yet been identified. Predictive markers of pemetrexed response can be inferred from its mechanism of action in inhibiting nucleotide synthesis. In the present study we evaluated the predictive role of BRCA1, RAP80, TS, REV3 and AEG1 mRNA levels in a series of mTCC samples from patients treated with carboplatin plus pemetrexed (CP) and correlated with pathological response to chemotherapy and median survival. Methods: We retrospectively analyzed 18 patients with mTCC. Eligible patients received pemetrexed 500 mg/m2 in combination with carboplatin at an area under the concentration curve of 5. Total treatment dose was given on day 1 of each cycle and repeated every 21 days for 6 cycles. Gene expression levels were quantified by real-time quantitative PCR from paraffin-embedded pre-treatment tumor samples obtained by transurethral resection. Results: Patients were male, mean age 71 years (range 51-83). Median overall survival was 3.5 years (95% CI, 0.377-3.623). Non-responders had average survival of 2.2 years (SE=0.436) compared to an average of 5.5 years for responders (SE=0.661) (Pearson X2=4.667, p=0.031). We found an association between non-responders and elevated RAP80 expression (paired t (df)=-2.69, p=0.028) (paired t (df)=2.372, p=0.039). In the multivariate analysis elevated TS level was the variable most predictive of shorter survival (OR=1.158, p=0.047). Conclusions: CP regimen demonstrated moderate activity in patients with mTCC. Our data indicates that RAP80 and TS could be predictors of poor outcome. Also, RAP80 expression may predict efficacy of CP as first-line treatment and could be a useful tool to customize therapy in bladder cancer patients. A prospective study is warranted to validate these observations.

Effect of Prostaglandin D2 on mRNA Expression of Three Isoforms of Hyaluronic Acid Synthase in Nasal Polyp Fibroblasts

2020 ◽  
Vol 35 (1) ◽  
pp. 44-51
Author(s):  
Yuji Hirata ◽  
Shin Kariya ◽  
Kengo Kanai ◽  
Tazuko Fujiwara ◽  
Sei-ichiro Makihara ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Mrna Expression ◽  
Nasal Polyp ◽  
Prostaglandin D2 ◽  
Mrna Levels ◽  
Real Time Quantitative Pcr ◽  
Selective Agonist ◽  
Selective Antagonists ◽  
Hyaluronic Acid Synthase ◽  
Pre Treatment

Background Hyaluronan is one of the major extracellular matrixes in chronic rhinosinusitis (CRS) associated with tissue remodeling. Prostaglandin D2 (PGD2) is also associated with the pathogenesis of CRS. However, little is known about whether PGD2 regulates hyaluronan production by human airway fibroblasts. Objective We sought to determine the effect of PGD2 on the mRNA expression of three isoforms of membrane-bound hyaluronic acid synthase (HAS1, HAS2 and HAS3) in fibroblasts, the major source of hyaluronan production, derived from CRS patients. Methods Nasal polyp-derived fibroblasts (NPDF) and uncinate tissue-derived fibroblasts (UTDF) were established from CRS patients with nasal polyps and those without, respectively. These fibroblasts were stimulated with PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. mRNA levels for HAS1, HAS2 and HAS3 were determined by real-time quantitative PCR. Results PGD2 (1 µM) significantly enhanced HAS1 but not HAS2 or HAS3 mRNA expression by NPDF. Enhanced HAS1 mRNA expression was also obtained by stimulation with a DP receptor-selective agonist, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced HAS1 mRNA expression was significantly inhibited by pre-treatment with DP receptor-selective antagonists. Similar induction of PGD2-induced HAS1 mRNA expression was seen in UTDF. Conclusion PGD2 selectively stimulates HAS1 mRNA expression in local fibroblasts in CRS via DP, but not CRTH2, receptors.

BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscle-invasive bladder cancer (MIBC) patients (p) treated with neoadjuvant cisplatin-based chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4579-4579
Author(s):  
Albert Font Pous ◽  
Pamela Celiz ◽  
Miquel Taron ◽  
Iman Chaib ◽  
Jose Luis Gago ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mrna Expression ◽  
Mrna Levels ◽  
Dna Breaks ◽  
Brca1 Expression ◽  
Expression Levels ◽  
Real Time Quantitative Pcr ◽  
Brca1 Mrna ◽  
Pre Treatment

4579 Background: Cystectomy remains the standard treatment in MIBC and only a minority of p are treated with neoadjuvant chemotherapy, suggesting that predictive markers of chemotherapy outcome are needed. Low BRCA1 mRNA expression is associated with an improvement in survival in bladder cancer p treated with cisplatin-based chemotherapy. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 is required for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1 expression and cause chemoresistance. Methods: Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results: 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels (p=0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (p=0.3). No differences in MS were observed according to RAP80 mRNA levels. Conclusions: BRCA1 can be a useful marker to predict the efficacy of neoadjuvant chemotherapy. Cisplatin-based chemotherapy should be recommended in p with low/intermediate BRCA1 expression. Further studies with larger numbers of p are warranted to elucidate the role of AEG-1 in this setting.

scholarly journals Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma

Endocrinology ◽  
2018 ◽  
Vol 159 (8) ◽  
pp. 2836-2849 ◽  
Author(s):  
Vasileios Chortis ◽  
Angela E Taylor ◽  
Craig L Doig ◽  
Mark D Walsh ◽  
Eirini Meimaridou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adrenocortical Carcinoma ◽  
Reduced Form ◽  
Polyamine Metabolism ◽  
Metabolome Analysis ◽  
Nucleotide Synthesis ◽  
Treatment Target ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
Response To Chemotherapy

Abstract Adrenocortical carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. In this study, we evaluated a potential new treatment target for ACC, focusing on the mitochondrial reduced form of NAD phosphate (NADPH) generator nicotinamide nucleotide transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized that NNT silencing in ACC cells will induce toxic levels of oxidative stress. To explore this, we transiently knocked down NNT in NCI-H295R ACC cells. As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. Steroidogenesis was paradoxically stimulated by NNT loss, as demonstrated by mass spectrometry–based steroid profiling. Next, we generated a stable NNT knockdown model in the same cell line to investigate the longer lasting effects of NNT silencing. After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed. This was associated with higher rates of oxygen consumption. The molecular pathways underpinning these responses were explored in detail by RNA sequencing and nontargeted metabolome analysis, revealing major alterations in nucleotide synthesis, protein folding, and polyamine metabolism. This study provides preclinical evidence of the therapeutic merit of antioxidant targeting in ACC as well as illuminating the long-term adaptive response of cells to oxidative stress.

scholarly journals Characterizing intra-tumor regions on quantitative ultrasound parametric images to predict breast cancer response to chemotherapy at pre-treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamidreza Taleghamar ◽  
Hadi Moghadas-Dastjerdi ◽  
Gregory J. Czarnota ◽  
Ali Sadeghi-Naini
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Quantitative Ultrasound ◽  
Parametric Imaging ◽  
Term Survival ◽  
Adaptive Boosting ◽  
Tumor Margin ◽  
Parametric Images ◽  
Response To Chemotherapy ◽  
Pre Treatment

AbstractThe efficacy of quantitative ultrasound (QUS) multi-parametric imaging in conjunction with unsupervised classification algorithms was investigated for the first time in characterizing intra-tumor regions to predict breast tumor response to chemotherapy before the start of treatment. QUS multi-parametric images of breast tumors were generated using the ultrasound radiofrequency data acquired from 181 patients diagnosed with locally advanced breast cancer and planned for neo-adjuvant chemotherapy followed by surgery. A hidden Markov random field (HMRF) expectation maximization (EM) algorithm was applied to identify distinct intra-tumor regions on QUS multi-parametric images. Several features were extracted from the segmented intra-tumor regions and tumor margin on different parametric images. A multi-step feature selection procedure was applied to construct a QUS biomarker consisting of four features for response prediction. Evaluation results on an independent test set indicated that the developed biomarker coupled with a decision tree model with adaptive boosting (AdaBoost) as the classifier could predict the treatment response of patient at pre-treatment with an accuracy of 85.4% and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.89. In comparison, the biomarkers consisted of the features derived from the entire tumor core (without consideration of the intra-tumor regions), and the entire tumor core and the tumor margin could predict the treatment response of patients with an accuracy of 74.5% and 76.4%, and an AUC of 0.79 and 0.76, respectively. Standard clinical features could predict the therapy response with an accuracy of 69.1% and an AUC of 0.6. Long-term survival analyses indicated that the patients predicted by the developed model as responders had a significantly better survival compared to the non-responders. Similar findings were observed for the two response cohorts identified at post-treatment based on standard clinical and pathological criteria. The results obtained in this study demonstrated the potential of QUS multi-parametric imaging integrated with unsupervised learning methods in identifying distinct intra-tumor regions in breast cancer to characterize its responsiveness to chemotherapy prior to the start of treatment.

scholarly journals The Expression and Clinical Significance of Different Forms of Mer Receptor Tyrosine Kinase in Systemic Lupus Erythematosus

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Huaqun Zhu ◽  
Xiaolin Sun ◽  
Lei Zhu ◽  
Fanlei Hu ◽  
Lianjie Shi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Clinical Significance ◽  
Receptor Tyrosine Kinase ◽  
Lupus Erythematosus ◽  
Healthy Subjects ◽  
Mrna Levels ◽  
Systemic Lupus ◽  
Real Time Quantitative Pcr ◽  
Cd163 Expression

Objective. To investigate the expression and clinical significance of trans-membrane MerTK (mMer) on circulating CD14+ monocytes/macrophages and soluble MerTK (sMer) levels in plasma in systemic lupus erythematosus (SLE).Method. 108 SLE patients and 42 healthy controls were recruited in this study. The expression of mMer on the surfaces of CD14+ monocytes/macrophages was evaluated by flow cytometry (FCM). The sMer levels were measured by ELISA. Real-time quantitative PCR was applied to evaluate the mRNA levels of MerTK and ADAM17.Results. Both mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma significantly increased in SLE patients compared to healthy subjects. The frequency of anti-inflammatory MerTK expressing CD14+CD16+ monocytes decreased in SLE. mMer expression was positively correlated with CD163 expression on CD14+ cells. Both the mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma were positively correlated with SLEDAI. Furthermore, more elevated mMer and sMer levels were found in patients with higher SLEDAI, presence of anti-SSA, anti-Sm autoantibodies, and lupus nephritis.Conclusion. Both mMer and sMer levels significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of MerTK expression may serve as a biomarker of the disease activity and severity of SLE.

scholarly journals Differential Expression of TXNIP Isoforms in the Peripheral Leukocytes of Patients with Acute Myocardial Infarction

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Yujing Zhang ◽  
Peng Zhong ◽  
Yingze Xu ◽  
Baokui Wang ◽  
Tao Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Venous Blood ◽  
Mrna Levels ◽  
Endogenous Inhibitor ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Real Time Quantitative Pcr ◽  
The Difference ◽  
Peripheral Leukocytes

Background. Acute myocardial infarction (AMI) is the most serious type of coronary atherosclerotic heart disease (CAD). The pathological changes are characterized by atherosclerosis. Oxidative stress plays an important role in atherosclerosis. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor and regulator of thioredoxin, could bind thioredoxin to regulate its expression and antioxidant activity negatively. The NCBI data show that there are two isoforms in TXNIP gene, namely, TXNIP1 and TXNIP2. Our previous studies have shown that TXNIP expression levels in patients with unstable angina pectoris (UAP) were increased compared with controls (CTR). However, no upregulation of TXNIP was detected in AMI patients. Methods. The leucocytes were isolated from peripheral venous blood, and total RNA of the leucocytes was extracted. Then, real-time quantitative PCR was performed. Results. mRNA levels of TXNIP2 in AMI were significantly increased compared with CTR (P<0.05). However, the expression of TXNIP1 was downregulated in AMI, but the difference was not statistically significant (P>0.05). Logistic regression analysis showed that TXNIP2 mRNA levels were significantly associated with AMI (OR = 2.207, P<0.05). Conclusions. The expression of TXNIP2, not TXNIP1, is upregulated in leukocytes of AMI patients, indicating that only TXNIP2 in circulating leucocytes may be involved in the pathogenesis of AMI.

scholarly journals Size of cervical lesion in locally advanced carcinoma cervix and response to neoadjuvant chemotherapy

2019 ◽  
Vol 8 (11) ◽  
pp. 4254
Author(s):  
Neetu Ahirwar
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Tumour Size ◽  
Locally Advanced ◽  
Vascular Supply ◽  
Cervical Lesion ◽  
Carcinoma Cervix ◽  
Advanced Carcinoma ◽  
Response To Chemotherapy ◽  
Treatment Volume ◽  
Pre Treatment

Background: Recently neoadjuvant chemotherapy has started being considered for advanced stage of carcinoma cervix. Drug delivery to pelvic tumour is optimal with neoadjuvant chemotherapy since tumour vascular supply has not been damaged by any previous pelvic interference. Tumor size and parametrial involvement have been reported to be important predictor of NACT response. Objective of this study was to find out association between size of cervical lesion in locally advanced carcinoma cervix and response to neoadjuvant chemotherapy.Methods: The present prospective cohort study was carried out in the Department of Obstetrics and Gynaecology with the collaboration of Department of Radiotherapy, Chhatrapati Shahuji Maharaj Medical University Lucknow for a period of 1-year august 2010 to august 2011. 26 patients with histologically proven locally advanced carcinoma cervix were studied. In all cases Cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 on day one was given at 14 days interval up to maximum of three courses. Evaluation of operability status was done two weeks after second course of chemotherapy. Those found operable were taken up for radical hysterectomy and rest were given 3rd course of chemotherapy. After two weeks of 3rd course again operability assessment was done and patient was taken up either for surgery or radiotherapy.Results: It was observed that out of 14 patients who had tumour size <4 cm, 9 (64.2%) responded completely (CR), 2 (14.2%) responded partially and 3 (21.4%) responded as SD while in 12 patients with tumour size >4 cm, 4 (33.3%) responded completely (CR) and rest 8 (66.6%) response was partial (PR).Conclusions: Response to chemotherapy was modified by pre-treatment volume of the tumour.

scholarly journals Expression of YAP/TAZ in Keratocystic Odontogenic Tumors and Its Possible Association with Proliferative Behavior

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Qi-Wen Man ◽  
Yan-Qi Ma ◽  
Jin-Yuan Liu ◽  
Yi Zhao ◽  
Bing Liu ◽  
...  
Keyword(s):  
Rank Correlation ◽  
Double Labelling ◽  
Keratocystic Odontogenic Tumor ◽  
Mrna Levels ◽  
Ki 67 ◽  
Normal Oral Mucosa ◽  
Real Time Quantitative Pcr ◽  
Close Relationship ◽  
Proliferative Growth ◽  
Spearman Rank Correlation Test

The aim of this study is to clarify whether YAP/TAZ is involved in the pathogenesis and proliferative growth of keratocystic odontogenic tumor (KCOT). The expression levels of YAP/TAZ and downstream proteins and genes in normal oral mucosa (OM) and KCOT were determined and compared by immunohistochemistry and real-time quantitative PCR. The results showed that the expression of YAP/TAZ and downstream proteins (Cyr61, CTGF) was significantly upregulated in KCOT with upregulation of Ki-67 compared to OM. Importantly, the mRNA levels of transcription factors (TEAD1, TEAD4, and RUNX2) and cell cycle related genes (CDK2, PCNA), which interact with the transcriptional coactivators YAP/TAZ, are also upregulated in the KCOT. In addition, the results from Spearman rank correlation test revealed the close relationship between YAP/TAZ and Ki-67, which was further evidenced by double-labelling immunofluorescence that revealed a synchronous distribution for YAP/TAZ with Ki-67 in KCOT samples. All the data suggested YAP/TAZ might be involved in the proliferative behavior of KCOT.

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