BRCA1 protein expression as a predictor of outcome following chemotherapy in sporadic epithelial ovarian cancer (EOC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5527-5527 ◽  
Author(s):  
J. E. Carser ◽  
J. E. Quinn ◽  
C. O. Michie ◽  
W. G. McCluggage ◽  
A. R. Williams ◽  
...  
Keyword(s):  
Protein Expression ◽  
Predictive Marker ◽  
Chemotherapy Response ◽  
Positive Staining ◽  
Brca1 Protein ◽  
Enhanced Sensitivity ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Taxane Chemotherapy

5527 Background: Reduced expression of BRCA1 is observed in a substantial proportion of sporadic EOC. First line management of EOC involves platinum and taxane based chemotherapy. In vitro studies demonstrate that reduction in BRCA1 protein expression leads to enhanced sensitivity to platinum but relative resistance to taxane chemotherapy. We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and survival in EOC patients, correlating outcome with type of chemotherapy received. Methods: 97 archival formalin-fixed, paraffin embedded tumour samples were identified from the Edinburgh Cancer Centre ovarian database. All patients received platinum based chemotherapy (platinum only n = 50, platinum/taxane n = 47). Tumour sections were stained for BRCA1 protein and scored by two independent reviewers. Tumours were graded from 0 (no BRCA1 protein) to 4 (>90% cells positive). BRCA1 protein expression was correlated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. Results: Overall, patients with no detectable BRCA1 protein had a significantly improved PFS compared to those with positive staining (17.4 months vs 12.2 months, p = 0.04). Specifically, patients receiving platinum only regimens had a significantly improved PFS if they had no detectable BRCA1 protein compared to those with positive staining (14.5 months vs 10.8 months, p = 0.035).In contrast, patients positive for BRCA1 protein (grades 1–4) had a significant increase in both OS (43.7 months vs 20.4 months, p = 0.03) and PFS (12.7 months vs 10.9 months p = 0.02) if they received platinum/taxane combination over platinum alone. Patients with no detectable BRCA1 protein (grade 0) had no significant difference in OS or PFS whether they were treated with combination or platinum only chemotherapy. Conclusions: This study provides initial evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic EOC. Specifically, patients with positive BRCA1 staining demonstrate a better clinical outcome with platinum/taxane based chemotherapy over platinum alone whereas no such difference was seen in those with no BRCA1. Further prospective clinical studies are required to validate these findings. No significant financial relationships to disclose.

scholarly journals Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response

2021 ◽  
Author(s):  
Noha Gwili ◽  
Stacey J. Jones ◽  
Waleed Al Amri ◽  
Ian M. Carr ◽  
Sarah Harris ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Predictive Marker ◽  
Therapy Resistance ◽  
Differentially Expressed ◽  
Molecular Profile ◽  
Chemotherapy Response ◽  
Breast Cancers

Abstract Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5503-5503
Author(s):  
W. K. Huh ◽  
J. M. Straughn ◽  
D. E. Cohn
Keyword(s):  
Endometrial Cancer ◽  
Single Agent ◽  
Response Rates ◽  
Chemotherapeutic Agents ◽  
Primary Objective ◽  
Stage I ◽  
Chemotherapy Response ◽  
Vitro Assay ◽  
Significant Difference

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]

Association of ERCC1 protein expression to platinum resistance in epithelial ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5530-5530
Author(s):  
K. D. Steffensen ◽  
M. Waldstrøm ◽  
A. Jakobsen
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Tumor Cells ◽  
Excision Repair ◽  
Positive Association ◽  
Platinum Resistance ◽  
Newly Diagnosed ◽  
Platinum Based Chemotherapy ◽  
Clinical Resistance ◽  
Significant Difference

5530 Background: Although platinum-based chemotherapy remains the cornerstone for treatment of ovarian cancer, some patients are resistant to the treatment and will therefore not benefit from the standard platinum-based chemotherapy. Preclinical and clinical data have suggested a potential use of ERCC1 (excision repair cross-complementation group 1 enzyme) as a molecular predictor of clinical resistance to platinum-based chemotherapy. ERCC1 is a key enzyme in the nucleotide excision repair pathway which is involved in the DNA repair mechanisms in tumor cells. The primary aim of the present study was to investigate if immunohistochemical expression of ERCC1 protein was associated with resistance to standard combination carboplatin and paclitaxel chemotherapy in newly diagnosed ovarian cancer patients. Methods: Formalin-fixed, paraffin-embedded tissue sections from 101 patients with newly diagnosed ovarian cancer were used for immunohistochemical staining for the ERCC1 protein. The percentage of positive tumor cells in each slide were scored as 0 if 0 % of the tumor cells were positive, 0.1 if 1 %-9 %; 0.5 if 10 %-49 %; and 1.0 if 50 % or more were positive. A semi quantitative H-score was calculated by multiplying the staining intensity (0–3) with the percentage score. The tumor was considered positive when the H-score was > 1.0. All patients received carboplatin-paclitaxel combination chemotherapy. Results: ERCC1 protein overexpression was found in 13.9 % of the tumors. Platinum resistance were found in 75 % of the tumors with positive ERCC1 protein expression compared to 27 % among the patients with negative tumor staining for ERCC1 (p = 0.0013). These findings translated into a significant difference in progression free survival in both univariate (p = 0.0012) and in multivariate analysis (p = 0.006). Conclusions: The data presented suggests a positive association between positive ERCC1 protein expression and clinical resistance to platinum-based chemotherapy. No significant financial relationships to disclose.

scholarly journals A possible Injectable Tissue Engineered Nucleus Pulposus constructed with platelet-rich plasma and ADSCs in Vitro

2020 ◽  
Author(s):  
Zhicheng Zhang ◽  
Jian Ma ◽  
Dajiang Ren ◽  
Fang Li
Keyword(s):  
Nucleus Pulposus ◽  
Platelet Rich Plasma ◽  
Positive Staining ◽  
Adipose Derived Stromal Cells ◽  
Genes Expression ◽  
Significant Difference ◽  
Safranin O ◽  
Collagen Genes ◽  
Prp Gel

Abstract Background: Injectable tissue engineered nucleus pulposus is a new idea for minimally invasive repair for degenerative intervertebral disc. The platelet-rich plasma (PRP) and adipose derived stromal cells(ADSCs) could be harvested from autologous tissue easily. PRP has mixed autologous growth factors and fibrous reticulate structure which may have the potential to make ADSCs differentiated into nucleus pulposus-like cells. The goal of this study was to explore the feasibility of constructing a possible injectable tissue engineered nucleus pulposus with PRP gel scaffold and ADSCs. Methods: After the rabbit ADSCs were identified with flow cytometry, the ADSCs were seeded into PRP gel and cultured in vitro. At the 2nd, 4th and 8th week, the PRP gel/ADSCs complex was observed by macroscopy, histological staining, BrdU immunofluorescence, and scanning electron microscopy. The glycosaminoglycans (GAG) in the PRP gel/ADSCs complex were measured by safranin O staining with spectrophotometry. PRP gel/ADSCs complex genes expression of HIF-1α, Aggrecan, Type Ⅱ collagen were detected by RT-PCR. The injectability of this complex was tested. Results: Macroscopically, the complex was solidified into gel with smooth surface and good elasticity. The safranin O staining confirmed almost no positive staining at 2nd week, however, the positive staining of extracellular matrix was enhanced obviously at 4th, 8th week. The HE staining and SEM demonstrated that the cells were well-distributed in the reticulate scaffold. BrdU immunofluorescence showed that ADSCs can survive and proliferate in PRP gel at each time points. The level of GAG at 4th week was higher than those at 2nd week (P<0.05), and significant difference was also noted between 4th and 8th week (P<0.05). HIF-1α, Aggrecan, Type Ⅱ collagen genes expression at 4th week were much more than those at 2nd week (P<0.05), and significant differences were also noted between 4th and 8th week (P<0.05). The flow rate of complex was 0.287 mL/min when passed through the 19-gauge needle with the 100mmHg pressure. Conclusions: The PRP gel made it possible for rabbit ADSCs differentiated into nucleus pulposus-like cells after mixed culture in vitro. Maybe, it is a better feasible method for construction of autologous injectable tissue engineered nucleus pulposus.

218 GENE AND PROTEIN EXPRESSION OF ANTIOXIDANT ENZYMES IN BOVINE EMBRYOS EXPOSED TO HEAT SHOCK

2009 ◽  
Vol 21 (1) ◽  
pp. 207
Author(s):  
M. Sakatani ◽  
K. Yamanaka ◽  
M. Takahashi
Keyword(s):  
Antioxidant Enzymes ◽  
Heat Shock ◽  
Protein Expression ◽  
Early Stage ◽  
Bovine Embryos ◽  
Cell Stage ◽  
Expression Levels ◽  
Gene And Protein Expression ◽  
Significant Difference

In a previous study, we reported that 8-cell-stage embryos exposed to a temperature of 41°C for 6 h had significantly increased embryonic mortality and intracellular reactive oxygen species (ROS). There have been some reports that ROS regulates the expression of genes encoding antioxidant enzymes in culture cells. In this study, we investigated the gene and protein expression of antioxidant enzymes in bovine 8-cell-stage embryos exposed to heat shock. In vitro-produced bovine embryos were used for the experiment. Embryos were cultured with CR1aa + 5% FCS at 38.5°C in 5% CO2 and 5% O2. On Day 2 after fertilization, 8-cell-stage embryos were exposed to heat shock at 41°C in 5% CO2 and 5% O2 for 6 h (HS). Eight-cell-stage embryos cultured at 38.5°C in 5% CO2 and 5% O2 were sampled at the same collection time as controls. After HS, 20 embryos were immediately collected for gene expression analysis. Expression of heat shock protein 70 (HSP70), CuZn-containing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxide (GPx) genes was examined by real-time polymerase chain reaction. Twenty embryos were also collected after 3 h of HS (3 h) and at 18 h after HS (18 h) to evaluate the expression of proteins. Expression of HSP70, SOD, and CAT proteins was examined by Western blotting. Both the gene and protein expression levels of HS groups were normalized to those of the controls to obtain the relative expression levels. All results were analyzed by Student’s t-test. Expression of the HSP70 gene significantly increased in HS embryos (P < 0.05). Expression of the SOD and CAT genes tended to increase in HS embryos (P < 0.07), but there were no significant differences in expression of the GPx gene. There was no significant difference in protein expression in all the antioxidant enzymes in 3-h-sampled embryos. Expression of the HSP70 protein increased significantly in heat-shocked embryos sampled at 18 h (P < 0.05). These results indicate that expression of antioxidant enzymes was not greatly affected in 8-cell-stage embryos exposed to HS. Thus, these results suggest the possibility that the early-stage embryos were stressed and damaged from heat shock because of their poor antioxidative potency. Table 1.Gene and protein expression of embryos This work was supported by KAKENHI [16780209, Grant-in-Aid for Young Scientists (B)].

scholarly journals Dexmedetomidine may decrease the bupivacaine toxicity to heart

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1070-1075
Author(s):  
Zhousheng Jin ◽  
Fangfang Xia ◽  
Tingting Lin ◽  
Yaoyao Cai ◽  
Hongfei Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Cell Activity ◽  
Cell Permeability ◽  
Cell Counting ◽  
Related Factors ◽  
Pi3k Inhibitors ◽  
Significant Difference ◽  
Bupivacaine Toxicity

Abstract Objective The purpose of our study was to explore the effect of dexmedetomidine on cardiac tolerance to bupivacaine. Method Human coronary endothelial cells were used to establish in vitro model. They were randomly divided into control (Con) group, dexmedetomidine (Dex) group, bupivacaine (Bupi) group, dexmedetomidine + bupivacaine group (DB group), and dexmedetomidine + bupivacaine + PI3K inhibitor (DB-inhibitor) group. Cell activity was measured by Cell counting kit-8 (CCK-8). Transwell was used to detect cell permeability. Western blotting was used to detect the protein expression of related factors. Results There were no notable differences in cell activity among the five groups (P > 0.05). Dexmedetomidine significantly reduced the permeability of endothelial cells to bupivacaine and increased the protein expression of Zonulaoeeludens-1 (ZO-1) (P < 0.01). However, the aforementioned effects of dexmedetomidine were disappeared after the addition of PI3K inhibitors. Furthermore, Dex and DB markedly increased the protein expression of PI3K, p-Akt, and p-PTEN in comparison with Con group (P < 0.001), but there was no significant difference in p-PTEN among DB-inhibitor, Con, and Bupi groups (P > 0.05). Conclusion Dex reduced Bupi-induced vasopermeability through protein expression of ZO-1 and PI3K/Akt pathway, which may lead to the decrease of Bupi-induced cardiotoxicity.

Abstract 640: Overexpression of Vasohibin-2 Exacerbates Development of Angiotensin II-Induced Thoracic Aortic Aneurysms Independent of VeEGF

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Michihiro Okuyama ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Yuki Kakio ◽  
Hidemi Takeuchi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Aortic Arch ◽  
Gelatin Zymography ◽  
Annexin V ◽  
Aortic Aneurysms ◽  
Tunel Staining ◽  
Significant Difference

Objective: Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Vasohibin-2 (VASH2) is known to cause angiogenesis at the sprouting front of neovascularization. The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs. Methods: Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 10 9 vp/100 μL) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by en face method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism. Result: Intima area of aortic arch was significantly larger in AngII + Ad VASH2 group than in AngII + Ad LacZ group (19.78 ± 0.40 mm 3 vs 17.74 ± 0.44 mm 3 , P < 0.001). Gelatin zymography demonstrated that AngII upregulated latent MMP-2 expression, and activated MMP-2 most prominently in AngII + VASH2 group. Protein expression of p21 and p53 in thoracic aortas was enhanced in AngII + VASH2 group. Positive TUNEL staining was observed in thoracic aortic wall of AngII + VASH2 group. No significant difference in intima area of aortic arch between AngII + Ad VASH2 + saline group and AngII + Ad VASH2 + bevacizumab group. In vitro, the same results were observed regarding protein expression of p21 and p53, and TUNEL staining. In addition, Annexin-V staining was detected only in AngII + VASH2 group. Conclusion: Overexpression of VASH2 accelerated development of AngII-induced TAAs in vivo. VASH2-induced cell apoptosis may influence AngII-induced TAA formation independent of VEGF.

scholarly journals LDHA and CPT2 association with therapy resistance in prostate cancer

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
F Q Vieira ◽  
A R Cardoso ◽  
D Gigliano ◽  
I Carneiro ◽  
R Henrique ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Predictive Marker ◽  
Selective Advantage ◽  
Therapy Resistance ◽  
Cancer Drug ◽  
Chi Square ◽  
Significant Difference ◽  
Blinded Manner ◽  
Chi Square Test

Abstract Background The aerobic glycolysis as energy source in cancer confers a selective advantage for its proliferation and survival. Previous in vitro studies demonstrated that treatment with [C16Pyr][Amp], a potential anti-cancer drug in prostate, decreased the transcript levels of LDHA and CPT2, both involved in metabolic plasticity. In fact, LDHA and CPT2 were reported to be overexpressed in cancer, with association with poor prognosis and resistance to chemo- and radiotherapy. Since LDHA and CPT2 can be potential therapy resistance biomarkers, the aim of this work was to assess LDHA and CPT2 expression using PCa tissues. Methods LDHA and CPT2 expression was evaluated by immunohistochemistry in 57 PCa tissues, 24 from patients that developed resistance to hormonal therapy and 33 without therapy resistance. For both proteins, percentage of positive tumor cells, intensity of immunostaining, and immunoexpression pattern was determined by a blinded manner. Comparisons between therapy variables and protein expression were assessed using the Chi square test. P &lt; 0.05 indicated a statistically significant difference. Results LDHA expression is significantly associated with therapy resistance (P &lt; 0.001). Moreover, CPT2 pattern’s immunoexpression is also associated with therapy resistant (P &lt; 0.001), being cytoplasmatic expression most frequent in patients that respond to therapy (41%), whereas both nuclear and cytoplasmatic expression is more prevalent in therapy-resistant cases (48%). Conclusions LDHA overexpression is significantly associated with therapy resistance in PCa cases, while CPT2 cell expression distribution might be a predictive marker.

Predictive Model for Live Birth at 12 Months After Starting In-Vitro Fertilization Treatment

MedPharmRes ◽  
2018 ◽  
Vol 2 (2) ◽  
pp. 5-20
Author(s):  
Vu Ho ◽  
Toan Pham ◽  
Tuong Ho ◽  
Lan Vuong
Keyword(s):  
In Vitro Fertilization ◽  
Live Birth ◽  
Cox Regression ◽  
Financial Burden ◽  
Oocyte Retrieval ◽  
Operating Characteristics ◽  
Vitro Fertilization ◽  
Cox Regression Analysis ◽  
Significant Difference

IVF carries a considerable physical, emotional and financial burden. Therefore, it would be useful to be able to predict the likelihood of success for each couple. The aim of this retrospective cohort study was to develop a prediction model to estimate the probability of a live birth at 12 months after one completed IVF cycle (all fresh and frozen embryo transfers from the same oocyte retrieval). We analyzed data collected from 2600 women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) at a single center in Vietnam between April 2014 and December 2015. All patients received gonadotropin-releasing hormone (GnRH) antagonist stimulation, followed by fresh and/or frozen embryo transfer (FET) on Day 3. Using Cox regression analysis, five predictive factors were identified: female age, total dose of recombinant follicle stimulating hormone used, type of trigger, fresh or FET during the first transfer, and number of subsequent FET after the first transfer. The area under the receiver operating characteristics curve for the final model was 0.63 (95% confidence interval [CI] 0.60‒0.65) and 0.60 (95% CI 0.57‒0.63) for the validation cohort. There was no significant difference between the predicted and observed probabilities of live birth (Hosmer-Lemeshow test, p > 0.05). The model developed had similar discrimination to existing models and could be implemented in clinical practice.

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