Predictive value of apoptosis, proliferation, HER-2, and topoisomerase IIalpha for anthracycline chemotherapy in locally advanced breast cancer

Purpose. Laboratory evidence indicates that tumor growth depends on the balance between cell proliferation and cell death, and many anticancer agents may exert their therapeutic effect by decreasing proliferation and increasing apoptosis. Additionally, clinical observations indicate that overexpression of HER-2 or topoisomerase II alpha ( topo II alpha) may be predictors of better response to anthracyclines in breast cancer. The objective of this study was to determine if proliferation ( Ki-67), apoptosis ( TUNEL), and expression of HER-2 and topo II alpha are affected by anthracycline treatment, and if these molecular markers predict anthracycline responsiveness. Experimental design. Thirty-three women with primary breast tumors >= 3 cm received either doxorubicin ( 75 mg/ m(2)) or epirubicin ( 120 mg/ m(2)) for 4 cycles before surgery. Clinical response was evaluated after 4 cycles of treatment. Changes in molecular markers were assessed from core needle biopsy taken before treatment (D0), at 24 - 48 h (Dl) and on day 7 (D7) while on treatment, and from the surgical specimen excised on day 84 (D84) after the fourth cycle of chemotherapy. Results. The overall clinical response rate was 51% (17 of 33 patients), with a 12% complete clinical response rate ( 4 of 33 patients). There were trends for tumors with higher apoptosis and topo IIa at baseline ( D0) to be more responsive to anthracyclines, p = 0.1 and p = 0.08, respectively. Median apoptosis increased from D0 to Dl ( p = 0.06) while median Ki-67 decreased ( p = 0.07). Overall, expression of HER-2 remained stable throughout the chemotherapy administration. By Day 84, topo II alpha had significantly decreased from baseline in responders, while it increased in non-responders, p = 0.03. Conclusions. In human primary breast cancer, anthracycline treatment causes an early increase in apoptosis and a decrease in proliferation. In this pilot study, higher apoptosis and topo II alpha a levels in primary tumors were associated with greater responsiveness to anthracyclines, and topo II alpha levels declined in responsive tumors

Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome

The aim of this study was to provide a better insight into breast cancer response to chemotherapy. Chemotherapy improves outcome in breast cancer patients. The effect of cytotoxic treatment cannot be predicted for individual patients. Therefore, the identification of tumour characteristics associated with tumour response and outcome is of great clinical interest. We studied 97 patients, who received anthracycline-based neoadjuvant chemotherapy. Tumour samples were taken prior to and after chemotherapy. We quantified the response to chemotherapy clinically and pathologically and determined histological and molecular tumour characteristics. We assessed changes in the expression of Bcl-2, ER, P53 HER2 and Ki-67. Association with response and outcome was tested for all parameters. The experimental results showed 15 clinical (17%) and three (3%) pathological complete remissions. There were 18 (20%) clinical vs 29 (33%) pathological nonresponders. The expression of most markers was similar before and after chemotherapy. Only Ki-67 was significantly decreased after chemotherapy. Factors correlated with response were: large tumour size, ER negativity, high Ki-67 count and positive P53 status. Tumour response and marker expression did not predict disease-free or overall survival. In conclusion, clinical and pathological response assessments are poorly associated. Proliferation decreases significantly after chemotherapy. ER negativity and a high proliferation index are associated with better response. HER2 status does not predict response, and outcome is not related to tumour response

Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability

<p>Abstract</p> <p>Background</p> <p>Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer.</p> <p>Methods</p> <p>To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR) cells.</p> <p>Results</p> <p>Heat-shock protein 27 (HSP27) expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex.</p> <p>Conclusion</p> <p>Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.</p

Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Epigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression.</p> <p>Methods</p> <p>Cell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. <it>In vivo </it>effect of EGCG on tumor growth was examined in a xenograft model.</p> <p>Results</p> <p>Treatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44°C for 1 h) or oxidative stress (H₂O₂, 500 μM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression.</p> <p>Conclusions</p> <p>Overall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer.</p

Gene therapy for carcinoma of the breast: Pro-apoptotic gene therapy

The dysregulation of apoptosis contributes in a variety of ways to the malignant phenotype. It is increasingly recognized that the alteration of pro-apoptotic and anti-apoptotic molecules determines not only escape from mechanisms that control cell cycle and DNA damage, but also endows the cancer cells with the capacity to survive in the presence of a metabolically adverse milieu, to resist the attack of the immune system, to locally invade and survive despite a lack of tissue anchorage, and to evade the otherwise lethal insults induced by drugs and radiotherapy. A multitude of apoptosis mediators has been identified in the past decade, and the roles of several of them in breast cancer have been delineated by studying the clinical correlates of pathologically documented abnormalities. Using this information, attempts are being made to correct the fundamental anomalies at the genetic level. Fundamental to this end are the design of more efficient and selective gene transfer systems, and the employment of complex interventions that are tailored to breast cancer and that are aimed concomitantly towards different components of the redundant regulatory pathways. The combination of such genetic modifications is most likely to be effective when combined with conventional treatments, thus robustly activating several pro-apoptotic pathways

Monitoring biological wastewater treatment processes: Recent advances in spectroscopy applications

Biological processes based on aerobic and anaerobic technologies have been continuously developed to wastewater treatment and are currently routinely employed to reduce the contaminants discharge levels in the environment. However, most methodologies commonly applied for monitoring key parameters are labor intensive, time-consuming and just provide a snapshot of the process. Thus, spectroscopy applications in biological processes are, nowadays, considered a rapid and effective alternative technology for real-time monitoring though still lacking implementation in full-scale plants. In this review, the application of spectroscopic techniques to aerobic and anaerobic systems is addressed focusing on UV--Vis, infrared, and fluorescence spectroscopy. Furthermore, chemometric techniques, valuable tools to extract the relevant data, are also referred. To that effect, a detailed analysis is performed for aerobic and anaerobic systems to summarize the findings that have been obtained since 2000. Future prospects for the application of spectroscopic techniques in biological wastewater treatment processes are further discussed.The authors thank the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684) and the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. The authors also acknowledge the financial support to Daniela P. Mesquita and Cristina Quintelas through the postdoctoral Grants (SFRH/BPD/82558/2011 and SFRH/BPD/101338/2014) provided by FCT - Portugal.info:eu-repo/semantics/publishedVersio

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Impact of portion control tools on portion size awareness, choice and intake. Systematic review and meta-analysis

Portion control utensils and reduced size tableware amongst other tools, have the potential to guide portion size intake but their effectiveness remains controversial. This review evaluated the breadth and effectiveness of existing portion control tools on learning/awareness of appropriate portion sizes (PS), PS choice, and PS consumption. Additional outcomes were energy intake and weight loss. Published records between 2006–2020 (n = 1241) were identified from PubMed and WoS, and 36 publications comparing the impact of portion control tools on awareness (n = 7 studies), selection/choice (n = 14), intake plus related measures (n = 21) and weight status (n = 9) were analyzed. Non-tableware tools included cooking utensils, educational aids and computerized applications. Tableware included mostly reduced-size and portion control/calibrated crockery/cutlery. Overall, 55% of studies reported a significant impact of using a tool (typically smaller bowl, fork or glass; or calibrated plate). A meta-analysis of 28 articles confirmed an overall effect of tool on food intake (d = −0.22; 95%CI: −0.38, −0.06; 21 comparisons), mostly driven by combinations of reduced-size bowls and spoons decreasing serving sizes (d = −0.48; 95%CI: −0.72, −0.24; 8 comparisons) and consumed amounts/energy (d = −0.22; 95%CI: −0.39, −0.05, 9 comparisons), but not by reduced-size plates (d = −0.03; 95%CI: −0.12, 0.06, 7 comparisons). Portion control tools marginally induced weight loss (d = −0.20; 95%CI: −0.37, −0.03; 9 comparisons), especially driven by calibrated tableware. No impact was detected on PS awareness; however, few studies quantified this outcome. Specific portion control tools may be helpful as potentially effective instruments for inclusion as part of weight loss interventions. Reduced size plates per se may not be as effective as previously suggested