Cytotoxic Properties on Cervical and Liver Cancer Cells of Two Plant Recipes from Burkina Faso

Cancer is one of the deadliest diseases in developing countries. In recent years, natural plant-based compounds have been used in the search for drugs to combat numerous diseases, including cancer. In this study, we evaluate the cytotoxic properties of paanfo tiben 1 and paanfo tiben 2, two traditional herbal formulations from Burkina Faso used in the treatment of cancer in Burkina Faso. To this end, the recipes were infused and freeze-dried. The dry extracts obtained were used to determine total phenolics and flavonoids content, assess antioxidant activity using the DPPH, ABTS and FRAP methods, evaluate anti-inflammatory properties by inhibiting 15-LOX, COX 1 and 2, and assess cytotoxic activity on HeLa cervical cancer and HePG2 liver cancer cell lines using the MTT test. The paanfo tiben 1 recipe showed the highest levels of total phenolics and flavonoids, as well as the best antioxidant activities, with IC50 values of 21.020 ± 0.6 µg/ml and 22.94 ± 0.57 µg/ml for DPPH and ABTS, and 165.15 mM EAA/mg dry extract for FRAP. It also exhibited the best cytotoxic activity with IC50 values of 112.02 ± 0.025 µg/ml on HeLa cells and 80.67 ± 6.08 µg/ml on HepG2 cells. On the other hand, paanfo tiben 2 exhibited the best anti-inflammatory activities through inhibition of 15-LOX and COX 1, with inhibition percentages at 100 µg/ml of 32.523% and 24.717 % respectively. These results could justify the traditional use of these two recipes by traditional health practitioners in the treatment of cancer sufferers in Burkina Faso.

mir-3168 targeted inhibition of TP53 promotes malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells

Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.

奈妥匹坦帕洛诺司琼预防化疗引起的恶心呕吐:从临床试验到日常临床实践

化疗引起的恶心呕吐(CINV)是众多抗癌药物治疗中常见的不良事件,不仅会对患者生活质量带来负面影响,还有可能影响化疗效果。目前,指南建议的止吐方案可以预防大部分癌症患者的CINV。但临床医师并不能始终遵循指南建议,患者也常常难以坚持医师处方的治疗。因此需要采取一些提高指南依从性的方法。奈妥匹坦帕洛诺司琼(NEPA)是首个也是唯一一个固定剂量复方止吐药,由奈妥匹坦(口服)/福奈妥匹坦(静脉给药)与帕洛诺司琼(PALO)组成。NEPA可以联合地塞米松组成三联止吐方案,这是用于高致吐性化疗(HEC)患者和部分中致吐性化疗(MEC)患者预防CINV的推荐方案。因此,NEPA止吐治疗操作简单便捷,可能有助于提高指南依从性。本综述对CINV进行了概括,评价了在临床试验和真实实践中积累的NEPA止吐效果及安全性方面的证据,同时也评价了在关键临床试验之外的环境下,即日常临床环境中使用NEPA进行止吐的初步证据。此外,本文还评述了化疗期间使用NEPA控制恶心症状和提高患者生活质量,这是癌症患者管理中面临的两个大挑战。

Micro RNAs in colorectal cancer:Role in metastasis and clinical perspectives

Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer related deaths in the United States. Almost 90% of the patients diagnosed with CRC die due to metastases. MicroRNAs (miRNAs) are evolutionarily conserved molecules that modulate the expression of their target genes post-transcriptionally, and they may participate in various physiological and pathological processes including CRC metastasis by influencing various factors in the human body. Recently, the role miRNAs play throughout the CRC metastatic cascade has gain attention. Many studies have been published to link them with CRC metastasis. In this review, we will briefly discuss metastatic steps in the light of miRNAs, along with their target genes. We will discuss how the aberration in the expression of miRNAs leads to the formation of CRC by effecting the regulation of their target genes. As miRNAs are being exploited for diagnosis, prognosis, and monitoring of cancer and other diseases, their high tissue specificity and critical role in oncogenesis make them new biomarkers for the diagnosis and classification of cancer as well as for predicting patients’ outcome. MiRNA signatures have been identified for many human tumors including CRC, and miRNA-based therapies to treat cancer have been emphasized lately. These will also be discussed in this review.

Nitrosamine and related food intake and gastric and oesophageal cancer risk: A systematic review of the epidemiological evidence

AIM： To study the association between nitrite and nitrosamine intake and gastric cancer （GC）, between meat and processed meat intake, GC and oesophageal cancer （OC）, and between preserved fish, vegetable and smoked food intake and GC. METHODS： In this article we reviewed all the published cohort and case-control studies from 1985-2005, and analyzed the relationship between nitrosamine and nitrite intake and the most important related food intake （meat and processed meat, preserved vegetables and fish, smoked foods and beer drinking） and GC or OC risk. Sixty-one studies, 11 cohorts and 50 case-control studies were included. RESULTS： Evidence from case-control studies supported an association between nitrite and nitrosamine intake with GC but evidence was insufficient in relation to OC. A high proportion of case-control studies found a positive association with meat intake for both tumours （11 of 16 studies on GC and 11 of 18 studies on OC）. A relatively large number of case-control studies showed quite consistent results supporting a positive association between processed meat intake and GC and OC risk （10 of 14 studies on GC and 8 of 9 studies on OC）. Almost all the case-control studies found a positive and significant association between preserved fish, vegetable and smoked food intake and GC. The evidence regarding OC was more limited. Overall the evidence from cohort studies was insufficient or more inconsistent than that from case-control studies.CONCLUSION： The available evidence supports a positive association between nitrite and nitrosamine intake and GC, between meat and processed meat intake and GC and OC, and between preserved fish, vegetable and smoked food intake and GC, but is not conclusive.

Analysis of risk factors for the interval time, number and pattern of hepatic metastases from gastric cancer after radical gastrectomy

AIM: To analyze the risk factors for interval time, number and pattern of hepatic metastases from gastric cancer after radical gastrectomy, and provide evidence for predicting and preventing hepatic metastasis from gastric cancer after radical gastrectomy. METHODS: A retrospective study of 87 patients with hepatic metastasis who underwent radical gastrectomy for gastric cancer from 1996 to 2001. The data was analyzed to evaluate significant risk factors for interval time, number and pattern of hepatic metastases originating from gastric cancer after radical gastrectomy. RESULTS: The size of gastric cancer and lymph node metastases were independently correlated with the interval time of hepatic metastases; the depth of invasion was independently correlated with the number of hepatic metastases; while the depth of invasion and Lauren classification were independently correlated with the pattern of hepatic metastases. CONCLUSION: We evaluated the interval time of hepatic metastases with the size of gastric cancer and lymph node metastases. The depth of invasion could be used to evaluate the number of hepatic metastases, while the depth of invasion and the Lauren classification could be used to evaluate the pattern of hepatic metastases in patients who underwent radical gastrectomy.

Long noncoding RNA NALT1-induced gastric cancer invasion and metastasis via NOTCH signaling pathway

BACKGROUNDLong noncoding RNAs (lncRNAs) are aberrant and play critical roles in gastriccancer (GC) progression and metastasis. Searching for coexpressed lncRNAclusters or representative biomarkers related to malignant phenotypes of GC mayhelp to elucidate the mechanism of tumor development and predict the prognosisof GC.AIMTo investigate the prognostic value of NOTCH1 associated with lncRNA in T cellacute lymphoblastic leukemia 1 (NALT1) in GC and the mechanism of itsinvolvement in GC invasion and metastasis.METHODSRNA sequencing and corresponding clinical data were downloaded from TheCancer Genome Atlas database. The significance module was studied byweighted gene coexpression network analysis. A total of 336 clinical sampleswere included in the study. Gene silencing, reverse transcription polymerasechain reaction, western blotting, scrape motility assay, and Transwell migrationassay were used to assess the function of hub-lncRNAs.RESULTSAt the transcriptome level, 3339 differentially expressed lncRNAs were obtained.weighted gene coexpression network analysis was used to obtain 15 lncRNAclusters and observe their coexpression. Pearson’s correlation showed that blue module was correlated with tumor grade and survival. NALT1 was the hublncRNAof blue module and was an independent risk factor for GC prognosis.NALT1 was overexpressed in GC and its expression was closely related toinvasion and metastasis. The mechanism may involve NALT1 regulation ofNOTCH1, which is associated with lncRNA in T cell acute lymphoblasticleukemia, through cis regulation, thereby affecting the expression of the NOTCHsignaling pathway.CONCLUSIONNALT1 is overexpressed and promotes invasion and metastasis of GC. Themechanism may be related to regulation of NOTCH1 by NALT1 and its effect onNOTCH signaling pathway expression.

Evaluation of rational extent lymphadenectomy for local advanced gastric cancer

Based upon studies from randomized clinical trials, the extended （D2） lymph node dissection is now recommended as a standard procedure for local advanced gastric cancer worldwide. However, the rational extent lymphadenectomy for local advanced gastric cancer has remained a topic of debate in the past decades. Due to the limitation of low metastatic rate in para-aortic nodes （PAN） in JCOG9501, the clinical benefit of D2＋ para-aortic nodal dissection （PAND） for patients with stage T4 and/or stage N3 disease, which is very common in China and other countries except Japan and Korea, cannot be determined. Furthermore, the role of splenectomy for complete resection of No.10 and No.l I nodes has been controversial, and however, the final results from the randomized trial ofJCOG0110 have yet to be completed. Gastric cancer with the No.14 and No.13 lymph node metastasis is defined as MI stage in the current version of the Japanese classification. We propose that D2~No.14v and ＋No.13 lymphadenectomy may be an option in a potentially curative gastrectomy for tumors with apparent metastasis to the No.6 nodes or infiltrate to duodenum. The examined lymph node and extranodal metastasis are significantly associated with the survival of gastric cancer patients.

Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer:efficacy,safety,and biomarker results from Chinese patients

Overexpression of human epidermal growth factor receptor-2(HER2) in metastatic breast cancer(MBC) is associated with poor prognosis.This single-arm open-label trial(EGF109491;NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC.The primary endpoint was clinical benefit rate(CBR).Secondary endpoints included progression-free survival(PFS),time to response(TTR),duration of response(DoR),central nervous system(CNS) as first site of relapse,and safety.The results showed that there were 23 patients with partial responses and 7 patients with stable disease,resulting in a CBR of 57.7%.The median PFS was 6.34 months(95% confidence interval,4.93-9.82 months).The median TTR and DoR were 4.07 months(range,0.03-14.78 months) and 6.93 months(range,1.45-9.72 months),respectively.Thirteen(25.0%) patients had new lesions as disease progression.Among them,2(3.8%) patients had CNS disease reported as the first relapse.The most common toxicities were palmar-plantar erythrodysesthesia(59.6%),diarrhea(48.1%),rash(48.1%),hyperbilirubinemia(34.6%),and fatigue(30.8%).Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample,baseline PIK3CA mutation status was not associated with CBR(P = 0.639) or PFS(P = 0.989).These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC,irrespective of PIK3CA status.

Psychological evaluation of patients after breast cancer surgery and care strategies improvement

Objective: The aim of the study was to investigate the level of self-image of patients after breast cancer surgery, and explore factors influencing self-image among patients who have experienced different types of surgeries, and set out a foundation for the improvement of care strategies. Methods: The 538 patients with primary breast cancer who underwent surgery in the Department of Breast Surgery, First Hospital of China Medical University, Shenyang, China, from January 2004 to January 2009 were included in the study. The psychological status of the patients was evaluated by body image after breast cancer questionnaire (BIBCQ), social support rating scale (SSRS), self-rating anxiety scale (SRAS), depression rating scale (DRS), and general information questionnaire. The factors influencing the self-image were selected by a stepwise regression analysis. Results: The patients who underwent breast-conserving surgery were the most satisfied with their body image, followed by those underwent surgery of modified radical mastectomy with reconstruction. However, cases treated by modified radical mastectomy without reconstruction had negative outcomes. Regardless of operation type, the self-image was influenced by anxiety, level of abuse by husband, and sexual satisfaction after operation. Conclusion: The self-image of patients who underwent different breast cancer surgeries was influenced by different factors, and individualized nursing should be offered in accordance with the specific situation.

Current and future molecular diagnostics in colorectal cancer and colorectal adenoma

Colorectal cancer(CRC)is one of the most prevalent cancers in developed countries.On the other hand,CRC is also one of the most curable cancers if it is detected in early stages through regular colonoscopy or sigmoidoscopy.Since CRC develops slowly from precancerous lesions,early detection can reduce both the incidence and mortality of the disease.Fecal occult blood test is a widely used non-invasive screening tool for CRC.Although fecal occult blood test is simple and cost-effective in screening CRC,there is room for improvement in terms of the accuracy of the test.Genetic dysregulations have been found to play an important role in CRC development.With better understanding of the molecular basis of CRC,there is a growing expectation on the development of diagnostic tests based on more sensitive and specific molecular markers and those tests may provide a breakthrough to the limitations of current screening tests for CRC.In this review,the molecular basis of CRC development,the characteristics and applications of different non-invasive molecular biomarkers,as well as the technologies available for the detection were discussed.This review intended to provide a summary on the current and future molecular diagnostics in CRC and its pre-malignant state,colorectal adenoma.

HER2 in gastric cancer: Comparative analysis of three different antibodies using whole-tissue sections and tissue microarrays

AIM:To compare the performance of three commercially available anti-human epidermalgrowth factor receptor 2(HER2)antibodies in whole-tissue sections and tissue microarrays(TMAs)of a series of gastric tumors.METHODS:We present a comparative analysis of three anti-HER2 antibodies(HercepTest,4B5 and SP3)using TMA and whole-tissue sections prepared from the same paraffin blocks of 199 gastric adenocarcinomas operated upon between January 2004 and December2008 at a Brazilian cancer hospital.The data on the patients’age,sex,the anatomical location of the tumor and the Lauren’s histological classification were collected from clinical and pathological records.The immunohistochemical(IHC)results were examined by two pathologists and the cases were classified as positive(3+),equivocal(2+)and negative(0 or 1+),according to the criteria of the IHC scoring system of gastric cancer.TMAs and whole-tissue sections were evaluated separately and independently.All cases yielding discordant IHC results and/or scored as 2+were subjected to dual-color in situ hybridization in order to determine the final HER2 status.Besides determining the sensitivity and predictive value for HER2-positive status,we measured the accuracy of each antibody by calculating the area under the receiver operating characteristic(ROC)curve.The agreement between the results obtained using the TMAs and those obtained using the whole-tissue sections was assessed by means of Kappa coefficient.RESULTS:Intratumoral heterogeneity of HER2 expression was observed with all antibodies.HER2-positive expression(3+)in the whole-tissue sections was observed in 23 cases(11.6%)using the 4B5 antibody,in 18 cases(9.1%)using the SP3 antibody and in 10 cases(5.1%)using the HercepTest antibody.In the TMAs,11 positive cases(5.6%)were identified using SP3 antibody,9(4.6%)using the 4B5 antibody and 6(3%)using the HercepTest antibody.The sensitivity using whole-tissue sections and TMA,respectively,was 95.2%and 42.9%with 4B5,90.5%and 66.7%with SP3 and 47.6%and42.9%with HercepTest.The accuracy,calculated from the area under the ROC curve,using whole-tissue sections and TMA,respectively,was 0.91 and 0.79 by 4B5,0.86 and 0.80 by SP3 and 0.73 and 0.71 by HercepTest.The concordance of the results obtained using wholetissue sections and TMA was 97.4%(Kappa 0.75)using HercepTest,85.6%(Kappa 0.56)using SP3 and 84.1%(Kappa 0.38)using 4B5.CONCLUSION:The use of the 4B5 antibody on wholetissue sections was the most accurate IHC method for evaluating HER2 expression in gastric adenocarcinoma.

Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population

Objective:Hereditary colorectal cancer(CRC)accounts for approximately 5%–10%of all CRC cases.The full profile of CRC-related germline mutations and the corresponding somatic mutational profile have not been fully determined in the Chinese population.Methods:We performed the first population study investigating the germline mutation status in more than 1,000(n=1,923)Chinese patients with CRC and examined their relationship with the somatic mutational landscape.Germline alterations were examined with a 58-gene next-generation sequencing panel,and somatic alterations were examined with a 605-gene panel.Results:A total of 92 pathogenic(P)mutations were identified in 85 patients,and 81 likely pathogenic(LP)germline mutations were identified in 62 patients,accounting for 7.6%(147/1,923)of all patients.MSH2 and APC was the most mutated gene in the Lynch syndrome and non-Lynch syndrome groups,respectively.Patients with P/LP mutations had a significantly higher ratio of microsatellite instability,highly deficient mismatch repair,family history of CRC,and lower age.The somatic mutational landscape revealed a significantly higher mutational frequency in the P group and a trend toward higher copy number variations in the non-P group.The Lynch syndrome group had a significantly higher mutational frequency and tumor mutational burden than the nonLynch syndrome group.Clustering analysis revealed that the Notch signaling pathway was uniquely clustered in the Lynch syndrome group,and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group.Population risk analysis indicated that the overall odds ratio was 11.13(95%CI:8.289–15.44)for the P group and 20.68(95%CI:12.89–33.18)for the LP group.Conclusions:Distinct features were revealed in Chinese patients with CRC with germline mutations.The Notch signaling pathway was uniquely clustered in the Lynch syndrome group,and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group.Patients with P/LP germline mutations exhibited higher CRC risk.

Circulating tumor and cancer stem cells in hepatitis C virusassociated liver disease

AIM: To assess the role of circulating tumor cells (CTCs) and cancer stem cells (CSCs) in hepatitis C virus (HCV)-associated liver disease.

Signs and genetics of rare cancer syndromes with gastroenterological features

Although the genetic bases of most hereditary cancer syndromes are known,and genetic tests are available for them,the incidence of the most rare of these syndromes is likely underestimated,partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs,though not necessarily tumors,that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis,and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.

Prognostic model of survival outcomes in non-small cell lung cancer patients initiated on afatinib: pooled analysis of clinical trial data

Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.

Comparative Study of Dose Distribution Homogeneity between 3D-Brachytherapy and Intensity Modulated Radiation Therapy Techniques in Cervix Cancer Tumors

Aim: The purpose of this study was to compare the dosimetric results of the techniques (3D-Brachytherapy and intensity-modulated radiotherapy IMRT) in patients with locally advanced cervical carcinoma (LACC). Method: There are 15 patients with locally advanced cervical carcinoma (LACC), after the completion of external beam radiotherapy (EBRT) for the whole pelvic irradiation 45 Gy/25 fractions, followed by 3D-Brachytherapy 24 Gy per weekly fractions and 36 Gy of IMRT per 18 fractions. Coverage of targets volume and doses received by normal tissue were compared in two techniques. Method: 15 patients of LACC treated with 3D-Brachytherapy were selected for this study. IMRT plans were also created for all the patients. 3D-Brachytherapy and IMRT plans were compared on the basis of target volume coverage, dose to Organs at risk (OAR’s), homogeneity index (HI) and conformity index (CI). Results: The results showed that D90% of HRCTV in the 3D-Brachytherapy was covered more than D90% of PTV in the IMRT of prescribed dose, the D2CC and the V60Gy values of Bladder and rectum were significantly lower than in 3D-Brachytherapy. The HI and CI in 3D-Brachytherapy were found better than IMRT. Conclusion: 3D-Brachytherapy significantly reduced the irradiated volume of OAR’s and improved dose coverage in tumor volume compared to that by IMRT.

Ca2+ influx and ROS generation trigger CDDO-Me-induced dilation of the ER and apoptosis in breast cancer cells

OBJECTIVE The synthetic triterpenoid 2-cyano-3,12-dioxoolean-1,9(11)-dien-C28-methyl ester(CDDO-Me)is considered a promising anti-tumorigenic compound.In this study,we investigated the anti-cancer effect of CDDO-Me on breast cancer cells and its underlying mechanisms.METHODS To investigate the effect of CDDO-Me on various breast cancer cells,cell viability assay using calcein-AM and EthD-1 as well as MTT assay was performed.To clarify the origin of CDDO-Me-induced vacuoles,electron microscopy as well as fluorescence microscopy using YFP-ER or YFP-Mito construct was performed.To measure the changes in intracellular Ca2+and ROS levels,flow cytometry using Fluo-3 and H2DCF-DA was performed.RESULTS CDDO-Me treatment induces progressive ER-derived vacuolation and subsequent apoptosis in various breast cancer cells.CDDO-Me-induced increases in intracellular Ca2+ levels,reflecting influx from the extracellular milieu,make a critical contribution to ER-derived vacuolation and subsequent cell death.In parallel with increasing 2+ Calevels,CDDO-Me markedly increases the generation of reactive oxygen species(ROS).Interestingly,we found that there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me.CONCLUSION ER-derived vacuolation via Ca2+ influx and ROS generation is responsible for the potent anticancer effects of CDDOMe on breast cancer cells.

Biological and molecular studies on specific immune cells treated with checkpoint inhibitors for the thera-personal approach of breast cancer patients(ex-vivo study)

Immunotherapy becomes a promising line of treatment for breast cancer(BC)however,its success rate is still limited.Methods:The study was designed to optimize the condition for producing an effective dendritic cell(DCs)based immunotherapy by using DCs and T lymphocytes together with tumor-infiltrating lymphocytes(TILs)and tumor-infiltrating DCs(TIDCs),treated with anti-PD1 and anti-CTLA4 monoclonal antibodies.This mixture of immune cells was co-cultured with autologous breast cancer cells(BCCs)isolated from 26 BC females.Results:There was a significant upregulation of CD86 and CD83 on DCs(p=0.001 and 0.017,respectively),similarly upregulation of CD8,CD4 and CD103 on T cells(p=0.031,0.027,and 0.011,respectively).While there was a significant downregulation of FOXP3 and combined CD25.CD8 expression on regulatory T cells(p=0.014 for both).Increased CD8/Foxp3 ratio(p<0.001)was also observed.CD133,CD34 and CD44 were downregulated on BCCs(p=0.01,0.021,and 0.015,respectively).There was a significant increase in interferon-γ(IFN-γ,p<0.001),lactate dehydrogenase(LDH,p=0.02),and a significant decrease in vascular endothelial growth factor(VEGF,p<0.001)protein levels.Gene expression of FOXP3 and Programmed cell death ligand 1(PDL-1)were downregulated in BCCs(p<0.001,for both),similarly cytotoxic T lymphocyte antigen-4(CTLA4,p=0.02),Programmed cell death 1(PD-1,p<0.001)and FOXP3(p<0.001)were significantly downregulated in T cells.Conclusion:Ex-vivo activation of immune cells(DCs,T cells,TIDCs,and TILs)with immune checkpoint inhibitors could produce a potent and effective BC immunotherapy.However,these data should be validated on an experimental animal model to be transferred to the clinical setting.

Preoperative [18]fluorodeoxyglucose-positron emission tomography/computed tomography in early stage breast cancer: Rates of distant metastases

AIM To investigate rates of distant metastases(DM) detected with [18]fluorodeoxyglucose-positron emissiontomography/computed tomography(^(18)FDG-PET/CT) in early stage invasive breast cancer.METHODS We searched the English language literature databases of PubM ed, EMBASE, ISI Web of Knowledge, Web of Science and Google Scholar, for publications on DM detected in patients who had ^(18)FDG-PET/CT scans as part of the staging for early stages of breast cancer(stage Ⅰ?and Ⅱ), prior to or immediately following surgery. Reports published between 2011 and 2017 were considered. The systematic review was conducted according to the PRISMA guidelines.RESULTS Among the 18 total studies included in the analysis, the risk of DM ranged from 0% to 8.3% and 0% to 12.9% for stage Ⅰ?and Ⅱ invasive breast cancer, respectively. Among the patients with clinical stage Ⅱ, the rate of occult metastases diagnosed by ^(18)FDG-PET/CT was 7.2%(range, 0%-19.6%) for stage ⅡA and 15.8%(range, 0%-40.8%) for stage ⅡB. In young patients(< 40-yearold), ^(18)FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology(i.e., triple-negative receptors and poorly differentiated grade).CONCLUSION Young patients with poorly differentiated tumors and stage ⅡB triple-negative breast cancer may benefit from ^(18)FDG-PET/CT at initial staging to detect occult DM prior to surgery.