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Find video protocols related to scientific articles indexed in Pubmed.
Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer.
J. Natl. Cancer Inst.
PUBLISHED: 11-01-2014
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Sipuleucel-T is a US Food and Drug Administration-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.
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An update on the safety and efficacy of regorafenib in the treatment of solid cancers.
Expert Opin Drug Metab Toxicol
PUBLISHED: 10-16-2014
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Regorafenib is a multi-targeted kinase inhibitor that has been approved recently for the treatment of certain gastrointestinal (GI) cancers. This review examines the scientific evidence on the efficacy and safety of this agent in Phase I to III studies.
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Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers?
Antioxid. Redox Signal.
PUBLISHED: 09-22-2014
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Abstract Estrogen and estrogen metabolite-induced reactive oxygen species generation can promote oxidative DNA base damage. If unrepaired, base damaging lesions could accelerate mutagenesis, leading to a "mutator phenotype" characterized by aggressive behavior in estrogen-estrogen receptor (ER)-driven breast cancer. To test this hypothesis, we investigated 1406 ER(+) early-stage breast cancers with 20 years' long-term clinical follow-up data for DNA polymerase ? (pol ?), flap endonuclease 1 (FEN1), AP endonuclease 1 (APE1), X-ray cross-complementation group 1 protein (XRCC1), single-strand monofunctional uracil glycosylase-1 (SMUG1), poly (ADP-ribose) polymerase 1 (PARP1), ataxia telangiectasia mutated and Rad3 related (ATR), ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Chk1, Chk2, p53, breast cancer susceptibility gene 1 (BRCA1), and topoisomerase 2 (TOPO2) expression. Multivariate Cox proportional hazards model was used to calculate a DNA repair prognostic index and correlated to clinicopathological variables and survival outcomes. Key base excision repair (BER) proteins, including XRCC1, APE1, SMUG1, and FEN1, were independently associated with poor breast cancer-specific survival (BCSS) (ps?0.01). Multivariate Cox model stratified patients into four distinct prognostic sub-groups with worsening BCSS (ps<0.01). In addition, compared with prognostic sub-group 1, sub-groups 2, 3, and 4 manifest increasing tumor size, grade, mitosis, pleomorphism, differentiation, lymphovascular invasion, high Ki67, loss of Bcl-2, luminal B phenotype (ps?0.01), and poor survival, including in patients who received tamoxifen adjuvant therapy (p<0.00001). Our observation supports the hypothesis that BER-directed stratification could inform appropriate therapies in estrogen-ER-driven breast cancers. Antioxid. Redox Signal. 21, 2262-2268.
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International validation of the Chinese University Prognostic Index for staging of hepatocellular carcinoma: a joint United Kingdom and Hong Kong study.
Chin J Cancer
PUBLISHED: 09-16-2014
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The outcome of hepatocellular carcinoma (HCC) patients significantly differs between western and eastern population centers. Our group previously developed and validated the Chinese University Prognostic Index (CUPI) for the prognostication of HCC among the Asian HCC patient population. In the current study, we aimed to validate the CUPI using an international cohort of patients with HCC and to compare the CUPI to two widely used staging systems, the Barcelona Clinic Liver Cancer (BCLC) classification and the Cancer of the Liver Italian Program (CLIP). To accomplish this goal, two cohorts of patients were enrolled in the United Kingdom (UK; n = 567; 2006-2011) and Hong Kong (HK; n = 517; 2007-2012). The baseline clinical data were recorded. The performances of the CUPI, BCLC, and CLIP were compared in terms of a concordance index (C-index) and were evaluated in subgroups of patients according to treatment intent. The results revealed that the median follow-up durations of the UK and HK cohorts were 27.9 and 29.8 months, respectively. The median overall survival of the UK and HK cohorts were 22.9 and 8.6 months, respectively. The CUPI stratified the patients in both cohorts into three risk subgroups corresponding to distinct outcomes. The median overall survival of the CUPI low-, intermediate-, and high-risk subgroups were 3.15, 1.24, and 0.29 years, respectively, in the UK cohort and were 2.07, 0.32, and 0.10 years, respectively, in the HK cohort. For the patients who underwent curative treatment, the prognostic performance did not differ between the three staging systems, and all were suboptimal. For those who underwent palliative treatment, the CUPI displayed the highest C-index, indicating that this staging system was the most informative for both cohorts. In conclusion, the CUPI is applicable to both western and eastern HCC patient populations. The performances of the three staging systems differed according to treatment intent, and the CUPI was demonstrated to be optimal for those undergoing palliative treatment. A more precise staging system for early-stage disease patients is required.
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A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma.
Cancer Res.
PUBLISHED: 09-12-2014
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Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function. Cancer Res; 74(21); 6236-47. ©2014 AACR.
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Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era.
Oncotarget
PUBLISHED: 07-16-2014
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Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in 'The Cancer Genome Atlas' (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 (p=0.031) and low PTEN (p=0.042) remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.
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Congestive heart failure: a case of protein misfolding.
Hawaii J Med Public Health
PUBLISHED: 06-25-2014
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This article describes an interesting case of a patient presenting with congestive heart failure found to have restrictive cardiomyopathy with initial laboratory evaluation showing hypogammaglobuminemia without a monoclonal band on serum and urine electrophoresis. This case highlights the clinically significant cardiac manifestation caused by protein misfolding, a defect in protein homeostasis. In addition, the utility of a relatively newer laboratory test, serum free light chains as well as the importance of clinical and pathophysiologic correlation is also discussed. We present a relatively uncommon cause of heart disease, cardiac amyloidosis in a patient with a systemic plasma cell dyscrasia, and multiple myeloma.
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Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers.
Breast Cancer Res. Treat.
PUBLISHED: 06-10-2014
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DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Pol? was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.
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Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.
J. Clin. Invest.
PUBLISHED: 05-08-2014
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Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPAR? with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.
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Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis.
Circulation
PUBLISHED: 04-28-2014
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The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension.
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Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy.
Mol Oncol
PUBLISHED: 04-15-2014
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BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol ? protein expression in two cohorts (n = 1602 sporadic and n = 50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol ? at mRNA and protein levels (p < 0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol ? expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol ? expressing BRCA1 negative tumours (ps < 0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol ?. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol ? expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy.
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A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer.
Oncologist
PUBLISHED: 04-04-2014
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In two randomized phase III trials of patients with metastatic breast cancer (MBC), gemcitabine-docetaxel (GD) and capecitabine-docetaxel (CD) had similar efficacy, but distinct safety profiles. Methods. Data from two GD versus CD studies were pooled; overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were determined. Cox proportional hazards models identified prognostic factors associated with improved OS and PFS. Using a multivariate prognostic model incorporating identified adverse prognostic factors, we grouped MBC patients into low-, intermediate-, and high-risk categories. Hazard ratios (HRs) of GD over CD for OS and PFS were determined for subsets of patients. Results. Baseline demographics of the pooled population were mostly well balanced. In the pooled population, there were no significant differences between GD versus CD for OS (HR = 1.02; p = .824), PFS (HR = 1.15; p = .079), and ORR (p = .526). In the pooled crossover population, there were trends toward improved OS (HR = 0.82; p = .171) and PFS (HR = 0.93; p = .557) with GD. Several prognostic factors (including prior adjuvant taxane) for improved OS or PFS were identified; however, there were no significant interactions between treatment arms and prognostic factors for PFS or OS, except number of metastatic sites. In the prognostic model, median OS and PFS were numerically lower in the high-risk group versus the intermediate- and low-risk groups. Conclusion. This analysis confirms the lack of efficacy difference between GD and CD in the pooled population, crossover population, and almost all subpopulations. Several prognostic factors were associated with improved outcomes in the pooled population.
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HER2/HER3 heterodimers and p21 expression are capable of predicting adjuvant trastuzumab response in HER2+ breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 03-14-2014
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Human epidermal growth factor receptor 2 (HER2) plays an important role in breast cancer progression and provides predictive information for response to targeted therapy including trastuzumab although this is limited. Downstream pathways, such as PI3K/Akt, are associated with HER2/HER3 heterodimerization promoting survival and proliferation amongst cancer cells. Thus, patient outcome and trastuzumab therapy effectiveness might be further characterised by HER2/HER3 dimerisation and its signalling pathways. HER2/HER3 dimerisation status was assessed, using chromogenic in situ Proximity Ligation Assay, in two breast cancer series: early stage primary breast cancer, including 224 HER2+ patients that were not submitted to trastuzumab, and HER2+ breast cancer where patients were treated with adjuvant trastuzumab (n = 143). Levels of biomarkers including PI3K, pAKT, ER, PgR, HER3, BCL2, p53, PTEN and p21 were measured using immunohistochemistry. Levels of HER2/HER3 heterodimers were compared with biomarker expression and patient outcome. An association between high levels of HER2/HER3 dimerisation and absence of hormone receptors, ER and PgR, was observed. We further show for the first time the presence of HER2/HER3 heterodimers and the loss of p21 expression in HER2+ breast cancer predicts a significantly poorer outcome when submitted to adjuvant trastuzumab. Breast cancer patients that reveal high levels of HER2/HER3 dimerisation and loss of p21 are associated with poor survival prognosis in patients with HER2+ breast cancer treated with adjuvant trastuzumab. Further quantification analysis of HER dimer/ligand complexes and downstream signalling pathways will begin to unravel the complex associations with patient outcome and its relationship with sensitivity to targeted treatment.
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Economic analysis of aprepitant-containing regimen to prevent chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy in Hong Kong.
Asia Pac J Clin Oncol
PUBLISHED: 02-28-2014
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We aim to evaluate the cost effectiveness of aprepitant-containing regimens for the prevention of chemotherapy-induced nausea and vomiting (CINV) among patients receiving high emetogenic chemotherapy (HEC) in Hong Kong.
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Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer.
Mol Oncol
PUBLISHED: 02-25-2014
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FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10(-57)), high mitotic index (p = 5.25 × 10(-28)), pleomorphism (p = 6.31 × 10(-19)), ER negative (p = 9.02 × 10(-35)), PR negative (p = 9.24 × 10(-24)), triple negative phenotype (p = 6.67 × 10(-21)), PAM50.Her2 (p = 5.19 × 10(-13)), PAM50. Basal (p = 2.7 × 10(-41)), PAM50.LumB (p = 1.56 × 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10(-12)), intClust.5 (p = 4.05 × 10(-12)) and intClust. 10 (p = 7.59 × 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10(-16)) and multivariate analysis (p = 9.19 × 10(-7)). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.
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An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells.
Biochim. Biophys. Acta
PUBLISHED: 02-07-2014
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Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation.
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Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma.
Histopathology
PUBLISHED: 02-07-2014
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The expression of stemness markers in hepatocellular carcinoma (HCC) is suggested to be associated with poor clinical outcome after surgical resection. There are few data on their independent prognostic role in addition to the existing AJCC TNM staging system.
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Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay.
Breast Cancer Res. Treat.
PUBLISHED: 02-06-2014
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HER2 plays an important role in breast cancer progression and provides predictive and prognostic information. HER2 receptor family members function through dimerisation, which can lead to impact on cell function, growth and differentiation; however, their value in breast cancer development remains to be defined. This study aims to examine the relationships of HER2 heterodimers to breast cancer characteristics in trastuzumab naïve and treated cases. HER2 protein (IHC), HER2 gene (chromogenic ISH) and HER2 heterodimerisation status [chromogenic in situ proximity ligation assay (PLA)] were assessed in two breast cancer series prepared in tissue microarray (TMA) format. A range of signals/cell for each HER2 heterodimer was detected (0-34.6 signals/cell). The vast majority of cases with HER2 heterodimers showed HER2 gene amplification and/or protein expression. There was an association between HER2 dimerisation with HER3 and HER4 and their protein expression level but no such association was found in with HER1 (EGFR). Of the HER2+ cases, 74, 66, and 58 % showed heterodimers with EGFR, HER3 and HER4, respectively. 51 % of HER2+ tumours expressed all three heterodimers whereas 23 % of the cases did not show expression of any of the three heterodimers. There was an inverse association between the presence and levels of HER2 heterodimers and hormone receptor expression in HER2+ tumours. Tumours exhibiting high levels of HER2 heterodimers demonstrated aggressive clinicopathological features and poor outcome. In the HER2+ cases, dimerisation with EGFR and HER3 but not with HER4 showed an association with aggressive features. There was no association between HER2 heterodimers with patient breast cancer-specific survival or recurrence in HER2+ breast cancer in those patients receiving trastuzumab or not. Our results demonstrate that HER2 dimerisation is a complex process that may underlie the biological heterogeneity of HER2 positive tumours and may identify patients suitable for a specific targeted therapy but does not predict patient outcome for those receiving trastuzumab. PLA proved to be a useful tool for detecting, visualising and quantifying the frequency of protein-protein interactions in archival formalin-fixed paraffin-embedded tissue samples.
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Systemic treatment for inoperable pancreatic adenocarcinoma: review and update.
Chin J Cancer
PUBLISHED: 01-29-2014
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There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents.
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Development of systemic therapy for hepatocellular carcinoma at 2013: updates and insights.
World J. Gastroenterol.
PUBLISHED: 01-19-2014
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A growing number of multi-targeted tyrosine kinase inhibitor (TKI) has undergone testing for hepatocellular carcinoma (HCC). Unfortunately, this enthusiasm has recently been discouraged by a number of negative phase III studies on several anti-angiogenic TKIs in HCC. Several postulations have been made to account for this phenomenon, namely the plateau effects of anti-angiogenesis approach, the heterogeneity of HCC in terms of background hepatitis/cirrhosis and tumor biology, as well as the way how clinical trials are designed. Regardless of the underlying reasons, these results suggested that alternative strategies are necessary to further develop systemic therapy for HCC. Several new strategies are currently evaluated: for examples, molecular agents with activities against targets other than vascular endothelial growth factor receptor are being evaluated in on-going clinical trials. In addition, different approaches of targeted agents in combination with various treatment modalities, such as concurrently with another molecular agent, cytotoxic chemotherapy or transarterial chemoembolization, are being developed. This review aims to give a summary on the results of recently released clinical trials on TKIs, followed by discussion on some of the potential novel agents and combinational approaches. Future directions for testing innovative systemic agents for HCC will also be discussed.
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Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise.
J. Appl. Physiol.
PUBLISHED: 01-16-2014
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Short nonprotein coding RNA molecules, known as microRNAs (miRNAs), are intracellular mediators of adaptive processes, including muscle hypertrophy, contractile force generation, and inflammation. During basal conditions and tissue injury, miRNAs are released into the bloodstream as "circulating" miRNAs (c-miRNAs). To date, the impact of extended-duration, submaximal aerobic exercise on plasma concentrations of c-miRNAs remains incompletely characterized. We hypothesized that specific c-miRNAs are differentially upregulated following prolonged aerobic exercise. To test this hypothesis, we measured concentrations of c-miRNAs enriched in muscle (miR-1, miR-133a, miR-499-5p), cardiac tissue (miR-208a), and the vascular endothelium (miR-126), as well as those important in inflammation (miR-146a) in healthy male marathon runners (N = 21) at rest, immediately after a marathon (42-km foot race), and 24 h after the race. In addition, we compared c-miRNA profiles to those of conventional protein biomarkers reflective of skeletal muscle damage, cardiac stress and necrosis, and systemic inflammation. Candidate c-miRNAs increased immediately after the marathon and declined to prerace levels or lower after 24 h of race completion. However, the magnitude of change for each c-miRNA differed, even when originating from the same tissue type. In contrast, traditional biomarkers increased after exercise but remained elevated 24 h postexercise. Thus c-miRNAs respond differentially to prolonged exercise, suggesting the existence of specific mechanisms of c-miRNA release and clearance not fully explained by generalized cellular injury. Furthermore, c-miRNA expression patterns differ in a temporal fashion from corollary conventional tissue-specific biomarkers, emphasizing the potential of c-miRNAs as unique, real-time markers of exercise-induced tissue adaptation.
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DNA polymerase ? deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts.
Mol Oncol
PUBLISHED: 01-02-2014
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Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol ? gene is localized to chromosome 8p12-p11 and encodes a key DNA base excision repair protein. Pol ? may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol ? in breast cancer. We investigated pol ? gene copy number changes in two cohorts (n = 128 &n = 1952), pol ? mRNA expression in two cohorts (n = 249 &n = 1952) and pol ? protein expression in two cohorts (n = 1406 &n = 252). Artificial neural network analysis for pol ? interacting genes was performed in 249 tumours. For mechanistic insights, pol ? gene copy number changes, mRNA and protein levels were investigated together in 128 tumours and validated in 1952 tumours. Low pol ? mRNA expression as well as low pol ? protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal-like phenotypes and poor survival (ps < 0.001). In oestrogen receptor (ER) positive sub-group that received tamoxifen, low pol ? protein remains associated with aggressive phenotype and poor survival (ps < 0.001). Artificial neural network analysis revealed ER as a top pol ? interacting gene. Mechanistically, there was strong positive correlation between pol ? gene copy number changes and pol ? mRNA expression (p < 0.0000001) and between pol ? mRNA and pol ? protein expression (p < 0.0000001). This is the first study to provide evidence that pol ? deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients.
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Clinicopathological significance of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in oestrogen-receptor-positive breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 01-01-2014
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Oestrogen metabolites can induce oxidative DNA base damage and generate potentially mutagenic apurinic sites (AP sites) in the genomic DNA. If unrepaired, mutagenic AP sites could drive breast cancer pathogenesis and aggressive phenotypes. Human apurinic/apyrimidinic endonuclease 1 (APE1) is a key DNA base excision repair (BER) protein and essential for processing AP sites generated either directly by oestrogen metabolites or during BER of oxidative base damage. Our hypothesis is that altered APE1 expression may be associated with aggressive tumour biology and impact upon clinical outcomes in breast cancer. In the current study, we have investigated APE1 protein expression in a large cohort of breast cancers (n = 1285) and correlated to clinicopathological features and survival outcomes. Low APE1 protein expression was associated with high histological grade (p < 0.000001), high mitotic index (p < 0.000001), glandular de-differentiation (p < 0.000001), pleomorphism (p = 0.003), absence of hormonal receptors (ER-/PgR-/AR-) (p < 0.0001) and presence of triple negative phenotype (p = 0.001). Low APE1 protein expression was associated with loss of BRCA1, low XRCC1, low FEN1, low SMUG1 and low pol ? (ps < 0.0001). High MIB1 (p = 0.048), bcl-2 negativity (p < 0.0001) and low TOP2A (p < 0.0001) were likely in low APE1 tumours. In the ER-positive sub-group, specifically, low APE1 remains significantly associated with high histological grade, high mitotic index, glandular de-differentiation (ps < 0.00001) and poor breast cancer specific survival (p = 0.007). In the ER-positive cohort that received adjuvant endocrine therapy, low APE1 protein expression is associated with poor survival (p = 0.006). In multivariate analysis, low APE1 remains independently associated with poor survival in ER-positive tumours (p = 0.048). We conclude that low APE1 expression may have prognostic and predictive significance in ER-positive breast cancers.
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Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial
Lancet Oncol.
PUBLISHED: 12-19-2013
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Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine).
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SHON Is a Novel Estrogen-Regulated Oncogene in Mammary Carcinoma That Predicts Patient Response to Endocrine Therapy.
Cancer Res.
PUBLISHED: 12-04-2013
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Endocrine therapies are the primary systemic intervention for patients with estrogen receptor-positive (ER(+)) breast cancer. However, a significant proportion of initially responsive ER(+) tumors develop resistance, with relapses occurring in up to 50% of patients. Lack of reliable predictive biomarkers remains an unfilled need for enhanced clinical management of this disease. In this study, we address this need in identifying a novel estrogen-regulated gene called SHON (secreted hominoid-specific oncogene). Enforced expression of SHON in breast cancer cells increased their proliferation, survival, migration, and invasion in vitro. Furthermore, SHON enhanced the oncogenicity of these cells in xenograft models of human breast cancer and was also sufficient to oncogenically transform MCF10A human mammary epithelial cells. Conversely, SHON attenuation mediated by RNA interference- or antibody-based methods reduced the oncogenicity of breast cancer cells. Mechanistic investigations indicated that the oncogenic transforming properties of SHON were mediated by BCL-2 and NF-?B. In primary clinical specimens, SHON was immunohistochemically detected in 62% of breast cancers, in which its expression was positively correlated with ER expression. In this setting, SHON expression predicted a favorable response to endocrine therapy in high-risk patients with ER(+) breast cancer. Taken together, our findings identify SHON as a novel human oncogene with predictive utility in ER(+) breast cancer, perhaps offering a simple biomarker to predict the therapeutic efficacy of antiestrogen therapy in patients with breast cancer. Cancer Res; 73(23); 6951-62. ©2013 AACR.
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Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy.
Breast Cancer Res. Treat.
PUBLISHED: 11-06-2013
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Uracil in DNA is an important cause of mutagenesis. SMUG1 is a uracil-DNA glycosylase that removes uracil through base excision repair. SMUG1 also processes radiation-induced oxidative base damage as well as 5-fluorouracil incorporated into DNA during chemotherapy. We investigated SMUG1 mRNA expression in 249 primary breast cancers. SMUG1 protein expression was investigated in 1,165 breast tumours randomised into two cohorts [training set (n = 583) and test set (n = 582)]. SMUG1 and chemotherapy response was also investigated in a series of 315 ER-negative tumours (n = 315). For mechanistic insights, SMUG1 was correlated to biomarkers of aggressive phenotype, DNA repair, cell cycle and apoptosis. Low SMUG1 mRNA expression was associated with adverse disease specific survival (p = 0.008) and disease-free survival (p = 0.008). Low SMUG1 protein expression (25 %) was associated with high histological grade (p < 0.0001), high mitotic index (p < 0.0001), pleomorphism (p < 0.0001), glandular de-differentiation (p = 0.0001), absence of hormonal receptors (ER-/PgR-/AR) (p < 0.0001), presence of basal-like (p < 0.0001) and triple-negative phenotypes (p < 0.0001). Low SMUG1 protein expression was associated with loss of BRCA1 (p < 0.0001), ATM (p < 0.0001) and XRCC1 (p < 0.0001). Low p27 (p < 0.0001), low p21 (p = 0.023), mutant p53 (p = 0.037), low MDM2 (p < 0.0001), low MDM4 (p = 0.004), low Bcl-2 (p = 0.001), low Bax (p = 0.003) and high MIB1 (p < 0.0001) were likely in low SMUG1 tumours. Low SMUG1 protein expression was associated with poor prognosis in univariate (p < 0.001) and multivariate analysis (p < 0.01). In ER+ cohort that received adjuvant endocrine therapy, low SMUG1 protein expression remains associated with poor survival (p < 0.01). In ER- cohort that received adjuvant chemotherapy, low SMUG1 protein expression is associated with improved survival (p = 0.043). Our study suggests that low SMUG1 expression may correlate to adverse clinicopathological features and predict response to adjuvant therapy in breast cancer.
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Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-04-2013
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We explored the detection of genome-wide hypomethylation in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer. Tumor-associated copy number aberrations (CNAs) could also be observed from the bisulfite DNA sequencing data. Hypomethylation and CNAs were detected in the plasma DNA of patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor. For the detection of nonmetastatic cancer cases, plasma hypomethylation gave a sensitivity and specificity of 74% and 94%, respectively, when a mean of 93 million reads per case were obtained. Reducing the sequencing depth to 10 million reads per case was found to have no adverse effect on the sensitivity and specificity for cancer detection, giving respective figures of 68% and 94%. This characteristic thus indicates that analysis of plasma hypomethylation by this sequencing-based method may be a relatively cost-effective approach for cancer detection. We also demonstrated that plasma hypomethylation had utility for monitoring hepatocellular carcinoma patients following tumor resection and for detecting residual disease. Plasma hypomethylation can be combined with plasma CNA analysis for further enhancement of the detection sensitivity or specificity using different diagnostic algorithms. Using the detection of at least one type of aberration to define an abnormality, a sensitivity of 87% could be achieved with a specificity of 88%. These developments have thus expanded the applications of plasma DNA analysis for cancer detection and monitoring.
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Unresectable Hepatocellular Carcinoma: Randomized Controlled Trial of Transarterial Ethanol Ablation versus Transcatheter Arterial Chemoembolization.
Radiology
PUBLISHED: 10-28-2013
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Purpose:To compare effectiveness of transarterial ethanol ablation (TEA) and transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma and determine whether TEA leads to better overall survival and tumor response than TACE.Materials and Methods:In this institutional review board-approved preregistered randomized controlled trial (n = 200), informed consent was obtained. Primary outcome was overall survival; secondary outcomes were time to progression (TTP), progression-free survival (PFS), tumor response at computed tomography, and treatment-related toxicity. Eligible patients were randomized at a 1:1 ratio. Treatment included transcatheter delivery of ethiodized oil-ethanol mixture (2:1 ratio by volume up to 60 mL) for TEA and cisplatin-ethiodized oil emulsion (0.5 mg cisplatin per milliliter up to 30 mg), followed by 1-mm gelatin-sponge pellets, for TACE. Study was terminated after interim analysis (n = 98); 90 patients were available for analysis. Overall survival, TTP, and PFS were analyzed with Kaplan-Meier method; differences were compared with log-rank test.Results:Study was terminated prematurely after interim analysis, which showed no difference in overall survival; this was unlikely to change with further patient accrual. Median overall survival in TEA and TACE was 24.3 months (95% confidence interval [CI]: 12.8, 32.7) and 20.1 months (95% CI: 9.3, 31.2), respectively (P = .358). Median TTP and PFS for intralesional progression were longer with TEA than TACE (TTP, 34.6 months [95% CI: 28.2, 41] vs 26.05 months [95% CI: 18.7, 33.3]; PFS, 14.8 months [95% CI: 10.2, 19.5] vs 9.3 months [95% CI: 7.1, 11.5]) (P = .028 and 0.029, respectively). Complete response rate on a tumor basis was persistently and significantly higher with TEA at 3 months (62 of 88 [70%] vs 39 of 76 [51%], P = .012), 6 months (64 of 88 [73%] vs 41 of 76 [54%], P = .012), and 12 months (66 of 88 [75%] vs 45 of 76 [59%], P = .031).Conclusion:Although there was no significant difference in overall survival, TEA demonstrated better complete tumor response, longer time to intralesional progression, and longer PFS.© RSNA, 2013Clinical trial registration no. NCT00467974.
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Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.
Lancet Oncol.
PUBLISHED: 10-04-2013
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New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials.
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Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of ?III-tubulin expression as a predictive marker.
Oncologist
PUBLISHED: 07-12-2013
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This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of ?III-tubulin as a predictive marker was also evaluated.
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Analysis of microRNA niches: techniques to measure extracellular microRNA and intracellular microRNA in situ.
Methods Mol. Biol.
PUBLISHED: 05-31-2013
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MicroRNAs (miRNAs) are small, noncoding RNA molecules that negatively regulate gene expression and control a wide range of cellular processes. Extracellular forms of miRNA circulating in the bloodstream (circulating miRNA, c-miRNA) are of increasing interest for their potential as biomarkers and long-range physiological signaling molecules. Precise measurement of intracellular miRNA expression is possible but can be challenging, especially in the context of specialized tissue niches in vivo. The accurate measurement of extracellular miRNA presents other obstacles stemming from their low concentrations and confounding sources of intracellular miRNA that contaminate RNA extraction protocols. Here, we describe multiple methods to isolate extracellular miRNA from cell culture media, serum, and plasma in order to accurately measure their variable expression under different conditions. We additionally describe an in situ staining protocol designed to not only quantify but also localize miRNA in formalin-fixed paraffin-embedded tissue that may prove useful in describing the action of c-miRNA before they leave their tissue of origin and after they potentially arrive at their target destination.
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Ineffective delivery of diet-derived microRNAs to recipient animal organisms.
RNA Biol
PUBLISHED: 05-03-2013
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Cross-kingdom delivery of specific microRNAs to recipient organisms via food ingestion has been reported recently. However, it is unclear if such delivery of microRNAs occurs frequently in animal organisms after typical dietary intake. We found substantial levels of specific microRNAs in diets commonly consumed orally by humans, mice, and honey bees. Yet, after ingestion of fruit replete with plant microRNAs (MIR156a, MIR159a, and MIR169a), a cohort of healthy athletes did not carry detectable plasma levels of those molecules. Similarly, despite consumption of a diet with animal fat replete in endogenous miR-21, negligible expression of miR-21 in plasma or organ tissue was observed in miR-21 -/- recipient mice. Correspondingly, when fed vegetarian diets containing the above plant microRNAs, wild-type recipient mice expressed insignificant levels of these microRNAs. Finally, despite oral uptake of pollen containing these plant microRNAs, negligible delivery of these molecules was observed in recipient honeybees. Therefore, we conclude that horizontal delivery of microRNAs via typical dietary ingestion is neither a robust nor a frequent mechanism to maintain steady-state microRNA levels in a variety of model animal organisms, thus defining the biological limits of these molecules in vivo.
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Hypoxia: a master regulator of microRNA biogenesis and activity.
Free Radic. Biol. Med.
PUBLISHED: 05-01-2013
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Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short noncoding RNAs that regulate gene expression through posttranscriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in the expression of a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated in order to integrate into the complex hierarchical regulatory network induced by hypoxia.
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Intermittent versus continuous erlotinib with concomitant modified "XELOX" (q3W) in first-line treatment of metastatic colorectal cancer: correlation with serum amphiregulin and transforming growth factor alpha.
Cancer
PUBLISHED: 04-25-2013
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This study evaluated the activity of 2 schedules of erlotinib in combination with chemotherapy, and the prognostic significance of serum amphiregulin (AREG) and transforming growth factor alpha (TGFa) in metastatic colorectal cancer.
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AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer.
J. Clin. Oncol.
PUBLISHED: 04-08-2013
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PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ? 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.
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Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect.
Eur. J. Clin. Invest.
PUBLISHED: 04-04-2013
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Pulmonary hypertension (PH) is an enigmatic vascular syndrome characterized by increased pulmonary arterial pressure and adverse remodelling of the pulmonary arterioles and often of the right ventricle. Drawing parallels with tumourigenesis, recent endeavours have explored the relationship between metabolic dysregulation and PH pathogenesis.
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Performance of serum ?-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass.
HPB (Oxford)
PUBLISHED: 03-21-2013
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The role of serum ?-fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass.
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Service-learning from the views of university teachers: a qualitative study based on focus groups.
Int J Adolesc Med Health
PUBLISHED: 03-01-2013
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Abstract Under the New Undergraduate Curriculum at The Hong Kong Polytechnic University (PolyU), students are required to take a 3-credit subject to fulfill service-learning requirements. To understand the views of teachers regarding service-learning, five focus group interviews (n=33) are conducted to examine the perceived characteristics and myths of service-learning as well as colleagues views on the policy at PolyU. Results showed that most informants are aware of service-learning and have seen its benefits to both students and teachers. Most informants also possess positive views about service-learning. Nevertheless, in terms of service-learning at PolyU, three different groups of views on service-learning are observed, namely, positive, negative, and mixed views. This paper also discusses teachers views on the anticipated difficulties of service-learning implementation and the ways, by which to promote the subject in the PolyU context.
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Development of an e-learning package on Service-Learning for university teachers: experience from Hong Kong.
Int J Adolesc Med Health
PUBLISHED: 03-01-2013
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Abstract To help university teachers to understand Service-Learning and develop Service-Learning subjects, a 3-h+ e-learning package was developed at The Hong Kong Polytechnic University (PolyU). There are seven units in this e-learning package: introduction session (Unit 1), what is Service-Learning? (Unit 2), impact and benefits of Service-Learning (Unit 3), myths and positive attitudes toward Service-Learning (Unit 4), developing a Service-Learning subject at PolyU (Unit 5), self-reflection about Service-Learning (Unit 6), and concluding session (Unit 7). To understand the views of the users on the e-learning package, the package was offered before formal launching. For the first offering, three focus group sessions were held. Results showed that the users were satisfied with the structural arrangement of the e-learning package and agreed that the e-learning package was useful for them to understand more about Service-Learning. For the second offering, colleagues were generally satisfied with the e-learning package and demonstrated gain in knowledge on Service-Learning. Suggestions for improvement were noted.
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Risk factors for febrile status epilepticus: a case-control study.
J. Pediatr.
PUBLISHED: 02-22-2013
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To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS).
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Phase I trial of recombinant modified vaccinia ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients.
Cancer Res.
PUBLISHED: 01-24-2013
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Epstein-Barr virus (EBV) is associated with several malignancies including nasopharyngeal carcinoma, a high incidence tumor in Chinese populations, in which tumor cells express the two EBV antigens EB nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). Here, we report the phase I trial of a recombinant vaccinia virus, MVA-EL, which encodes an EBNA1/LMP2 fusion protein designed to boost T-cell immunity to these antigens. The vaccine was delivered to Hong Kong patients with nasopharyngeal carcinoma to determine a safe and immunogenic dose. The patients, all in remission more than 12 weeks after primary therapy, received three intradermal MVA-EL vaccinations at three weekly intervals, using five escalating dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming unit (pfu). Blood samples were taken during prescreening, immediately before vaccination, one week afterward and at intervals up to one year later. Immunogenicity was tested by IFN-? ELIspot assays using complete EBNA1 and LMP2 15-mer peptide mixes and known epitope peptides relevant to patient MHC type. Eighteen patients were treated, three per dose level one to four and six at the highest dose, without dose-limiting toxicity. T-cell responses to one or both vaccine antigens were increased in 15 of 18 patients and, in many cases, were mapped to known CD4 and CD8 epitopes in EBNA1 and/or LMP2. The range of these responses suggested a direct relationship with vaccine dose, with all six patients at the highest dose level giving strong EBNA1/LMP2 responses. We concluded that MVA-EL is both safe and immunogenic, allowing the highest dose to be forwarded to phase II studies examining clinical benefit.
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Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer.
Clin. Cancer Res.
PUBLISHED: 01-22-2013
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Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent.
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Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.
PLoS ONE
PUBLISHED: 01-17-2013
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Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response.
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Enhancer of zeste homolog 2 silences microRNA-218 in human pancreatic ductal adenocarcinoma cells by inducing formation of heterochromatin.
Gastroenterology
PUBLISHED: 01-09-2013
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Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is overexpressed by pancreatic ductal adenocarcinoma (PDAC) cells and increases their aggressiveness. We identified microRNAs (miRs) that are regulated by EZH2 and studied their functions in PDAC cells.
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Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma.
Int J Hepatol
PUBLISHED: 01-04-2013
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Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60-87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.
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Preclinical evaluation of combined TKI-258 and RAD001 in hepatocellular carcinoma.
Cancer Chemother. Pharmacol.
PUBLISHED: 01-02-2013
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RAD001 targets at the mammalian target of rapamycin (mTOR), while TKI-258 is a potent tyrosine kinase inhibitor targeting at fibroblast growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor and c-kit. We aim to study the activity of combined RAD001 and TKI-258 in cell lines and xenograft model of hepatocellular carcinoma (HCC), with reference to the parallel and upstream pathways of Akt-mTOR axis.
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Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells.
Aging Cell
PUBLISHED: 01-02-2013
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Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferrin saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound (58) Fe, the amount of (58) Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to bone morphogenetic protein (BMP)-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP/Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.
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Predictability of the polymorphs of small organic compounds: crystal structure predictions of four benchmark blind test molecules.
Phys Chem Chem Phys
PUBLISHED: 10-13-2011
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Predicting the crystal structure of an organic molecule from first principles has been a major challenge in physical chemistry. Recently, the application of Density Functional Theory including a dispersive energy correction (the DFT(d) method) has been shown to be a reliable method for predicting experimental structures based purely on their ranking according to lattice energy. Further validation results of the application of the DFT(d) method to four organic molecules are presented here. The compounds were targets (labelled molecule II, VI, VII and XI) in previous blind tests of crystal structure prediction, and their structures proved difficult to predict. However, this study shows that the DFT(d) approach is capable of predicting the solid state structures of these small molecules. For molecule VII, the most stable (rank 1) predicted crystal structure corresponds to the experimentally observed structure. For molecule VI, the rank 1, 2 and 3 predicted structures correspond to the three experimental polymorphs, forms I, III and II, respectively. For molecules II and XI, their rank 1 predicted structures are energetically more stable than those corresponding to the experimental crystal structures, and were not found amongst the structures submitted by the participants in the blind tests. The rank 1 structure of molecule II is predicted to exist under high pressure, whilst the rank 1 structure predicted for molecule XI has the same space group and hydrogen bonding pattern as observed in the crystal of 1-amino-1-methyl-cyclopropane, which is structurally related to molecule XI. The experimental crystal structure of molecule II corresponds to the rank 4 prediction, 0.8 kJ mol(-1) above the global minimum structure, and the experimental structure of molecule XI corresponds to the rank 2 prediction, 0.4 kJ mol(-1) above the global minimum.
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A study of circulating interleukin 10 in prognostication of unresectable hepatocellular carcinoma.
Cancer
PUBLISHED: 08-30-2011
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The level of circulating interleukin 10 (IL-10) is elevated in a proportion of patients with hepatocellular carcinoma (HCC). The objective of the current study was to evaluate the prognostic significance of serum the IL-10 level in patients with unresectable HCC.
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Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training.
J. Physiol. (Lond.)
PUBLISHED: 06-20-2011
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MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based circulating miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 ± 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a and VO2max (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes in VO2max (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation.
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Seasonal abundance and suppression of fruit-piercing moth Eudocima phalonia (L.) in a citrus orchard in Sarawak.
ScientificWorldJournal
PUBLISHED: 05-28-2011
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Seasonal population of the fruit-piercing moths Eudocima spp. was monitored throughout the citrus growing seasons in a citrus orchard and in site adjacent to secondary forest from July 2007 to June 2009. The moth was detected practically throughout the year with activity lowest during the wet months (September-February) when fruits are still available and while highest during the dry months (May-June) which also coincided with the main fruiting season. The effects of an nC24 horticultural mineral oil (HMO) on the citrus fruit damage caused by fruit-piecing moths was also determined. The percent fruit damage was significantly lowest (P?0.05) in HMO-treated plots (8.4), followed by Dimethoate-treated plots (11.6) and untreated plots (22.5). However, there was no significant difference between HMO and Dimethoate treated plots indicating HMO is effective in reducing percent fruit damage.
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Sources of distress during medical training and clinical practice: Suggestions for reducing their impact.
Med Teach
PUBLISHED: 05-26-2011
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Medical students and doctors experience several types of professional distress. Their causes ("stressors") are commonly classified as exogenous (adapting to medical school or clinical practice) and endogenous (due to personality traits). Attempts to reduce distress have consisted of providing students with support and counseling, and improving doctors management of work time and workload.
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Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer.
J. Clin. Oncol.
PUBLISHED: 05-09-2011
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This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC).
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Stereotactic radiotherapy for hepatocellular carcinoma: report of a local single-centre experience.
Hong Kong Med J
PUBLISHED: 04-08-2011
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To evaluate the efficacy and toxicities of stereotactic radiotherapy for unresectable hepatocellular carcinoma.
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Incubating isolated mouse EDL muscles with creatine improves force production and twitch kinetics in fatigue due to reduction in ionic strength.
PLoS ONE
PUBLISHED: 03-09-2011
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Creatine supplementation can improve performance during high intensity exercise in humans and improve muscle strength in certain myopathies. In this present study, we investigated the direct effects of acute creatine incubation on isolated mouse fast-twitch EDL muscles, and examined how these effects change with fatigue.
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Calpain-1 expression is associated with relapse-free survival in breast cancer patients treated with trastuzumab following adjuvant chemotherapy.
Int. J. Cancer
PUBLISHED: 03-08-2011
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The calpain family, and their endogenous inhibitor calpastatin, has been implicated in cancer progression, and recent in vitro data have indicated a role in trastuzumab resistance. The aims of our study were to examine expression levels of calpastatin, calpain-1 and calpain-2 in breast tumours from patients treated with trastuzumab following adjuvant chemotherapy to determine their potential as biomarkers to predict therapeutic response. The expression of calpastatin, calpain-1 and calpain-2 was determined, using immunohistochemistry (IHC), in tumours from a series of 93 patients with primary breast cancer treated with surgery and adjuvant chemotherapy with or without trastuzumab followed by trastuzumab to complete 1 year of therapy. IHC was performed using tissue microarrays constructed from cores taken from intratumour and peripheral tumour areas. Expression was correlated with clinicopathologic variables and patient outcome. Calpastatin expression was correlated with Nottingham prognostic index (p = 0.003) and lymph node status (p = 0.007). Trastuzumab resistance was defined as disease relapse during therapy. Calpain-1 expression is associated with relapse-free survival (p = 0.001) and remained significant in multivariate analysis accounting for confounding pathological and treatment variables (hazard ratio 4.60, 95% confidence interval 1.05-20.25; p = 0.043). Calpain-1 may be a useful biomarker to predict relapse-free survival in breast cancer patients treated with adjuvant trastuzumab and chemotherapy. A larger verification study is warranted.
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RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
J. Clin. Oncol.
PUBLISHED: 03-07-2011
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This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.
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Use of antiviral therapy in surveillance: impact on outcome of hepatitis B-related hepatocellular carcinoma.
Liver Int.
PUBLISHED: 03-02-2011
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Antiviral therapy for hepatitis B virus (HBV) infection is frequently prescribed for patients with chronic HBV infection during surveillance for hepatocellular carcinoma (HCC). In patients who subsequently develop HCC, the impact of antiviral therapy on the outcome of HCC remains unclear.
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Prospective validation of the Chinese University Prognostic Index and comparison with other staging systems for hepatocellular carcinoma in an Asian population.
J. Gastroenterol. Hepatol.
PUBLISHED: 01-26-2011
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Hepatitis B viral (HBV) infection is the predominant etiology of hepatocellular carcinoma (HCC) in Asia. Our group previously reported a staging system known as the Chinese University Prognostic Index (CUPI) for HCC populations of which HBV infection is the predominant etiology. This study aims to validate CUPI and compare with other published staging systems.
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Pulmonary vascular disease related to hemodynamic stress in the pulmonary circulation.
Compr Physiol
PUBLISHED: 01-01-2011
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Hemodynamic stress in the pulmonary vessel is directly linked to the development of vascular remodeling and dysfunction, ultimately leading to pulmonary hypertension. Recently, some advances have been made in our molecular understanding of the exogenous upstream stimuli that initiate hemodynamic pertubations as well as the downstream vasoactive effectors that control these responses. However, much still remains unknown regarding how these complex signaling pathways connect in order to result in these characteristic pathophysiological changes. This chapter will describe our current understanding of and needed areas of research into the clinical, physiological, and molecular changes associated with pressure/volume overload in the pulmonary circulation.
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A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer.
Onkologie
PUBLISHED: 09-06-2010
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Filgrastim was developed to treat chemotherapy-induced neutropenia. This phase III study was designed to demonstrate bioequivalence of Amgen filgrastim and a biosimilar filgrastim developed by Hospira (Study GCF071; sponsored by Hospira).
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The effect of ?-actinin-3 deficiency on muscle aging.
Exp. Gerontol.
PUBLISHED: 07-15-2010
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Deficiency of the fast-twitch muscle protein ?-actinin-3 due to homozygosity for a nonsense polymorphism (R577X) in the ACTN3 gene is common in humans. ?-Actinin-3 deficiency (XX) is associated with reduced muscle strength/power and enhanced endurance performance in elite athletes and in the general population. The association between R577X and loss in muscle mass and function (sarcopenia) has previously been investigated in a number of studies in elderly humans. The majority of studies report loss of ACTN3 genotype association with muscle traits in the elderly, however, there is some indication that the XX genotype may be associated with faster muscle function decline. To further explore these potential age-related effects and the underlying mechanisms, we examined the effect of ?-actinin-3 deficiency in aging male and female Actn3 knockout (KO) mice (2, 6, 12, and 18 months). Our findings support previous reports of a diminished influence of ACTN3 genotype on muscle performance in the elderly: genotype differences in intrinsic exercise performance, fast muscle force generation and male muscle mass were lost in aged mice, but were maintained for other muscle function traits such as grip strength. The loss of genotype difference in exercise performance occurred despite the maintenance of some "slower" muscle characteristics in KO muscles, such as increased oxidative metabolism and greater force recovery after fatigue. Interestingly, muscle mass decline in aged 18 month old male KO mice was greater compared to wild-type controls (WT) (-12.2% in KO; -6.5% in WT). These results provide further support that ?-actinin-3 deficient individuals may experience faster decline in muscle function with increasing age.
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Age- and gender-related changes in contractile properties of non-atrophied EDL muscle.
PLoS ONE
PUBLISHED: 06-01-2010
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In humans, ageing causes skeletal muscles to become atrophied, weak, and easily fatigued. In rodent studies, ageing has been associated with significant muscle atrophy and changes in the contractile properties of the muscles. However, it is not entirely clear whether these changes in contractile properties can occur before there is significant atrophy, and whether males and females are affected differently.
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The ECM protein LTBP-2 is a suppressor of esophageal squamous cell carcinoma tumor formation but higher tumor expression associates with poor patient outcome.
Int. J. Cancer
PUBLISHED: 05-31-2010
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Our previous studies of chromosome 14 transfer into tumorigenic esophageal squamous cell carcinoma (ESCC) cell line, SLMT, suggested the existence of tumor suppressor genes on chromosome 14. Gene expression profiling of microcell hybrids and the tumor segregants identified an interesting gene, LTBP-2 (latent transforming growth factor ? binding protein 2), which has been analyzed here for its role in ESCC. LTBP-2 maps to 14q24 and encodes a secreted protein, which is a component of the extracellular matrix microfibrils. LTBP-2 expression was downregulated in ESCC cell lines and tumor tissues. Promoter hypermethylation was found to be involved in LTBP-2 inactivation. Functional studies indicated its tumor-suppressive roles in ESCC. In the in vitro colony formation and Matrigel three-dimensional culture assays, LTBP-2 decreased the colony-forming abilities of ESCC cell lines. LTBP-2 expression was associated with reduction of cell migrating and invasive abilities. LTBP-2 could also reduce the tube-forming ability of endothelial cells. Moreover, LTBP-2 induced tumor suppression in in vivo nude mouse assays. Tissue microarray immunohistochemical staining analysis indicated that LTBP-2 expression is reduced in tumor tissues when compared to normal tissues, and LTBP-2 expression correlated significantly with the survival of ESCC patients. Thus, LTBP-2 appears to play an important role in ESCC.
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Scenario analysis and strategic planning: practical applications for radiology practices.
J Am Coll Radiol
PUBLISHED: 05-05-2010
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Modern business science has many tools that can be of great value to radiologists and their practices. One of the most important and underused is long-term planning. Part of the problem has been the pace of change. Making a 5-year plan makes sense only if your develop robust scenarios of possible future conditions you will face. Scenario analysis is one of many highly regarded tools that can improve your predictive capability. However, as with many tools, it pays to have some training and to get practical tips on how to improve their value. It also helps to learn from other peoples mistakes rather than your own. The authors discuss both theoretical and practical issues in using scenario analysis to improve your planning process. They discuss actionable ways this set of tools can be applied in a group meeting or retreat.
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Properties of extensor digitorum longus muscle and skinned fibers from adult and aged male and female Actn3 knockout mice.
Muscle Nerve
PUBLISHED: 04-27-2010
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Absence of ?-actinin-3, encoded by the ACTN3 "speed gene," is associated with poorer sprinting performance in athletes and a slowing of relaxation in fast-twitch muscles of Actn3 knockout (KO) mice. Our first aim was to investigate, at the individual-fiber level, possible mechanisms for this slowed relaxation. Our second aim was to characterize the contractile properties of whole extensor digitorum longus (EDL) muscles from KO mice by age and gender. We examined caffeine-induced Ca(2+) release in mechanically skinned EDL fibers from KO mice, and measured isolated whole EDL contractile properties. The sarcoplasmic reticulum of KO muscle fibers loaded Ca(2+) more slowly than that of wild-types (WTs). Whole KO EDL muscles had longer twitch and tetanus relaxation times than WTs, and reduced mass and cross-sectional area. These effects occurred in both male and female mice, but they diminished with age. These changes in KO muscles and fibers help to explain the effects of ?-actinin-3 deficiency observed in athletes.
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Estrogen receptor expression and docetaxel efficacy in patients with metastatic breast cancer: a pooled analysis of four randomized trials.
Oncologist
PUBLISHED: 04-26-2010
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Differences in the efficacy of various chemotherapies in patients with estrogen receptor (ER)(+) metastatic breast cancer are not well understood. In the present study, we assessed the efficacy of docetaxel in patients with metastatic breast cancer according to ER expression.
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A sensitive and specific liquid chromatography-tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 04-03-2010
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A novel, sensitive and reliable liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of belinostat (PXD101) in human plasma. Oxamflatin was used as the internal standard. Liquid-liquid extraction of the plasma sample was performed using tert-butyl methyl ether as the organic solvent. Chromatographic separation was achieved on a BDS Hypersil C18 column (2.1 mm x1 00 mm, 5 microm) using gradient elution mode using 0.05% formic acid in water and 0.05% formic acid in acetonitrile as solvents A and B, respectively, 60/40. The run time was 6 min. The mass spectrometer was operated under a positive electrospray ionization condition and a multiple reaction monitoring mode. An excellent linear calibration was achieved in the range of 0.5-1000 ng/mL. An average recovery of belinostat for four quality controls was 72.6% and the recovery of the internal standard at 1000 ng/mL was 67.8%. The intra-day and inter-day precisions for belinostat were
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Redox protein expression predicts progression-free and overall survival in ovarian cancer patients treated with platinum-based chemotherapy.
Free Radic. Biol. Med.
PUBLISHED: 04-01-2010
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Ovarian cancer is primarily treated with platinum-based chemotherapy, with ROS generation implicated in cytotoxicity. We examined redox protein expression in ovarian tumors, focusing on the thioredoxin system, to determine the role it might play in mediating response to therapy. Nuclear and cytoplasmic expression of thioredoxin, thioredoxin reductase, thioredoxin-interacting protein, metallothionein, and glutathione S-transferase Pi was assessed, using standard immunohistochemical techniques, on a tissue microarray of 154 primary ovarian carcinomas obtained from patients subsequently treated with adjuvant platinum-based chemotherapy. Low cytoplasmic expression of thioredoxin (p=0.032) and negative nuclear expression of metallothionein (p=0.04) significantly correlated with better progression-free survival. When nuclear and cytoplasmic expression patterns were combined those patients with tumors with low cytoplasmic but high nuclear expression of thioredoxin exhibited better progression-free (p=0.003) and overall survival (p=0.004). This combination was, using multivariate analysis, an independent predictive factor for overall survival (p=0.034). Improved progression-free survival was also seen with negative expression of metallothionein, cytoplasmic and nuclear (p=0.038), and was independent of other clinical parameters (p=0.048). Such results support the suitability of using redox protein expression to predict response and, potentially, to alter treatment options accordingly.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.