JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Related JoVE Video
Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.
J. Med. Chem.
PUBLISHED: 11-11-2014
Show Abstract
Hide Abstract
Structure-based rational design and extensive SAR led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with an 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition = 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo anti-tumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
Related JoVE Video
LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.
J. Clin. Invest.
PUBLISHED: 10-16-2014
Show Abstract
Hide Abstract
Estrogen receptor-positive (ER+) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER+ tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER+ breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER+ LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYND189Y has higher catalytic activity than WT protein. Further, LYND189Y exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYNWT. Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYND189Y overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER+ breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER+ xenografts but not LYND189Y-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER+ breast cancers.
Related JoVE Video
Development of Human Serine Protease-Based Therapeutics Targeting Fn14 and Identification of Fn14 as a New Target Overexpressed in TNBC.
Mol. Cancer Ther.
PUBLISHED: 09-19-2014
Show Abstract
Hide Abstract
The cytokine TWEAK and its receptor, Fn14, have emerged as potentially valuable targets for cancer therapy. Granzyme B (GrB)-containing Fn14-targeted constructs were generated containing either the Fn14 ligand TWEAK (GrB-TWEAK) or an anti-Fn14 humanized single-chain antibody (GrB-Fc-IT4) as the targeting moieties. Both constructs showed high affinity and selective cytotoxicity against a panel of Fn14-expressing human tumor cells including triple-negative breast cancer (TNBC) lines. Cellular expression of the GrB inhibitor PI-9 in target cells had no impact on the cytotoxic effect of either construct. Cellular expression of MDR1 showed no cross-resistance to the fusion constructs. GrB-TWEAK and GrB-Fc-IT4 activated intracellular caspase cascades and cytochrome c-related proapoptotic pathways consistent with the known intracellular functions of GrB in target cells. Treatment of mice bearing established HT-29 xenografts with GrB-TWEAK showed significant tumor growth inhibition compared with vehicle alone (P < 0.05). Both GrB-TWEAK and GrB-Fc-IT4 displayed significant tumor growth inhibition when administered to mice bearing orthotopic MDA-MB-231 (TNBC) tumor xenografts. The Cancer Genome Atlas analysis revealed that Fn14 mRNA expression was significantly higher in TNBC and in HER2-positive disease (P < 0.0001) compared with hormone receptor-positive breast cancer, and in basal-like 2 tumors (P = 0.01) compared with other TNBC molecular subtypes. IHC analysis of a 101 patient TNBC tumor microarray showed that 55 of 101 (54%) of tumors stained positive for Fn14, suggesting that this may be an excellent potential target for precision therapeutic approaches. Targeting Fn14 using fully human, GrB-containing fusion constructs may form the basis for a new class of novel, potent, and highly effective constructs for targeted therapeutic applications. Mol Cancer Ther; 13(11); 2688-705. ©2014 AACR.
Related JoVE Video
Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer.
Oncologist
PUBLISHED: 08-12-2014
Show Abstract
Hide Abstract
A biomarker that predicts bone metastasis based on a protein laboratory assay has not been demonstrated. Reverse-phase protein array (RPPA) enables quantification of total and phosphorylated proteins, providing information about their functional status. The aim of this study was to identify bone-metastasis-related markers in patients with primary breast cancer using RPPA analysis.
Related JoVE Video
[Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients.]
Enferm. Infecc. Microbiol. Clin.
PUBLISHED: 08-11-2014
Show Abstract
Hide Abstract
Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution.
Related JoVE Video
Continuous drip flow system to develop biofilm of E. faecalis under anaerobic conditions.
ScientificWorldJournal
PUBLISHED: 07-14-2014
Show Abstract
Hide Abstract
To evaluate a structurally mature E. faecalis biofilm developed under anaerobic/dynamic conditions in an in vitro system.
Related JoVE Video
Peroxiredoxin-1 protects estrogen receptor ? from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer.
Breast Cancer Res.
PUBLISHED: 07-01-2014
Show Abstract
Hide Abstract
Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer.
Related JoVE Video
Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.
Oncotarget
PUBLISHED: 07-01-2014
Show Abstract
Hide Abstract
Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.
Related JoVE Video
Influence of biospecimen variables on proteomic biomarkers in breast cancer.
Clin. Cancer Res.
PUBLISHED: 06-03-2014
Show Abstract
Hide Abstract
PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers.
Related JoVE Video
Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study.
J. Clin. Oncol.
PUBLISHED: 06-02-2014
Show Abstract
Hide Abstract
Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients.
Related JoVE Video
Isolation and prominent aboriginal maternal legacy in the present-day population of La Gomera (Canary Islands).
Eur. J. Hum. Genet.
PUBLISHED: 05-12-2014
Show Abstract
Hide Abstract
The present-day population structure of La Gomera is outstanding in its high aboriginal heritage, the greatest in the Canary Islands. This was earlier confirmed by both mitochondrial DNA and autosomal analyses, although genetic drift due to the fifteenth century European colonization could not be excluded as the main factor responsible. The present mtDNA study of aboriginal remains and extant samples from the six municipal districts of the island indeed demonstrates that the pre-Hispanic colonization of La Gomera by North African people involved a strong founder event, shown by the high frequency of the indigenous Canarian U6b1a lineage in the aboriginal samples (65%). This value is even greater than that observed in the extant population (44%), which in turn is the highest of all the seven Canary Islands. In contrast to previous results obtained for the aboriginal populations of Tenerife and La Palma, haplogroups related to secondary waves of migration were not detected in La Gomera aborigines, indicating that isolation also had an important role in shaping the current population. The rugged relief of La Gomera divided into several distinct valleys probably promoted subsequent aboriginal intra-insular differentiation that has continued after the European colonization, as seen in the present-day population structure observed on the island.European Journal of Human Genetics advance online publication, 19 November 2014; doi:10.1038/ejhg.2014.251.
Related JoVE Video
The history of the North African mitochondrial DNA haplogroup U6 gene flow into the African, Eurasian and American continents.
BMC Evol. Biol.
PUBLISHED: 05-09-2014
Show Abstract
Hide Abstract
Complete mitochondrial DNA (mtDNA) genome analyses have greatly improved the phylogeny and phylogeography of human mtDNA. Human mitochondrial DNA haplogroup U6 has been considered as a molecular signal of a Paleolithic return to North Africa of modern humans from southwestern Asia.
Related JoVE Video
Residual tumor thickness at the tumor-normal tissue interface predicts the recurrence-free survival in patients with liver metastasis of breast cancer.
Ann Diagn Pathol
PUBLISHED: 05-07-2014
Show Abstract
Hide Abstract
Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin-stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy.
Related JoVE Video
Impact of prior virologic failure and nucleos(t)ide genotypic resistance mutations on the efficacy of switching from ritonavir-boosted protease inhibitors to raltegravir.
Antivir. Ther. (Lond.)
PUBLISHED: 05-06-2014
Show Abstract
Hide Abstract
The virologic efficacy of switching from a boosted protease inhibitor (PI/r) to raltegravir (RAL) containing regimens remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virologic outcome.
Related JoVE Video
Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline.
J. Clin. Oncol.
PUBLISHED: 05-05-2014
Show Abstract
Hide Abstract
To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.
Related JoVE Video
Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline.
J. Clin. Oncol.
PUBLISHED: 05-05-2014
Show Abstract
Hide Abstract
To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.
Related JoVE Video
TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.
PLoS Pathog.
PUBLISHED: 04-01-2014
Show Abstract
Hide Abstract
Many of the factors that contribute to CD8+ T cell immunodominance hierarchies during viral infection are known. However, the functional differences that exist between dominant and subdominant epitope-specific CD8+ T cells remain poorly understood. In this study, we characterized the phenotypic and functional differences between dominant and subdominant simian immunodeficiency virus (SIV) epitope-specific CD8+ T cells restricted by the major histocompatibility complex (MHC) class I allele Mamu-A*01 during acute and chronic SIV infection. Whole genome expression analyses during acute infection revealed that dominant SIV epitope-specific CD8+ T cells had a gene expression profile consistent with greater maturity and higher cytotoxic potential than subdominant epitope-specific CD8+ T cells. Flow-cytometric measurements of protein expression and anti-viral functionality during chronic infection confirmed these phenotypic and functional differences. Expression analyses of exhaustion-associated genes indicated that LAG-3 and CTLA-4 were more highly expressed in the dominant epitope-specific cells during acute SIV infection. Interestingly, only LAG-3 expression remained high during chronic infection in dominant epitope-specific cells. We also explored the binding interaction between peptide:MHC (pMHC) complexes and their cognate TCRs to determine their role in the establishment of immunodominance hierarchies. We found that epitope dominance was associated with higher TCR:pMHC affinity. These studies demonstrate that significant functional differences exist between dominant and subdominant epitope-specific CD8+ T cells within MHC-restricted immunodominance hierarchies and suggest that TCR:pMHC affinity may play an important role in determining the frequency and functionality of these cell populations. These findings advance our understanding of the regulation of T cell immunodominance and will aid HIV vaccine design.
Related JoVE Video
Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres.
J. Med. Chem.
PUBLISHED: 03-27-2014
Show Abstract
Hide Abstract
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
Related JoVE Video
Implications of functional proteomics in breast cancer.
Oncologist
PUBLISHED: 03-24-2014
Show Abstract
Hide Abstract
Breast cancer is one of the major public health problems of the Western world. Recent advances in genomics and gene expression-profiling approaches have enriched our understanding of this heterogeneous disease. However, progress in functional proteomics in breast cancer research has been relatively slow. Allied with genomics, the functional proteomics approach will be important in improving diagnosis through better classification of breast cancer and in predicting prognosis and response to different therapies, including chemotherapy, hormonal therapy, and targeted therapy. In this review, we will present functional proteomic approaches with a focus on the recent clinical implications of utilizing the reverse-phase protein array platform in breast cancer research.
Related JoVE Video
Concordance of genomic alterations between primary and recurrent breast cancer.
Mol. Cancer Ther.
PUBLISHED: 03-07-2014
Show Abstract
Hide Abstract
There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.
Related JoVE Video
Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.
J. Med. Chem.
PUBLISHED: 03-04-2014
Show Abstract
Hide Abstract
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Related JoVE Video
A Phase II study of Gefitinib in Patients with Advanced Salivary Gland Cancers.
Head Neck
PUBLISHED: 02-24-2014
Show Abstract
Hide Abstract
Purpose: Determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer. Methods: Phase II study in adenoid cystic (ACC) and non-adenoid cystic (non-ACC) carcinomas. Gefitinib was administered 250mg orally daily. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and disease control rates (DCR). EGFR and HER2 expression were evaluated and correlated with outcomes. Results: Thirty-seven patients were enrolled, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC respectively. DCR at 8 weeks was higher in ACC patients. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes. Conclusions: We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002. Head Neck, 2014.
Related JoVE Video
Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.
J. Med. Chem.
PUBLISHED: 02-05-2014
Show Abstract
Hide Abstract
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Related JoVE Video
Analysis of MET Genetic Aberrations in Patients With Breast Cancer at MD Anderson Phase I Unit.
Clin. Breast Cancer
PUBLISHED: 01-29-2014
Show Abstract
Hide Abstract
c-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit.
Related JoVE Video
Evaluation of long-term antibody responses to two inactivated bovine viral diarrhoea virus (BVDV) vaccines.
Vet. J.
PUBLISHED: 01-28-2014
Show Abstract
Hide Abstract
The aim of the present study was to determine the serological response of heifers after vaccination with two inactivated bovine viral diarrhoea virus (BVDV) vaccines by means of various ELISA tests. Three dairy farms were selected from the Galicia region of Spain. In each herd, a batch of heifers to be vaccinated for the first time was selected and followed for 15 months. Heifers from farm 1 (n=25) were vaccinated with Vaccine A, whereas heifers from farm 2 (n=16) were vaccinated with Vaccine B. Heifers from farm 3 (n=17), where no BVDV vaccines were used, acted as controls. Blood samples were analyzed periodically for BVDV antibodies, using five commercial ELISAs, based on BVDV p80 antigen or whole virus. At the end of the study, none of the animals vaccinated with Vaccine A seroconverted according to p80 antibody status, whereas up to 80% tested positive by ELISA against whole virus antigen. For the animals vaccinated with Vaccine B, 2/16 animals seroconverted according to p80 antibody ELISAs, whereas all had seroconverted according to the ELISA against whole virus antigen. In most cases, based on the use of ELISAs to detect specific antibodies against the p80 protein, at 15 months post-vaccination with inactivated BVDV vaccines the responses did not seem to interfere with detection of antibody to BVDV infection. However, the finding of a small proportion of vaccinated animals seropositive against BVDV p80 antigen suggests that antibodies that interfere with diagnosis of BVDV infection within the herd could exist, even when using p80 ELISAs.
Related JoVE Video
Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer.
J. Clin. Oncol.
PUBLISHED: 01-27-2014
Show Abstract
Hide Abstract
For patients with breast cancer (BC), the optimal time to initiation of adjuvant chemotherapy (TTC) after definitive surgery is unknown. We evaluated the association between TTC and survival according to breast cancer subtype and stage at diagnosis.
Related JoVE Video
A randomized, double-blind, 2-period, placebo-controlled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients.
Cancer J
PUBLISHED: 01-22-2014
Show Abstract
Hide Abstract
This study assessed the efficacy of methylphenidate versus placebo for cancer-related fatigue reduction. Other objectives were to analyze cytokine levels and to determine the effects of methylphenidate on other symptoms, cognitive function, work yield, and patients' perceptions and preferences.
Related JoVE Video
Prospective evaluation of the conversion rate in the receptor status between primary breast cancer and metastasis: results from the GEICAM 2009-03 ConvertHER study.
Breast Cancer Res. Treat.
PUBLISHED: 01-11-2014
Show Abstract
Hide Abstract
The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally. Overall, 196 patients were included and 184 patients were considered evaluable. Reasons for non-evaluability included the inability to perform biopsy (n = 4) or biopsy results showing normal tissue (n = 3), benign disease (n = 3) or a second neoplasia (n = 2). Conversion rates determined at local level were higher than those determined centrally (HER2: 16 vs. 3 %, ER: 21 vs. 13 %, PR: 35 vs. 28 %, respectively). There was substantial agreement regarding the expression of HER2 in primary tumors and metastases, and ER at metastases, between local and central laboratories. PR at any site and ER at primary site showed moderate agreement. Oncologists altered their treatment plans in 31 % of patients whose tumor subtype had changed. These results reinforce the recommendation for performing confirmatory biopsies of metastases, not only to avoid misdiagnosis of breast cancer relapse, but also to optimize treatment (clinicaltrials.gov identifier: NCT01377363).
Related JoVE Video
PD-L1 expression in triple-negative breast cancer.
Cancer Immunol Res
PUBLISHED: 01-10-2014
Show Abstract
Hide Abstract
Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1(+) tumors had greater CD8(+) T-cell infiltrate than PD-L1(-) tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses.
Related JoVE Video
Genetic analysis of single-locus and epistatic QTLs for seed traits in an adapted × nuña RIL population of common bean (Phaseolus vulgaris L.).
Theor. Appl. Genet.
PUBLISHED: 01-03-2014
Show Abstract
Hide Abstract
The QTLs analyses here reported demonstrate the significant role of both individual additive and epistatic effects in the genetic control of seed quality traits in the Andean common bean. Common bean shows considerable variability in seed size and coat color, which are important agronomic traits determining farmer and consumer acceptability. Therefore, strategies must be devised to improve the genetic base of cultivated germplasm with new alleles that would contribute positively to breeding programs. For that purpose, a population of 185 recombinant inbred lines derived from an Andean intra-gene pool cross, involving an adapted common bean (PMB0225 parent) and an exotic nuña bean (PHA1037 parent), was evaluated under six different--short and long-day--environmental conditions for seed dimension, weight, color, and brightness traits, as well as the number of seed per pod. A multi-environment Quantitative Trait Loci (QTL) analysis was carried out and 59 QTLs were mapped on all linkage groups, 18 of which had only individual additive effects, while 27 showed only epistatic effects and 14 had both individual additive and epistatic effects. Multivariate models that included significant QTL explained from 8 to 68 % and 2 to 15 % of the additive and epistatic effects, respectively. Most of these QTLs were consistent over environment, though interactions between QTLs and environments were also detected. Despite this, QTLs with differential effect on long-day and short-day environments were not found. QTLs identified were positioned in cluster, suggesting that either pleiotropic QTLs control several traits or tightly linked QTLs for different traits map together in the same genomic regions. Overall, our results show that digenic epistatic interactions clearly play an important role in the genetic control of seed quality traits in the Andean common bean.
Related JoVE Video
cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer.
J Cancer
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines.
Related JoVE Video
Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation.
J Int AIDS Soc
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Monotherapy with protease-inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation.
Related JoVE Video
Differences in gene and protein expression and the effects of race/ethnicity on breast cancer subtypes.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 12-02-2013
Show Abstract
Hide Abstract
Background: Differences in gene or protein expression patterns between breast cancers according to race/ethnicity and cancer subtype. Methods: Transcriptional profiling was performed using Affymetrix HG-U133A platform in 376 patients and reverse phase protein array analysis (RPPA) was done for 177 proteins in 255 patients from a separate cohort. Unsupervised clustering was conducted, as well as supervised comparison by race and tumor subtype. Standard statistical methods, BRB-Array tools and Ingenuity Pathways software packages were used to analyze the data. Results: Median age was 50 years in both cohorts. In the RPPA cohort 54.5% of the tumors were HR-positive, 20.7% HER2-positive and 24.71% triple-negative (TNBC). One hundred and forty-seven (57.6%), 47 (18.43%), 46 (18.1%) of the patients were White, Hispanic and Black, respectively. Unsupervised hierarchal clustering of the protein expression data showed no distinct clusters by race (p-values were 0.492, 0.489 and 0.494 for the HR-positive, HER2-positive and TNBC tumors respectively). In the gene expression cohort, 54.2% of the tumors were HR-positive, 16.5% HER2-positive and 29.3% TNBC. Two hundred and sixteen (57.5%), 111 (29.52%), and 32 (8.52%) patients were white, Hispanic and black, respectively. No probe set with an FDR < 0.05 showed an association with race by breast cancer subtype; similar results were obtained using pathway and gene set enrichment analysis methods. Conclusions: we did not detect significant variation in RNA or protein expression comparing different race/ethnicity groups of women with breast cancer Impact: More research on the complex network of factors that result in outcomes differences among race/ethnicities is needed.
Related JoVE Video
Breast cancer multifocality and multicentricity and locoregional recurrence.
Oncologist
PUBLISHED: 10-17-2013
Show Abstract
Hide Abstract
The impact of multifocal (MF) or multicentric (MC) breast cancer on locoregional (LR) control rates is unknown. Methods. MF was defined as two or more separate invasive tumors in the same quadrant of the breast. MC was defined as two or more separate invasive tumors occupying more than one quadrant of the same breast. Patients were categorized by LR treatment: breast conservation therapy (BCT; n = 256), mastectomy (n = 466), or mastectomy plus postmastectomy radiation therapy (PMRT; n = 184). All patients with MC disease had mastectomy (10 patients treated with BCT for MC disease were excluded). The Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were used to determine independent associations of multifocality or multicentricity with LR control. Results. A total of 906 patients had either MF disease (n = 673) or MC disease (n = 233). With median follow-up of 52 months, the 5-year LR control rate was 99% for MF, 96% for MC, and 98% for unifocal tumors (p = .44). Subset analysis revealed no difference in LR control regardless of the LR treatment (p = .67 for BCT, p = .37 for mastectomy, p = .29 for mastectomy plus PMRT). There were five in-breast recurrences after BCT in the MF group. MF and MC did not have an independent impact on LR control rate on multivariate analysis. Conclusion. MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had rates of LR control similar to those of their unifocal counterparts. These data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for PMRT.
Related JoVE Video
Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study.
J. Antimicrob. Chemother.
PUBLISHED: 10-14-2013
Show Abstract
Hide Abstract
Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients.
Related JoVE Video
[Pott puffy tumor: case report].
Arch Argent Pediatr
PUBLISHED: 10-05-2013
Show Abstract
Hide Abstract
We present the case of a child with frontal sinusitis, who also suffers from a severe intracranial disease. Although sinusitis intracranial issues are rare nowadays, they include a wide range of serious entities such as meningitis, brain abscesses and thrombosis of the cavernous sinus. We emphasize the importance of early diagnosis and an adequate initial empirical treatment to prevent possible complications. Once they are presented, an aggressive surgical medical treatment is required for its resolution.
Related JoVE Video
Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial.
Clin. Cancer Res.
PUBLISHED: 10-04-2013
Show Abstract
Hide Abstract
This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies.
Related JoVE Video
Cell-based fuzzy metrics enhance high-content screening (HCS) assay robustness.
J Biomol Screen
PUBLISHED: 09-17-2013
Show Abstract
Hide Abstract
High-content screening (HCS) allows the exploration of complex cellular phenotypes by automated microscopy and is increasingly being adopted for small interfering RNA genomic screening and phenotypic drug discovery. We introduce a series of cell-based evaluation metrics that have been implemented and validated in a mono-parametric HCS for regulators of the membrane trafficking protein caveolin 1 (CAV1) and have also proved useful for the development of a multiparametric phenotypic HCS for regulators of cytoskeletal reorganization. Imaging metrics evaluate imaging quality such as staining and focus, whereas cell biology metrics are fuzzy logic-based evaluators describing complex biological parameters such as sparseness, confluency, and spreading. The evaluation metrics were implemented in a data-mining pipeline, which first filters out cells that do not pass a quality criterion based on imaging metrics and then uses cell biology metrics to stratify cell samples to allow further analysis of homogeneous cell populations. Use of these metrics significantly improved the robustness of the monoparametric assay tested, as revealed by an increase in Z factor, Kolmogorov-Smirnov distance, and strict standard mean difference. Cell biology evaluation metrics were also implemented in a novel supervised learning classification method that combines them with phenotypic features in a statistical model that exceeded conventional classification methods, thus improving multiparametric phenotypic assay sensitivity.
Related JoVE Video
Mitochondrial DNA and Y-chromosome structure at the mediterranean and atlantic façades of the iberian peninsula.
Am. J. Hum. Biol.
PUBLISHED: 09-03-2013
Show Abstract
Hide Abstract
The aim of this study is to analyze mitochondrial DNA and Y-chromosome lineages in a range of Atlantic and Mediterranean populations of the Iberian Peninsula in search of genetic differences between both façades and to uncover the most probable geographic origin and coalescence ages of lineages.
Related JoVE Video
Decorin prevents the development of juvenile communicating hydrocephalus.
Brain
PUBLISHED: 08-29-2013
Show Abstract
Hide Abstract
In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-? has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-? antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-?/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-?1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-?-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.
Related JoVE Video
Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes.
Clin. Cancer Res.
PUBLISHED: 08-15-2013
Show Abstract
Hide Abstract
The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and colleagues is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.
Related JoVE Video
Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds.
Neurobiol. Dis.
PUBLISHED: 07-29-2013
Show Abstract
Hide Abstract
In the injured central nervous system (CNS), transforming growth factor (TGF)-?1/2-induced scarring and wound cavitation impede axon regeneration implying that a combination of both scar suppression and axogenic treatments is required to achieve functional recovery. After treating acute and chronic dorsal funicular spinal cord lesions (DFL) in adult rats with the pan-TGF?1/2 antagonist Decorin, we report that in: (1), acute DFL, the development of all injury parameters was significantly retarded e.g., wound cavitation by 68%, encapsulation of the wound by a glia limitans accessoria (GLA) by 65%, GLA basal lamina thickness by 94%, fibronectin, NG2 and Sema-3A deposition by 87%, 48% and 48%, respectively, and both macrophage and reactive microglia accumulation by 60%; and (2), chronic DFL, all the above parameters were attenuated to a lesser extent e.g., wound cavitation by 11%, GLA encapsulation by 25%, GLA basal lamina thickness by 31%, extracellular fibronectin, NG2 and Sema-3A deposition by 58%, 22% and 29%, respectively, and macrophage and reactive microglia accumulation by 44%. Moreover, in acute and chronic DFL, levels of tissue plasminogen activator (tPA) were raised (by 236% and 482%, respectively), as were active-MMP-2 (by 64% and 91%, respectively) and active-MMP-9 (by 122% and 18%, respectively), while plasminogen activator inhibitor-1 (PAI-1) was suppressed (by 56% and 23%, respectively) and active-TIMP-and active TIMP-2 were both lower but only significantly suppressed in acute DFL (by 56 and 21%, respectively). These findings demonstrate that both scar tissue mass and cavitation are attenuated in acute and chronic spinal cord wounds by Decorin treatment and suggest that the dominant effect of Decorin during acute scarring is anti-fibrogenic through suppression of inflammatory fibrosis by neutralisation of TGF?1/2 whereas, in chronic lesions, Decorin-induction of tPA and MMP (concomitant with reduced complimentary levels of TIMP and PAI-1) leads to dissolution of the mature established scar by fibrolysis. Decorin also promoted the regeneration of similar numbers of axons through acute and chronic wounds. Accordingly, intrathecal delivery of Decorin offers a potential translatable treatment for scar tissue attenuation in patients with spinal cord injury.
Related JoVE Video
Progress in the biological understanding and management of breast cancer-associated central nervous system metastases.
Oncologist
PUBLISHED: 06-05-2013
Show Abstract
Hide Abstract
Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.
Related JoVE Video
Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer.
Clin. Cancer Res.
PUBLISHED: 05-22-2013
Show Abstract
Hide Abstract
Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer.
Related JoVE Video
HER2 testing: Current status and future directions.
Cancer Treat. Rev.
PUBLISHED: 05-16-2013
Show Abstract
Hide Abstract
Accurate determination of human epidermal growth factor receptor 2 (HER2) status is critical for optimizing breast cancer outcomes. In 2007, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed guidelines for HER2 testing to reduce inaccuracy. However, current ASCO/CAP criteria may restrict access to HER2-targeted therapy for some patient groups who would derive a clear clinical benefit. ASCO/CAP are currently reviewing their guidelines to further optimize HER2 testing and include emerging techniques. Guidelines are critical for optimizing care, as is ongoing research into techniques that accurately and reproducibly assess HER2 status.
Related JoVE Video
Outcomes After Multidisciplinary Treatment of Inflammatory Breast Cancer in the Era of Neoadjuvant HER2-directed Therapy.
Am. J. Clin. Oncol.
PUBLISHED: 05-08-2013
Show Abstract
Hide Abstract
OBJECTIVES:: We previously reported survival trends among patients with inflammatory breast cancer (IBC) over a 30-year period before 2005. Here we evaluated survival outcomes for women with IBC diagnosed before or after October 2006, in the era of HER2-directed therapy and after opening a dedicated multidisciplinary IBC clinic. METHODS:: We retrospectively identified and reviewed 260 patients with newly diagnosed IBC without distant metastasis, 168 treated before October 2006 and 92 treated afterward. Most patients received anthracycline and taxane-based neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Survival outcomes were compared between the 2 groups. RESULTS:: Median follow-up time was 29 months for the entire cohort (39 and 24 mo for patients treated before and after October 2006). Patients treated more recently were more likely to have received neoadjuvant HER2-directed therapy for HER2-positive tumors (100% vs. 54%, P=0.001). No differences were found in receipt of hormone therapy. Three-year overall survival rates were 63% for those treated before and 82% for those treated after October 2006 (log-rank P=0.02). Univariate Cox analysis demonstrated better overall survival among patients treated after October 2006 than among those treated beforehand [hazard ratio (HR) 0.5; 95% confidence interval (CI), 0.34-0.94]; a trend toward improved survival was noted in the multivariate analysis (HR=0.47; 95% CI, 0.19-1.16; P=0.10). Significant factors in the multivariate model included HER2-directed therapy (HR=0.38; 95% CI, 0.17-0.84; P=0.02) and estrogen receptor positivity (HR=0.32; 95% CI, 0.14-0.74; P=0.01). CONCLUSIONS:: Survival improved in the context of the IBC clinic and prompt initiation of neoadjuvant HER2-directed therapeutics.
Related JoVE Video
An evaluation of the impact of technical bias on the concordance rate between primary and recurrent tumors in breast cancer.
Breast
PUBLISHED: 04-16-2013
Show Abstract
Hide Abstract
Whether or not to biopsy the metastasis in recurrent breast cancer has become mired in controversy. Several studies have shown an important discordance of the immunohistochemical (IHC) determinations for ER, PR and HER2 between primary (PT) and recurrent tumors (RT). Yet it remains unknown within this what impact technical issues have. The aim of our study was to assess whether technical variability might have an impact on the concordance between PT and RT.
Related JoVE Video
In vitro antimicrobial activity of 20 selected climber species from the Bignoniaceae family.
Nat. Prod. Res.
PUBLISHED: 04-11-2013
Show Abstract
Hide Abstract
Hydroalcoholic and aqueous extracts of some climber species from the Bignoniaceae family that grow in the north of Argentina were evaluated for in vitro antibacterial activity against Gram-positive and Gram-negative strains. By means of bioautography and disc diffusion methods, it could be determined that all infusions were not active, whereas the hydroalcoholic extracts of seven species were able to inhibit bacterial growth. The minimum inhibitory concentration and minimum bactericidal concentration observed were between 62.5 and 1000 ?g gallic acid equivalent (GAE)/mL and between 125 and 1000 ?g GAE/mL, respectively. The tested extracts were more active against Gram-positive microorganisms. Time-kill experiments indicated that all extracts have bacteriostatic activity. Phytochemical screening showed the presence of terpenoids, phenols and flavonoids. The amount of phenolic compounds and flavonoids was higher in tinctures when compared with infusions. These results suggest the presence of antibacterial substances in the hydroalcoholic extracts, which could be used for the treatment of infections.
Related JoVE Video
Stress hyperglycaemia in hospitalized patients with coronary artery disease and type 2 diabetes risk.
Eur. J. Clin. Invest.
PUBLISHED: 04-10-2013
Show Abstract
Hide Abstract
Aims: (i) To evaluate glucometabolic status of patients without known diabetes hospitalized due to coronary artery disease (CAD), (ii) to assess markers of systemic inflammation determined during admission and to evaluate their relationship with glucometabolic status and (iii) to analyse usefulness of HbA1c determined during admission in patients with CAD to detect abnormal glucose regulation (AGR).
Related JoVE Video
Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer.
Oncologist
PUBLISHED: 04-10-2013
Show Abstract
Hide Abstract
The purpose of this analysis was to compare disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) between pregnant and nonpregnant patients with breast cancer.
Related JoVE Video
Characterization and expression analysis of SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) genes in sexual and apomictic Paspalum notatum.
Plant Mol. Biol.
PUBLISHED: 04-02-2013
Show Abstract
Hide Abstract
The SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) gene plays a fundamental role in somatic embryogenesis of angiosperms, and is associated with apomixis in Poa pratensis. The objective of this work was to isolate, characterize and analyze the expression patterns of SERK genes in apomictic and sexual genotypes of Paspalum notatum. A conserved 200-bp gene fragment was amplified from genomic DNA with heterologous primers, and used to initiate a chromosomal walking strategy for cloning the complete sequence. This procedure allowed the isolation of two members of the P. notatum SERK family; PnSERK1, which is similar to PpSERK1, and PnSERK2, which is similar to ZmSERK2 and AtSERK1. Phylogenetic analyses indicated that PnSERK1 and PnSERK2 represent paralogous sequences. Southern-blot hybridization indicated the presence of at least three copies of SERK genes in the species. qRT-PCR analyses revealed that PnSERK2 was expressed at significantly higher levels than PnSERK1 in roots, leaves, reproductive tissues and embryogenic calli. Moreover, in situ hybridization experiments revealed that PnSERK2 displayed a spatially and chronologically altered expression pattern in reproductive organs of the apomictic genotype with respect to the sexual one. PnSERK2 is expressed in nucellar cells of the apomictic genotype at meiosis, but only in the megaspore mother cell in the sexual genotype. Therefore, apomixis onset in P. notatum seems to be correlated with the expression of PnSERK2 in nucellar tissue.
Related JoVE Video
Machine learning and social network analysis applied to Alzheimers disease biomarkers.
Curr Top Med Chem
PUBLISHED: 01-25-2013
Show Abstract
Hide Abstract
Due to the fact that the number of deaths due Alzheimer is increasing, the scientists have a strong interest in early stage diagnostic of this disease. Alzheimers patients show different kind of brain alterations, such as morphological, biochemical, functional, etc. Currently, using magnetic resonance imaging techniques is possible to obtain a huge amount of biomarkers; being difficult to appraise which of them can explain more properly how the pathology evolves instead of the normal ageing. Machine Learning methods facilitate an efficient analysis of complex data and can be used to discover which biomarkers are more informative. Moreover, automatic models can learn from historical data to suggest the diagnostic of new patients. Social Network Analysis (SNA) views social relationships in terms of network theory consisting of nodes and connections. The resulting graph-based structures are often very complex; there can be many kinds of connections between the nodes. SNA has emerged as a key technique in modern sociology. It has also gained a significant following in medicine, anthropology, biology, information science, etc., and has become a popular topic of speculation and study. This paper presents a review of machine learning and SNA techniques and then, a new approach to analyze the magnetic resonance imaging biomarkers with these techniques, obtaining relevant relationships that can explain the different phenotypes in dementia, in particular, different stages of Alzheimers disease.
Related JoVE Video
Introducing the Algerian mitochondrial DNA and Y-chromosome profiles into the North African landscape.
PLoS ONE
PUBLISHED: 01-15-2013
Show Abstract
Hide Abstract
North Africa is considered a distinct geographic and ethnic entity within Africa. Although modern humans originated in this Continent, studies of mitochondrial DNA (mtDNA) and Y-chromosome genealogical markers provide evidence that the North African gene pool has been shaped by the back-migration of several Eurasian lineages in Paleolithic and Neolithic times. More recent influences from sub-Saharan Africa and Mediterranean Europe are also evident. The presence of East-West and North-South haplogroup frequency gradients strongly reinforces the genetic complexity of this region. However, this genetic scenario is beset with a notable gap, which is the lack of consistent information for Algeria, the largest country in the Maghreb. To fill this gap, we analyzed a sample of 240 unrelated subjects from a northwest Algeria cosmopolitan population using mtDNA sequences and Y-chromosome biallelic polymorphisms, focusing on the fine dissection of haplogroups E and R, which are the most prevalent in North Africa and Europe respectively. The Eurasian component in Algeria reached 80% for mtDNA and 90% for Y-chromosome. However, within them, the North African genetic component for mtDNA (U6 and M1; 20%) is significantly smaller than the paternal (E-M81 and E-V65; 70%). The unexpected presence of the European-derived Y-chromosome lineages R-M412, R-S116, R-U152 and R-M529 in Algeria and the rest of the Maghreb could be the counterparts of the mtDNA H1, H3 and V subgroups, pointing to direct maritime contacts between the European and North African sides of the western Mediterranean. Female influx of sub-Saharan Africans into Algeria (20%) is also significantly greater than the male (10%). In spite of these sexual asymmetries, the Algerian uniparental profiles faithfully correlate between each other and with the geography.
Related JoVE Video
Mesothelin expression and survival outcomes in triple receptor negative breast cancer.
Clin. Breast Cancer
PUBLISHED: 01-11-2013
Show Abstract
Hide Abstract
Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes.
Related JoVE Video
Status of the anaplastic lymphoma kinase (ALK) gene in inflammatory breast carcinoma.
Springerplus
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Although preliminary reports suggest that ALK gene amplification may occur in inflammatory breast cancer (IBC), data are limited. We performed a comprehensive investigation of the status of ALK gene in IBC.
Related JoVE Video
Use of ACE Inhibitors and Angiotensin Receptor Blockers and Primary Breast Cancer Outcomes.
J Cancer
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy.
Related JoVE Video
Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer.
Oncologist
PUBLISHED: 12-06-2011
Show Abstract
Hide Abstract
Numerous studies have demonstrated that expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2 is important for predicting overall survival (OS), distant relapse (DR), and locoregional relapse (LRR) in early and advanced breast cancer patients. However, these findings have not been confirmed for inflammatory breast cancer (IBC), which has different biological features than non-IBC.
Related JoVE Video
Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors.
J. Clin. Oncol.
PUBLISHED: 11-28-2011
Show Abstract
Hide Abstract
We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) -positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors.
Related JoVE Video
Novel staging system for predicting disease-specific survival in patients with breast cancer treated with surgery as the first intervention: time to modify the current American Joint Committee on Cancer staging system.
J. Clin. Oncol.
PUBLISHED: 11-14-2011
Show Abstract
Hide Abstract
American Joint Committee on Cancer (AJCC) staging is used to determine breast cancer prognosis, yet patient survival within each stage shows wide variation. We hypothesized that differences in biology influence this variation and that addition of biologic markers to AJCC staging improves determination of prognosis.
Related JoVE Video
Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1? in acinar cell homeostasis.
Gut
PUBLISHED: 09-23-2011
Show Abstract
Hide Abstract
During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis.
Related JoVE Video
A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer.
Cancer Res.
PUBLISHED: 09-09-2011
Show Abstract
Hide Abstract
Estrogen receptor ? (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.
Related JoVE Video
Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 08-30-2011
Show Abstract
Hide Abstract
The purpose of this study was to determine local-regional recurrence (LRR) risk according to whether postmastectomy radiation therapy (PMRT) was used to treat breast cancer patients with clinical T3N0 disease who received neoadjuvant chemotherapy (NAC) and mastectomy.
Related JoVE Video
ZNF668 functions as a tumor suppressor by regulating p53 stability and function in breast cancer.
Cancer Res.
PUBLISHED: 08-18-2011
Show Abstract
Hide Abstract
Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability.
Related JoVE Video
Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 08-18-2011
Show Abstract
Hide Abstract
Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chronic-like pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, ?-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-?1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-?1 (185 ± 40 vs. 15 ± 2 ng/ml; P <0.01) that was blunted by TRF (53 ± 19; P < 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. ?-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 ± 0.3% vs. 0.2 ± 0.2%), collagen network complexity (fractal dimension 1.52 ± 0.03 vs. 1.42 ± 0.01; P < 0.001), and inhomogeneity (lacunarity 0.63 ± 0.03 vs. 0.40 ± 0.02; P < 0.001), which were all reduced by TRF (1.3 ± 0.4%, 1.43 ± 0.02%, and 0.51 ± 0.03%, respectively; P < 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r = 0.88) and both parameters with pancreatic weight (r = -0.91 and -0.79, respectively). TRF administered only before pancreatitis best, but not fully, recapitulated the beneficial effects of TRF. Tocotrienols improve quantitative measures of chronic pancreatic damage. They may be of benefit in human chronic pancreatitis.
Related JoVE Video
Mitochondrial DNA and Y-chromosome microstructure in Tunisia.
J. Hum. Genet.
PUBLISHED: 08-11-2011
Show Abstract
Hide Abstract
Mitochondrial DNA (mtDNA) and Y-chromosome variation has been studied in Bou Omrane and Bou Saâd, two Tunisian Berber populations. In spite of their close geographic proximity, genetic distances between them were high and significant with both uniparental markers. A global analysis, including all previously studied Tunisian samples, confirmed the existence of a high female and male population structure in this country. Analyses of molecular variance analysis evidenced that this differentiation was not attributable to ethnic differences. Mantel test showed that, in all cases, Y-chromosome haplotypic distances correlated poorly with geography, whereas after excluding the more isolated samples of Bou Omrane and Bou Saâd, the mtDNA pattern of variation is significantly correlated with geography. Congruently, the N(m) ratio of males versus females pointed to a significant excess of female migration rate across localities, which could be explained by patrilocality, a common marriage system in rural Tunisia. In addition, it has been observed that cultural isolation in rural communities promotes, by the effect of genetic drift, stronger loss of diversity and larger genetic differentiation levels than those observed in urban areas as deduced from comparisons of their respective mean genetic diversity and their respective mean genetic distances among populations. It is likely that the permanent exodus from rural to urban areas will have important repercussions in the future genetic structure of this country.
Related JoVE Video
Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations.
Breast Cancer Res. Treat.
PUBLISHED: 07-26-2011
Show Abstract
Hide Abstract
More than 75% of breast cancers that develop in BRCA1 mutation carriers are triple-negative breast cancers (TNBC). The aim of this study was to compare the recurrence-free survival (RFS) and overall survival (OS) in high-risk patients with TNBC with and without deleterious BRCA1/2 mutations. A total of 227 women with TNBC who were referred for genetic counseling and underwent BRCA genetic testing between 1997 and 2010 were included in the study. The relationships between clinical variables and outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. Of 227 high-risk women with TNBC, 50% (n = 114) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA non-carriers and carriers. At a median follow-up of 3.4 years, the 5-year RFS rates were 74 and 81% (P = 0.21), and 5-year OS rates were 85 and 93% in BRCA non-carriers and BRCA carriers, respectively (P = 0.11). In a multivariate model, after adjusting for age and disease stage, BRCA carriers tended to have a decreased risk of recurrence (HR = 0.67; 95% CI: 0.38-1.19; P = 0.17) or death (HR = 0.51; 95% CI:0.23-1.17; P = 0.11) compared to non-carriers. Our data indicate a 50% prevalence of deleterious BRCA1/2 mutations in high-risk women diagnosed with TNBC. Overall prognosis of TNBC in BRCA carriers and non-carriers is not significantly different within the first 5 years following an initial diagnosis. Further studies need to evaluate whether different therapies will change the outcome in these subgroups of TNBC.
Related JoVE Video
Susceptibility to primary angle closure glaucoma in Saudi Arabia: the possible role of mitochondrial DNA ancestry informative haplogroups.
Mol. Vis.
PUBLISHED: 07-25-2011
Show Abstract
Hide Abstract
In a previous preliminary analysis we reported that mitochondrial DNA (mtDNA) haplogroup R0a was significantly more frequent in primary angle closure glaucoma (PACG) Saudi patients than in healthy Saudi controls. This result prompted us to extend our work using a significant larger Saudi PACG cohort and more healthy controls.
Related JoVE Video

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.