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Find video protocols related to scientific articles indexed in Pubmed.
A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.
Blood
PUBLISHED: 10-29-2014
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The cutaneous CD30-positive lymphoproliferative spectrum of disorders (LPD) includes lymphomatoid papulosis (LYP) and primary cutaneous anaplastic large cell lymphoma (ALCL). Chromosomal translocations targeting tyrosine kinases in CD30-positive LPD have not been described. Using whole transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) which encodes an NPM1- TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, STAT1, STAT3 and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, shRNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2 and highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
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Survival in patients with limited-stage peripheral T-cell lymphomas.
Leuk. Lymphoma
PUBLISHED: 09-25-2014
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The natural history of limited-stage peripheral T-cell lymphoma (PTCL) remains poorly defined. Therefore, we examined outcomes in patients with the most common PTCL subtypes (PTCL, not otherwise specified [PTCL, NOS], angioimmunoblastic T-cell lymphoma [AITL], anaplastic large cell lymphoma [ALCL]) and limited-stage disease. In this retrospective, multicenter study, 75 patients with limited-stage disease were identified. The median event-free survival (EFS) and overall survival (OS) observed were 2.1 and 6.5 years, respectively. In a landmark analysis excluding patients with primary refractory disease, no significant benefit was observed for patients undergoing consolidative radiation therapy. With the exception of patients undergoing salvage hematopoietic stem cell transplant, survival following disease relapse or progression was poor, thus highlighting the need for improved therapeutic strategies.
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The medium and the message: fitting sound health promotion methodology into 160 characters.
JMIR Mhealth Uhealth
PUBLISHED: 09-24-2014
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Text messaging health promotion projects continue to proliferate due to their relative low-cost, simplicity, non-intrusiveness, and proven effectiveness in several randomized controlled trials. In these past trials, participants have typically been recruited through traditional means, received the text messaging intervention, and then completed evaluation. In this issue of the Journal of Medical Internet Research, Sheoran et al have demonstrated how use of text messaging alone can be a feasible method for all three stages: recruitment, intervention, and evaluation. Use of text messages without any other modes of communication could be a key to population-level dissemination and wider uptake of health promotion messages. However, in the rush to utilize new technologies and in the brevity of 160 characters, it should not be forgotten that quality, rigour, and careful development remain essential in any health promotion practice.
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Fbxo45 Inhibits Calcium-sensitive Proteolysis of N-cadherin and Promotes Neuronal Differentiation.
J. Biol. Chem.
PUBLISHED: 08-20-2014
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Fbxo45 is an atypical E3 ubiquitin ligase, which specifically targets proteins for ubiquitin-mediated degradation. Fbxo45 ablation results in defective neuronal differentiation and abnormal formation of neural connections; however, the mechanisms underlying these defects are poorly understood. Using an unbiased mass spectrometry-based proteomic screen, we show here that N-cadherin is a novel interactor of Fbxo45. N-cadherin specifically interacts with Fbxo45 through two consensus motifs overlapping the site of calcium-binding and dimerization of the cadherin molecule. N-cadherin interaction with Fbxo45 is significantly abrogated by calcium treatment. Surprisingly, Fbxo45 depletion by RNAi-mediated silencing results in enhanced proteolysis of N-cadherin. Conversely, ectopic expression of Fbxo45 results in decreased proteolysis of N-cadherin. Fbxo45 depletion results in dramatic reduction in N-cadherin expression, impaired neuronal differentiation, and diminished formation of neuronal processes. Our studies reveal an unanticipated role for an F-box protein that inhibits proteolysis in the regulation of a critical biological process.
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Sexual identity, same-sex partners and risk behaviour among a community-based sample of young people in Australia.
Int. J. Drug Policy
PUBLISHED: 08-01-2014
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Young people who are same-sex attracted report higher rates of substance use, sexual risk behaviour, and mental health problems. Numerous studies have shown that sexual identity, sexual behaviour and sexual attraction do not always correspond, particularly among young people. We describe sexual identity, sexual partners, and associations between sexual identity and risk in a community-based sample of young people.
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Young people's comparative recognition and recall of an Australian Government Sexual Health Campaign.
Int J STD AIDS
PUBLISHED: 07-10-2014
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In 2009, the Australian Government's National Sexually Transmitted Infection Prevention Program launched a multi-million dollar sexual health campaign targeting young people. We assessed campaign recognition among a community sample of young people. Individuals aged 16-29 years self-completed a questionnaire at a music festival. Participants were asked whether they recognised the campaign image and attempted to match the correct campaign message. Recognition of two concurrent campaigns, GlaxoSmithKline's The Facts genital herpes campaign (targeting young women) and the Drama Downunder campaign (targeting gay men) were assessed simultaneously. Among 471 participants, just 29% recognised the National Sexually Transmitted Infection Prevention Program campaign. This compared to 52% recognising The Facts and 27% recognising Drama Downunder. Of 134 who recognised the National Sexually Transmitted Infection Prevention Program campaign, 27% correctly recalled the campaign messages compared to 61% of those recognising the Facts campaign, and 25% of those recognising the Drama Downunder campaign. There was no difference in National Sexually Transmitted Infection Prevention Program campaign recognition by gender or age. Campaign recognition and message recall of the National Sexually Transmitted Infection Prevention Program campaign was comparatively low. Future mass media sexual health campaigns targeting young people can aim for higher recognition and recall rates than that achieved by the National Sexually Transmitted Infection Prevention Program campaign. Alternative distribution channels and message styles should be considered to increase these rates.
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Activating FGFR2-RAS-BRAF Mutations in Ameloblastoma.
Clin. Cancer Res.
PUBLISHED: 07-03-2014
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Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway.
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High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis.
Blood
PUBLISHED: 06-30-2014
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Langerhans cell histiocytosis (LCH) represents a clonal proliferation of Langerhans cells. BRAF V600E mutations have been identified in approximately 50% of cases. To discover other genetic mechanisms underlying LCH pathogenesis, we studied 8 cases of LCH using a targeted next-generation sequencing platform. An E102_I103del mutation in MAP2K1 was identified in one BRAF wild-type case and confirmed by Sanger sequencing. Analysis of 32 additional cases using BRAF V600E allele-specific polymerase chain reaction and Sanger sequencing of MAP2K1 exons 2 and 3 revealed somatic, mutually exclusive BRAF and MAP2K1 mutations in 18 of 40 (45.0%) and 11 of 40 (27.5%) cases, respectively. This is the first report of MAP2K1 mutations in LCH that occur in 50% of BRAF wild-type cases. The mutually exclusive nature of MAP2K1 and BRAF mutations implicates a critical role of oncogenic MAPK signaling in LCH. This finding may also have implications in the use of BRAF and MEK inhibitor therapy.
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Analysis of laboratory testing results collected in an enhanced chlamydia surveillance system in Australia, 2008-2010.
BMC Infect. Dis.
PUBLISHED: 06-06-2014
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Chlamydial infection is the most common notifiable disease in Australia, Europe and the US. Australian notifications of chlamydia rose four-fold from 20,274 cases in 2002 to 80,846 cases in 2011; the majority of cases were among young people aged less than 29 years. Along with test positivity rates, an understanding of the number of tests performed and the demographics of individuals being tested are key epidemiological indicators. The ACCESS Laboratory Network was established in 2008 to address this issue.
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Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.
Blood
PUBLISHED: 05-13-2014
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The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.
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Early age at first sex: associations with sexual health and sociodemographic factors among a sample of young music festival attendees in Melbourne.
Sex Health
PUBLISHED: 03-20-2014
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Background Age at first sex (AFS) is associated with adverse outcomes. We explore associated factors and correlates of 'early' AFS (<16 years).
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Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study.
Lancet Respir Med
PUBLISHED: 03-17-2014
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Assessment of the effect of influenza on populations, including risk of infection, illness if infected, illness severity, and consultation rates, is essential to inform future control and prevention. We aimed to compare the community burden and severity of seasonal and pandemic influenza across different age groups and study years and gain insight into the extent to which traditional surveillance underestimates this burden.
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Young people's comfort receiving sexual health information via social media and other sources.
Int J STD AIDS
PUBLISHED: 03-10-2014
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Social media are growing in popularity and will play a key role in future sexual health promotion initiatives. We asked 620 survey participants aged 16 to 29 years about their time spent using social media and their comfort in receiving information about sexual health via different channels. Median hours per day spent using social network sites was two; 36% spent more than 2 hours per day using social network sites. In multivariable logistic regression, being aged less than 20 years and living in a major city (compared to rural/regional Australia) were associated with use of social media more than 2 hours per day. Most participants reported being comfortable or very comfortable accessing sexual health information from websites (85%), followed by a doctor (81%), school (73%), and the mainstream media (67%). Fewer reported being comfortable getting information from social media; Facebook (52%), apps (51%), SMS (44%), and Twitter (36%). Several health promotion programmes via social media have demonstrated efficacy; however, we have shown that many young people are not comfortable with accessing sexual health information through these channels. Further research is needed to determine how to best take advantage of these novel opportunities for health promotion.
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Trends in chlamydia positivity among heterosexual patients from the Victorian Primary Care Network for Sentinel Surveillance, 2007-2011.
Med. J. Aust.
PUBLISHED: 02-18-2014
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To describe trends in chlamydia positivity from 2007 to 2011 among heterosexual people tested for chlamydia at selected clinics that provide services to people at high risk in Victoria, Australia.
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Prevalence, correlates and attitudes towards sexting among young people in Melbourne, Australia.
Sex Health
PUBLISHED: 02-13-2014
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Background 'Sexting' is the exchange of sexually explicit material via communication technologies. Despite significant media attention, there has been little examination of sexting in the Australian setting. This study aimed to provide insight into sexting behaviours and attitudes among young Australians.
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Requisite Analytic and Diagnostic Performance Characteristics for the Clinical Detection of BRAF V600E in Hairy Cell Leukemia: A Comparison of 2 Allele-specific PCR Assays.
Appl. Immunohistochem. Mol. Morphol.
PUBLISHED: 02-08-2014
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Detection of high-frequency BRAF V600E mutations in hairy cell leukemia (HCL) has important diagnostic utility. However, the requisite analytic performance for a clinical assay to routinely detect BRAF V600E mutations in HCL has not been clearly defined. In this study, we sought to determine the level of analytic sensitivity needed for formalin-fixed, paraffin-embedded (FFPE) and frozen samples and to compare the performance of 2 allele-specific polymerase chain reaction (PCR) assays. Twenty-nine cases of classic HCL, including 22 FFPE bone marrow aspirates and 7 frozen specimens from blood or bone marrow were evaluated using a laboratory-developed allele-specific PCR assay and a commercially available allele-specific quantitative PCR assay-myT BRAF Ultra. Also included were 6 HCL variant and 40 non-HCL B-cell lymphomas. Two cases of classic HCL, 1 showing CD5 expression, were truly BRAF V600E-negative based on negative results by PCR and sequencing despite high-level leukemic involvement. Among the remaining 27 specimens, V600E mutations were detected in 88.9% (17/20 FFPE; 7/7 frozen) and 81.5% (15/20 FFPE; 7/7 frozen), for the laboratory-developed and commercial assays, respectively. No mutations were detected among the 46 non-HCL lymphomas. Both assays showed an analytic sensitivity of 0.3% involvement in frozen specimens and 5% in FFPE tissue. On the basis of these results, an assay with high analytic sensitivity is required for the clinical detection of V600E mutations in HCL specimens. Two allele-specific PCR assays performed well in both frozen and FFPE bone marrow aspirates, although detection in FFPE tissue required 5% or more involvement.
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GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.
Blood
PUBLISHED: 02-04-2014
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The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.
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Global phosphoproteomic profiling reveals distinct signatures in B-cell non-Hodgkin lymphomas.
Am. J. Pathol.
PUBLISHED: 01-02-2014
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Deregulation of signaling pathways controlled by protein phosphorylation underlies the pathogenesis of hematological malignancies; however, the extent to which deregulated phosphorylation may be involved in B-cell non-Hodgkin lymphoma (B-NHL) pathogenesis is largely unknown. To identify phosphorylation events important in B-NHLs, we performed mass spectrometry-based, label-free, semiquantitative phosphoproteomic profiling of 11 cell lines derived from three B-NHL categories: Burkitt lymphoma, follicular lymphoma, and mantle-cell lymphoma. In all, 6579 unique phosphopeptides, corresponding to 1701 unique phosphorylated proteins, were identified and quantified. The data are available via ProteomeXchange with identifier PXD000658. Hierarchical clustering highlighted distinct phosphoproteomic signatures associated with each lymphoma subtype. Interestingly, germinal center-derived B-NHL cell lines were characterized by phosphorylation of proteins involved in the B-cell receptor signaling. Of these proteins, phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) was identified with the most phosphorylated tyrosine peptides in Burkitt lymphoma and follicular lymphoma. PAG1 knockdown resulted in perturbation of the tyrosine phosphosignature of B-cell receptor signaling components. Significantly, PAG1 knockdown increased cell proliferation and response to antigen stimulation of these germinal center-derived B-NHLs. These data provide a detailed annotation of phosphorylated proteins in human lymphoid cancer. Overall, our study revealed the utility of unbiased phosphoproteome interrogation in characterizing signaling networks that may provide insights into pathogenesis mechanisms in B-cell lymphomas.
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ALK-driven tumors and targeted therapy: focus on crizotinib.
Pharmgenomics Pers Med
PUBLISHED: 01-01-2014
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Receptor tyrosine kinases have emerged as promising therapeutic targets for a diverse set of tumors. Overactivation of the tyrosine kinase anaplastic lymphoma kinase (ALK) has been reported in several types of malignancies such as anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and non-small-cell lung carcinoma. Further characterization of the molecular role of ALK has revealed an oncogenic signaling signature that results in tumor dependence on ALK. ALK-positive tumors display a different behavior than their ALK-negative counterparts; however, the specific role of ALK in some of these tumors remains to be elucidated. Although more studies are required to establish selective targeting of ALK as a definitive therapeutic option, initial trials have shown extraordinary results in the majority of cases.
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Fusion peptides from oncogenic chimeric proteins as putative specific biomarkers of cancer.
Mol. Cell Proteomics
PUBLISHED: 07-08-2013
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Chromosomal translocations encoding chimeric fusion proteins constitute one of the most common mechanisms underlying oncogenic transformation in human cancer. Fusion peptides resulting from such oncogenic chimeric fusions, though unique to specific cancer subtypes, are unexplored as cancer biomarkers. Here we show, using an approach termed fusion peptide multiple reaction monitoring mass spectrometry, the direct identification of different cancer-specific fusion peptides arising from protein chimeras that are generated from the juxtaposition of heterologous genes fused by recurrent chromosomal translocations. Using fusion peptide multiple reaction monitoring mass spectrometry in a clinically relevant scenario, we demonstrate the specific, sensitive, and unambiguous detection of a specific diagnostic fusion peptide in clinical samples of anaplastic large cell lymphoma, but not in a diverse array of benign lymph nodes or other forms of primary malignant lymphomas and cancer-derived cell lines. Our studies highlight the utility of fusion peptides as cancer biomarkers and carry broad implications for the use of protein biomarkers in cancer detection and monitoring.
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Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma.
Blood
PUBLISHED: 06-27-2013
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The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.
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MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma.
Blood
PUBLISHED: 06-25-2013
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Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(-) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(-) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17?92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway.
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Potential therapies for anaplastic lymphoma kinase-driven tumors in children: progress to date.
Paediatr Drugs
PUBLISHED: 05-23-2013
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Anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase that is deregulated due to a variety of molecular mechanisms in pediatric cancer. They include chromosomal translocations, activation mutations, and gene amplifications. Since the initial discovery of ALK as an oncogenic tyrosine kinase involved in the chromosomal translocation t(2, 5)(p23;q35) in 1994, more than 20 translocation partners of ALK have been identified in various cancers. Furthermore, deregulation of ALK tyrosine kinase activity is critical for the pathogenesis of several other pediatric tumors, including neuroblastomas and inflammatory myofibroblastic tumors. The recent discovery of ALK translocations in adult lung cancer patients (non-small cell lung cancer) has accelerated the development of inhibitors of ALK tyrosine kinase as therapeutic agents. While excellent clinical response has been observed in many patients, the acquisition of clinical resistance to ALK inhibition highlights the need for development of second-generation ALK kinase inhibitors and/or combination therapies that target downstream signaling mediators or antibody drug conjugates. This article provides an update on the spectrum of ALK-driven tumors in the pediatric population and the potential therapies which target these tumors.
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Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Childrens Oncology Group phase 1 consortium study.
Lancet Oncol.
PUBLISHED: 04-16-2013
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Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.
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Is rectal gonorrhoea a lead indicator of HIV transmission among men who have sex with men in Victoria, Australia?
Sex Health
PUBLISHED: 04-16-2013
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Objectives To examine whether rectal gonorrhoea (RG; Neisseria gonorrhoeae) can be used as a lead indicator of trends in HIV diagnosis in men who have sex with men (MSM). Methods: Data from a metropolitan sexual health centre in Victoria, Australia, on RG and HIV tests in HIV-negative MSM from January 2006 to December 2011 were examined. Results: Allowing RG a 12-month lead over HIV showed no concordance in proportion positive (r=0.27; P-value=0.28). Conclusions: The data do not support use of RG trends as a lead indicator of trends in HIV among MSM.
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Laboratory practice guidelines for detecting and reporting JAK2 and MPL mutations in myeloproliferative neoplasms: a report of the Association for Molecular Pathology.
J Mol Diagn
PUBLISHED: 04-12-2013
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Recurrent mutations in JAK2 and MPL genes are genetic hallmarks of BCR-ABL1-negative myeloproliferative neoplasms. Detection of JAK2 and MPL mutations has been incorporated into routine diagnostic algorithms for these diseases. This Special Article summarizes results from a nationwide laboratory survey of JAK2 and MPL mutation analysis. Based on the current practice pattern and the literature, this Special Article provides recommendations and guidelines for laboratory practice for detection of mutations in the JAK2 and MPL genes, including clinical manifestations for prompting the mutation analysis, current and recommended methodologies for testing the mutations, and standardization for reporting the test results. This Special Article also points to future directions for genomic testing in BCR-ABL1-negative myeloproliferative neoplasms.
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Differential expression of aurora-A kinase in T-cell lymphomas.
Mod. Pathol.
PUBLISHED: 02-15-2013
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Aurora-A is a mitotic kinase implicated in oncogenesis and is known to be overexpressed in B-cell lymphomas and plasma cell myeloma. The expression of Aurora-A kinase (henceforth referred to as Aurora-A) in T-cell lymphomas is not well characterized. In this study, we assessed Aurora-A expression by immunohistochemical analysis in 100 lymphomas encompassing a variety of T-cell lymphomas as categorized in the World Health Organization classification. Aurora-A expression was highest in anaplastic large-cell lymphomas and variably expressed in other types of T-cell lymphomas. In addition, the pattern of Aurora-A expression was predominantly cytoplasmic in ALK-positive anaplastic large-cell lymphoma and was nuclear in ALK-negative anaplastic large-cell lymphoma and other T-cell lymphomas, suggesting altered biochemical mechanisms of Aurora-A nuclear transport in ALK-positive anaplastic large-cell lymphoma. Reverse transcriptase-PCR analysis showed that Aurora-A is more highly expressed in ALK-positive anaplastic large-cell lymphoma than in ALK-negative anaplastic large-cell lymphoma, and is relatively lower in peripheral T-cell lymphomas. Using western blot analysis and the DEL cell line (derived from ALK-positive anaplastic large-cell lymphoma), we showed that Aurora-A expression is decreased after treatment with either MYC or MEK inhibitors, consistent with the MYC and MAP kinase signaling pathways being involved in driving Aurora-A expression; the greatest decrease was observed after MYC inhibition. These findings provide insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora-A inhibition could be a potential therapeutic approach for patients with anaplastic large-cell lymphoma.
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Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 02-04-2013
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Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.
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Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors.
Genes Dev.
PUBLISHED: 08-11-2011
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A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity.
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Impact evaluation of a youth sexually transmissible infection awareness campaign using routinely collected data sources.
Sex Health
PUBLISHED: 05-20-2011
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Young people are at high risk of sexually transmissible infections (STI) and notifications of chlamydia are rising rapidly. In 2007, a Victorian multimedia campaign aimed to increase STI testing and condom use among 18-25-year-olds. We conducted a retrospective impact evaluation using multiple sources of routinely collected data.
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Determining the impact of text messaging for sexual health promotion to young people.
Sex Transm Dis
PUBLISHED: 05-03-2011
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The use of new technologies, such as mobile phones and internet, has increased dramatically in recent years. Text messages offer a novel method of sexual health promotion to young people who are the greatest users of new technology and are also at high risk of sexually transmitted infections (STIs).
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Impact of text and email messaging on the sexual health of young people: a randomised controlled trial.
J Epidemiol Community Health
PUBLISHED: 03-17-2011
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To carry out a randomised controlled trial on the effect of a new method of health promotion-email and mobile phone text messages (short messaging service (SMS))-on young peoples sexual health.
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Unnatural deaths in South African platinum miners, 1992-2008.
PLoS ONE
PUBLISHED: 01-21-2011
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The mortality rate from unnatural deaths for South Africa is nearly double the world average. Reliable data are limited by inaccurate and incomplete ascertainment of specific causes of unnatural death. This study describes trends in causes of unnatural death between 1992 and 2008 in a cohort of South African miners.
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Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as retroperitoneal fibrosis.
Hum. Pathol.
PUBLISHED: 01-21-2011
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Retroperitoneal fibrosis is a rare fibroinflammatory condition involving the abdominal aorta, iliac vessels, and ureters that carries an association with several other autoimmune conditions. Most cases of retroperitoneal fibrosis are thought to be idiopathic. The disorder can affect all age groups but is most common in persons between the ages of 50 and 70 years. A subset of cases is associated with an underlying immunohematologic abnormality including lymphoma. We describe in this case report a highly unusual presentation of a young woman who died with a diagnosis of "idiopathic retroperitoneal fibrosis" based on multiple biopsy procedures. Postmortem examination, however, revealed disseminated anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. The clinical and histopathologic importance of this very unusual presentation of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with retroperitoneal fibrosis is discussed.
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Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies.
Mod. Pathol.
PUBLISHED: 12-17-2010
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Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization (FISH) for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. In all, 9 of 45 (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, FISH for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99 and 90%, respectively (P=0.00002, Fishers exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98 and 90%, respectively (P=0.005). FISH abnormalities other than translocations and IRF4 protein expression were seen in 13 and 65% of cases, respectively, but were nonspecific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all FISH studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.
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Whats in a message? Delivering sexual health promotion to young people in Australia via text messaging.
BMC Public Health
PUBLISHED: 09-02-2010
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Advances in communication technologies have dramatically changed how individuals access information and communicate. Recent studies have found that mobile phone text messages (SMS) can be used successfully for short-term behaviour change. However there is no published information examining the acceptability, utility and efficacy of different characteristics of health promotion SMS. This paper presents the results of evaluation focus groups among participants who received twelve sexual health related SMS as part of a study examining the impact of text messaging for sexual health promotion to on young people in Victoria, Australia.
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Surveillance of drug use among young people attending a music festival in Australia, 2005-2008.
Drug Alcohol Rev
PUBLISHED: 05-08-2010
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In order to monitor trends in illicit drug use among youth, surveillance of drug use behaviours among a variety of populations in different settings is required. We monitored drug use among music festival attendees.
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Establishing a linked sentinel surveillance system for blood-borne viruses and sexually transmissible infections: methods, system attributes and early findings.
Sex Health
PUBLISHED: 04-14-2010
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To describe the attributes and key findings from implementation of a new blood-borne virus (BBV) and sexually transmissible infection (STI) sentinel surveillance system based on routine testing at clinical sites in Victoria, Australia.
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mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.
Cell Stem Cell
PUBLISHED: 03-29-2010
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Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells, and the mTOR inhibitor, rapamycin, blocks these effects. Understanding the opposite effects of mTOR activation on HSCs versus leukemia-initiating cells could improve antileukemia therapies. We found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced, and rapamycin attenuated, the expression of p16(Ink4a) and p53 in HSCs, and p19(Arf) and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16(Ink4a) also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19(Arf) strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose after Pten deletion. mTOR activation therefore depletes HSCs by a tumor suppressor response that is attenuated by secondary mutations in leukemogenic clones.
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Surveillance of STI risk behaviour among young people attending a music festival in Australia, 2005-08.
Aust N Z J Public Health
PUBLISHED: 10-09-2009
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To explain rising rates of sexually transmitted infections it is necessary to monitor trends among high risk groups, such as youth. Surveillance of risk behaviours and testing among a variety of populations in different settings is required. We monitored self-reported sexual behaviour among music festival attendees.
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Immunomodulator agent-related lymphoproliferative disorders.
Mod. Pathol.
PUBLISHED: 09-18-2009
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The recent development of inhibitors of key immune response proteins has revolutionized the therapy of autoimmune diseases; these immunomodulator agents include monoclonal antibodies and receptor antagonists. However, as with all therapies, these new agents are not without side effects and complications. In particular, anti-tumor necrosis factor alpha (TNFalpha) agents have been reported to be associated with an increased incidence of lymphoproliferative disorders, infections, and vasculitis. We evaluated the clinicopathological features of 18 cases of immunomodulator agent-related lymphoproliferative disorders (IAR-LPD) from several institutions. These included 6 cases of B-cell lymphoma, 2 cases of T-cell lymphoma, 3 cases of classical Hodgkin lymphoma, and 7 atypical lymphoid proliferations that did not fulfill diagnostic criteria for lymphoma; two of the latter regressed after discontinuation of the immunomodulator agent therapy. All eight lymphoma patients with available information had also received prior chemotherapy (methotrexate or 6-mercaptopurine). EBV was strongly associated with the B-cell and classical Hodgkin lymphomas. This case series illustrates that a broad range of lymphoid proliferations can occur after immunomodulator agent therapy and that these immunomodulator agent-related lymphoproliferative disorders have considerable overlap with other well-defined lymphoproliferative diseases associated with iatrogenic immunosuppression. Further study is warranted to evaluate how these therapies interact with other immunosuppressive agents and the underlying abnormal immune system to enhance the development of lymphomas and atypical lymphoid proliferations.
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Randomised controlled trial of paper, online and SMS diaries for collecting sexual behaviour information from young people.
J Epidemiol Community Health
PUBLISHED: 09-18-2009
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Diaries are used in sexual behaviour research to reduce recall bias. Diary collection via mobile phone text messaging (SMS) has not been trialled previously in sexual behaviour research. This randomised controlled trial compared SMS, paper and online diaries on response rate, timeliness, completeness of data and acceptability. The correlation between behaviour reported in all three types of diaries and data collected in a retrospective questionnaire was also determined.
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P38 mitogen activated protein kinase expression and regulation by interleukin-4 in human B cell non-Hodgkin lymphomas.
J Hematop
PUBLISHED: 07-23-2009
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The prevalence and regulation of p38 mitogen activated protein kinase (MAPK) expression in human lymphomas have not been extensively studied. In order to elucidate the role of p38 MAPK in lymphomagenesis, we examined the expression of native and phosphorylated p38 (p-p38) MAPK in cell lines derived from human hematopoietic neoplasms including B cell lymphoma-derived cell lines using Western blot analysis. The p-p38 MAPK protein was also analyzed in 30 B cell non-Hodgkin lymphoma (NHL) tissue biopsies by immunohistochemistry. Our results show that the expression of p38 MAPK was up-regulated in most of the cell lines as compared with peripheral blood lymphocytes, while the expression of p-p38 MAPK was more variable. A subset of B cell NHL biopsies showed increased expression of p-p38 MAPK relative to reactive germinal center cells. Interleukin-4 (IL-4) induced a dose-dependent increase in the expression of p-p38 MAPK (1.6- to 2.8-fold) in cell lines derived from activated B cell-like diffuse large B cell lymphoma (DLBCL) but not those from germinal center-like DLBCL. No change was seen in native p38 MAPK. The in vitro kinase activity of p38 MAPK, however, was induced (1.6- to 3.2-fold) in all five cell lines by IL-4. Quantitative fluorescent RT-PCR demonstrated that all four isoforms of p38 MAPK gene were expressed in the lymphoma cell lines, with p38gamma and p38beta isoforms being predominant. IL-4 stimulation increased the expression of beta, gamma, and delta isoforms but not alpha isoform in two cell lines. In conclusion, there is constitutive expression and activation of p38 MAPK in a large number of B-lymphoma-derived cell lines and primary lymphoma tissues, supportive of its role in lymphomagenesis. The differential IL-4 regulation of p38 MAPK expression in cell lines derived from DLBCL may relate to the cellular origin of these neoplasms.
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The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.
Blood
PUBLISHED: 06-16-2009
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Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)-driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.
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Quantitative proteomic analysis of follicular lymphoma cells in response to rituximab.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 05-12-2009
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Rituximab is a monoclonal antibody that targets the uniquely expressed B-cell CD20 receptor. Although recently approved for treatment of follicular lymphomas, the intracellular events that occur when rituximab binds to CD20 are largely unknown. Quantitative proteomic analysis of B-cell lymphoma-derived cells exposed to rituximab was performed. Differentially expressed proteins belonged to functional groups involved in migration, adhesion, calcium-induced signaling, ubiquitination, and components of the phosphoinositol and NF-kappaB pathways. Our studies reveal the proteomic consequences of rituximab treatment and provide novel insights into the mechanism of action of the drug in susceptible B-cell lymphoproliferative disorders.
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Commentary on the 2008 WHO classification of mature T- and NK-cell neoplasms.
J Hematop
PUBLISHED: 04-29-2009
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In 2008, the World Health Organization (WHO) published a revised and updated edition of the classification of tumors of the hematopoietic and lymphoid tissues. The aims of the fourth edition of the WHO classification was to incorporate new scientific and clinical information in order to refine diagnostic criteria for previously described neoplasms and to introduce newly recognized disease entities. The recognition that T-cell lymphomas are related to the innate and adaptive immune system, as well as enhanced understanding of other T-cell subsets, such as the regulatory T-cell and follicular helper T-cells, has contributed to our understanding of the morphologic, histologic, and immunophenotypic features of T- and NK-cell neoplasms. The purpose of this review is to highlight major changes in the classification of T- and NK-cell neoplasms and to explain the rationale for these changes.
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Expression of Grb2 distinguishes classical Hodgkin lymphomas from primary mediastinal B-cell lymphomas and other diffuse large B-cell lymphomas.
Hum. Pathol.
PUBLISHED: 04-01-2009
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Growth factor receptor-bound protein 2 is an adaptor molecule that mediates B-cell receptor (BCR) signaling pathways, but the expression of growth factor receptor-bound protein 2 in lymphoma tissues has not been reported. We sought to characterize growth factor receptor-bound protein 2 protein expression in reactive tonsillar tissues and lymphoma tissues obtained from diagnostic biopsies of classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and 20 low-grade B-cell lymphomas. Growth factor receptor-bound protein 2 expression was assessed in tissues by immunohistochemistry and in lymphoma cell lines by immunoblotting. In reactive lymphoid tissues, growth factor receptor-bound protein 2 was expressed in the cytoplasm of B-cells and histiocytes but not T-cells. Strong, cytoplasmic growth factor receptor-bound protein 2 expression was seen in the neoplastic cells of follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, splenic marginal zone lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, and nodular lymphocyte predominant Hodgkin lymphoma. In contrast, only 10% of the classical Hodgkin lymphomas showed growth factor receptor-bound protein 2 expression in the neoplastic cells. Growth factor receptor-bound protein 2 protein expression was detected by Western blotting in all lymphoma cell lines tested with higher levels in primary mediastinal large B-cell lymphoma compared with classical Hodgkin lymphoma cell lines. These findings support a role for growth factor receptor-bound protein 2 in the diagnostically challenging workup of classical Hodgkin lymphoma versus primary mediastinal large B-cell lymphoma and warrant further studies to evaluate the biologic significance of growth factor receptor-bound protein 2 in the pathogenesis of classical Hodgkin lymphoma.
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Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule.
J Hematop
PUBLISHED: 02-12-2009
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Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14-1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14-1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14-1 induced a dose- (IC(50)?=?10 ?M) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14-1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14-1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27(kip1), Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14-1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas.
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T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary.
J Hematop
PUBLISHED: 02-09-2009
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The enhanced risk of development of lymphoproliferative disorders in patients with inflammatory bowel disease has been attributed to immunosuppressive/immunomodulatory therapies. Infliximab is a chimeric monoclonal immunoglobulin G1 antibody directed against tumor necrosis factor alpha (TNF-?) that was approved by the Food and Drug Administration (FDA) in 1998 as an effective therapeutic agent against inflammatory bowel disease. Malignant lymphomas of both B and T cell lineage have been described in patients undergoing therapy involving TNF-? blockade. To date, eight cases of Epstein-Barr virus (EBV)-negative hepatosplenic T cell lymphoma associated with infliximab have been reported to the FDAs Adverse Event Reporting System, as well as several other T cell lymphoproliferative disorders with aggressive clinical outcomes. We present the histologic, immunophenotypic, and molecular features of a T cell lymphoproliferative disorder involving the axillary lymph node of a 33-year-old male following infliximab treatment for ulcerative colitis. These EBV-negative lymphomas suggest that lymphoproliferative disorders following infliximab treatment for inflammatory bowel disease may involve EBV-independent immune dysregulation. The spectrum of lymphoproliferative disorders associated with infliximab and the potential mechanisms by which they occur are discussed.
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Discrepancies between young peoples self-reported sexual experience and their perceptions of normality.
Sex Health
PUBLISHED: 01-05-2009
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Young peoples sexual behaviour is influenced by their perceptions of peer norms. In this survey of 445 people aged 16 to 29 years, 69% of participants believed they had fewer lifetime sexual partners than average. The mean number of actual lifetime partners reported was 5.5 and the mean perceived average partners for peers was 6.6 (P < 0.01). When broken down by age and sex, the discrepancy was only significant for females aged 16 to 19. Comparison to a national survey also showed that peers average sexual experience was overestimated. Adolescents are highly susceptible to the influence of peer norms, hence it is concerning that their perceptions of these norms are so distorted.
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Childrens Oncology Groups 2013 blueprint for research: non-Hodgkin lymphoma.
Pediatr Blood Cancer
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Non-Hodgkin lymphomas account for approximately 7% of cancers diagnosed in patients less than 20 years of age, with approximately 800 cases diagnosed annually at COG institutions. With current therapies, cure rates range from 70% to over 90%, even for children with disseminated disease. However, two major challenges need to be overcome: (i) to optimize upfront treatment to prevent relapse since prognosis for patients with relapsed disease remains poor and (ii) minimize long-term side effects in survivors. Hence, the future initiatives for the treatment of pediatric NHL are to utilize novel targeted therapies to not only improve outcomes but to decrease bystander organ toxicities and late effects.
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Measuring the accuracy of self-reported height and weight in a community-based sample of young people.
BMC Med Res Methodol
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Self-reported anthropometric data are commonly used to estimate prevalence of obesity in population and community-based studies. We aim to: 1) Determine whether survey participants are able and willing to self-report height and weight; 2) Assess the accuracy of self-reported compared to measured anthropometric data in a community-based sample of young people.
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Trends in sexual behavior, testing, and knowledge in young people; 2006-2011.
Sex Transm Dis
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Cross-sectional surveys were conducted annually from 2006 to 2011 at a music festival. Eight thousand one hundred sixty-five young people completed surveys. STI testing rates increased over time, but there was an increase in the prevalence of some sexual risk behaviors and little improvement in STI knowledge between 2006 and 2011.
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Image microarrays derived from tissue microarrays (IMA-TMA): New resource for computer-aided diagnostic algorithm development.
J Pathol Inform
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Conventional tissue microarrays (TMAs) consist of cores of tissue inserted into a recipient paraffin block such that a tissue section on a single glass slide can contain numerous patient samples in a spatially structured pattern. Scanning TMAs into digital slides for subsequent analysis by computer-aided diagnostic (CAD) algorithms all offers the possibility of evaluating candidate algorithms against a near-complete repertoire of variable disease morphologies. This parallel interrogation approach simplifies the evaluation, validation, and comparison of such candidate algorithms. A recently developed digital tool, digital core (dCORE), and image microarray maker (iMAM) enables the capture of uniformly sized and resolution-matched images, with these representing key morphologic features and fields of view, aggregated into a single monolithic digital image file in an array format, which we define as an image microarray (IMA). We further define the TMA-IMA construct as IMA-based images derived from whole slide images of TMAs themselves.
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Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.
J. Exp. Med.
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Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (?25%) cases of SMZL and in 1 of 19 (?5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
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Concomitant BCR-ABL1 translocation and JAK2(V617F) mutation in three patients with myeloproliferative neoplasms.
Diagn. Mol. Pathol.
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Chronic myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells, which fall into distinct categories based on a number of characteristics including the presence of the BCR-ABL1 gene fusion (chronic myelogenous leukemia) or the JAK2(V617F) mutation (polycythemia vera, primary myelofibrosis, and essential thrombocythemia). One of the criteria in the 2008 World Health Organization Classification divides MPN into different categories based on the presence of an underlying genetic abnormality, however the WHO does not currently address the classification of myeloproliferative neoplasms that have more than one genetic abnormality. The coexistence of a JAK2(V617F) mutation and BCR-ABL1 is rare, and to our knowledge, less than 25 cases have been reported in the literature. Our case series examines the clinical, histopathologic, and genetic features of 3 patients with myeloproliferative neoplasms characterized by concomitant BCR-ABL1 and JAK2(V617F). The implications for diagnosis and treatment of patients with concomitant BCR-ABL1 and JAK2(V617F) are discussed as well as how the BCR-ABL1 and JAK2(V617F)-positive clones may be related to one another.
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The impact of HIV, an antiretroviral programme and tuberculosis on mortality in South African platinum miners, 1992-2010.
PLoS ONE
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HIV and tuberculosis (TB) are the most common causes of death in South Africa. Antiretroviral therapy (ART) programmes should have had an impact on mortality rates. This study describes the impact of HIV, a Wellness (HIV/ART) programme and TB on population-wide trends in mortality and causes of death among South African platinum miners, from before the HIV epidemic into the ART era.
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Correlates of Chlamydia trachomatis infection in a primary care sentinel surveillance network.
Sex Health
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Chlamydia is the most commonly notified infection in Australia. Prevention strategies should be informed by routine data on at-risk populations.
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Conjugated polyelectrolyte-antibody hybrid materials for highly fluorescent live cell-imaging.
Adv. Mater. Weinheim
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Conjugated polyelectrolyte-antibody hybrid materials promise to enhance the utility of conjugated polymers in bioimaging field. Polymer-antibody conjugates that are biologically safe and highly sensitive and selective to cells are designed to image human T or B lymphocytes. In the clear state, the observed efficiency of luminescence is superior to that of commercially available FITC-antibody probe.
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Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.
Blood
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Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, -6q), and abnormalities unique to the pediatric cases (-4p14, -19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma.
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The B7 homologues and their receptors in hematologic malignancies.
Eur. J. Haematol.
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The B7 homologues and their receptors regulate both peripheral tolerance and adaptive immunity. This field is rapidly evolving as new ligands and receptors are being identified. Much of the work supporting their role in the regulation of host anti-tumor immunity has been derived from experimental models and clinical trials in solid malignancies. However, a growing body of evidence demonstrates that the B7-H family has important immunologic and non-immunologic functions in a variety of hematologic malignancies. Herein, we will review recent evidence that supports the therapeutic targeting of the B7 homologues in hematologic malignancies.
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Cyclin D1-negative blastoid mantle cell lymphoma identified by SOX11 expression.
Am. J. Surg. Pathol.
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SOX11 expression has been recently shown to be useful in the diagnosis of mantle cell lymphoma (MCL), including cyclin D1-negative MCL with typical morphology. We evaluated SOX11 expression pattern in B-cell non-Hodgkin lymphoma (B-NHL) subtypes to confirm specificity and used it as a feature to identify the first reported cases of cyclin D1-negative blastoid MCL. SOX11 expression was evaluated by immunohistochemistry in 140 cases of mature B-NHL, including 4 cases of suspected blastoid MCL that lacked cyclin D1 expression and 8 cases of CD5-positive diffuse large B-cell lymphoma (DLBL). In addition, 5 cases of B or T lymphoblastic lymphoma were included. Nuclear expression of SOX11 was found in cyclin D1-positive MCL (30/30, 100%) and in a case of cyclin D1-negative MCL with typical morphology. SOX11 was also expressed in Burkitt lymphoma (1/5, 20%) and lymphoblastic lymphoma (2/3 T-LBLs, 2/2 B-LBLs, overall 4/5, 80%), whereas all cases of DLBL (including CD5 DLBL) and other small B-NHL were negative. The 4 suspected cases of blastoid MCL were also SOX11. These cases had a complex karyotype that included 12p abnormalities. We confirmed prior reports that stated that SOX11 nuclear expression was a specific marker for MCL, including cyclin D1-negative MCL with typical morphology. To our knowledge, this is the first report regarding its use in identifying cases of cyclin D1-negative blastoid MCL. Routine use of SOX11 in cases of suspected CD5 DLBL might help identify additional cases of cyclin D1-negative blastoid MCL.
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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.