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HIV pre-exposure prophylaxis (PrEP) is a preventative strategy that involves taking a daily, oral medication to reduce the risk of contracting HIV. Advancements in recent years may have changed the ways in which PrEP is discussed in public discourse, and the use of social media for openly discussing and disseminating PrEP-related promotion messages has been understudied. Thus, this study focuses on understanding the current discourse surrounding PrEP on Twitter. Through a quantitative content analysis, this study examined the messaging, sources, and sentiments and emotions expressed in PrEP-related tweets posted from April 2019 to April 2020, six months before and after the FDA approval of Descovy for PrEP. After the approval of Descovy, there was a significant decrease in tweets relating to barriers for using PrEP; further, informational tweets about PrEP significantly increased. However, a large proportion of tweets still discussed barriers (29.9%), suggesting that addressing barriers to PrEP remains a top priority for promoting PrEP uptake. A lack of tweets discussing individual attitudes, norms, and behavioral control about PrEP may suggest that the social media discourse is not covering the important aspects of behavioral determinants for PrEP adoption. Health communication researchers can focus on developing message strategies that target these theoretical constructs to promote the adoption of PrEP among key target populations.

Supplementary Methods

Tumor proliferation measured as Ki67 index in (A) mSEP-CR(-)RTBDNb and (B) mCPC treated with the indicated dose and route of administration of gemcitabine.

information on drugs used in preclinical studies

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy.Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.

Supplementary Figure 2 from Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors

Mice lacking p53 and one or two alleles of the cyclin D–dependent kinase inhibitor p18Ink4c are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1+/− mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild-type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c−/−, p53−/− mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These “engineered” tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation. [Cancer Res 2007;67(6):2676–84]

Supplementary Figure 1 from Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors

XLSX file - 146K, Table S1- Data on the genes that differ in expression between primary tumors Th- MYCN, Caspase-8 wild type levels with no BMM, and primary tumors Th-MYCN, deficient caspase-8 with BMM (p

PDF file - 709K, Figure S1. Correlation of relative mean fold changes in expression of genes and microRNAs of the mouse tumor groups by expression- array and by quantitative RT-PCR. Figure S2. Levels of caspase-8 protein in primary tumors and BM secondary tumors. Figure S3. Primary tumors from wild-type or caspase-8 deficient (fl/ko, fl/fl or wt/ko caspase-8) mice had neuroblastoma morphology and stained positive for neuronal markers typical for neuroblastoma. Figure S4. Age at maximum tumor burden of neuroblastoma primary tumors in the Th-MYCN mouse groups. Figure S5. Measuring apoptosis levels by immunostaining for cleaved caspase-3. Figure S6. MYCN expression in the primary Th-MYCN, Th-Cre neuroblastoma tumors. Figure S7. Secondary tumors observed in both the Th-MYCN Caspase-8 wt/wt and the Th-MYCN deficient caspase-8 mouse models.

XLSX file - 77K, Table S3- Data on the microRNAs that differ in expression between primary tumors Th- MYCN, Caspase-8 wild type levels with no BMM, and primary tumors Th-MYCN, deficient caspase-8 with BMM (p

Supplementary Figure Legends 1-2 from Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors

Supplementary Table 1 from Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors

Supplementary Methods from Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblasoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model. Cancer Res; 73(13); 4086–97. ©2013 AACR.

Supplementary Figure 1 from Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas

XLSX file - 175K, Table S2- Data on the genes that differ in expression between primary tumors Th- MYCN, Caspase-8 wild type with no BMM, and primary tumors Th-MYCN, deficient caspase-8 without BMM (p

CRISPR-Cas9, a recent gene editing technology, has potential to greatly impact medicine, agriculture, and the environment; therefore, it is increasingly important to understand the public’s percept...

One effective preventative measure to reduce the number of new HIV infections is through the uptake of daily oral HIV pre-exposure prophylaxis (PrEP). Although previous clinical trials have proven the effectiveness of on-demand PrEP uptake, daily PrEP uptake is the most popular prevention method among PrEP users and is still recommended by most healthcare professionals and organizations. Informed by the integrative model of behavioral prediction, the current study examined the socio-behavioral factors associated with PrEP non-adherence. The present study conducted a cross-sectional survey of 210 gay male daily PrEP users living in California and New York. The results showed more than two-thirds of the sample indicated that they had skipped taking PrEP within the last 30 days, averaging around four to five missed doses. General attitudes toward desirable and undesirable outcomes, perceived behavioral control, and social-level barriers were associated with daily PrEP uptake non-adherence. The findings highlight providers' role in PrEP adherence and the importance of habit-forming, which can be enhanced by cost-effective strategies and technological innovations.

Genome editing is an emerging socio-scientific issue. This study uses semantic network analysis to determine the concepts and frames the public is exposed to when seeking information about “genome editing” in Wikipedia and Google. Four frames were identified in Wikipedia: (1) methodology/terminology, (2) applications, (3) common approaches, and (4) DNA repair mechanisms. Three frames were identified in the Google webpages: (1) scientific contributions, (2) applications, and (3) methodology/terminology. Both representations of genome editing focused on technical information rather than social concerns. Most of the words in both networks were neutral in sentiment, suggesting an opportunity for encouraging engagement around this technology.

Social media vaccine misinformation can negatively influence vaccine attitudes. It is urgent to develop communication approaches to reduce the misinformation's impact. This study aimed to test the effects of fact-checking labels for misinformation on attitudes toward vaccines. An online survey experiment with 1198 participants recruited from a U.S. national sample was conducted in 2018. Participants were randomly assigned to six conditions: misinformation control, or fact-checking label conditions attributed to algorithms, news media, health institutions, research universities, or fact-checking organizations. We analyzed differences in vaccine attitudes between the fact-checking label and control conditions. Further, we compared perceived expertise and trustworthiness of the five categories of fact-checking sources. Fact-checking labels attached to misinformation posts made vaccine attitudes more positive compared to the misinformation control condition (P = .003, Cohen's d= 0.21). Conspiracy ideation moderated the effect of the labels on vaccine attitudes (P = .02). Universities and health institutions were rated significantly higher on source expertise than other sources. Mediation analyses showed labels attributed to universities and health institutions indirectly resulted in more positive attitudes than other sources through perceived expertise. Exposure to fact-checking labels on misinformation can generate more positive attitudes toward vaccines in comparison to exposure to misinformation. Incorporating labels from trusted universities and health institutions on social media platforms is a promising direction for addressing the vaccine misinformation problem. This points to the necessity for closer collaboration between public health and research institutions and social media companies to join efforts in addressing the current misinformation threat.

Social media provide an innovative platform for health promotion, yet research suggests these platforms are not leveraged effectively. Instead, campaigns struggle to actively engage with participants beyond simple interactions. Inspiring user-generated content (UGC), wherein individuals create and post their own content, is a strategy that has potential to improve health promotion, especially among young people who are heavy users of social media. However, inspiring UGC is difficult. This chapter presents a comparative case study analysis of three campaigns that were highly successful in leveraging social media, and UGC in particular, in support of health-related goals. Through this analysis, four similarities were identified across all three campaigns. These similarities include the facilitation of online community, the cultivation of positive affect, the support of celebrity influencers, and the opportunity for creative self-expression. While these campaigns also received criticism, they each were, nonetheless, effective at making an impact on social media and achieving campaign goals. Through these case study analyses and a review of current research, a holistic assessment of the theory and practice of social media for health promotion is presented. Moreover, future directions for both the research and practice of health promotion on social media are identified.

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.

The promise of CRISPR-Cas9 (CRISPR) genomic editing applied to agriculture is promoted widely by scientists. We utilized textual analysis methods to compare perceptions of this innovation held by various stakeholder groups — scientists, policymakers, farmers, and the general public. Results reveal distinctions in the semantic structure and concepts emphasized across groups. Scientists and policymakers exhibited a high level of technical sophistication while emphasizing the potential societal benefits, while farmers and the general public focused on perceived personal benefits and familiarity with the issue. These results will aid development of message strategies bridging the gap between the scientific community and key publics.

As smartphone’s computing power continues to grow and as mobile applications (apps) continue to dominate digital engagement, apps have become a new frontier for advancing field experiment methodology. Using apps may help researchers to scale up the reach, precisely control randomization and experiment materials, collect a variety of objective and self-reported data over time, and more conveniently replicate and adapt an experiment. We performed a systematic review on field experiments involving apps published between 2007 and 2017. Seven databases were scanned using a predefined search strategy. The database search retrieved 4,810 citations; 101 articles met the inclusion criteria. Our review suggests that scholars have only started to employ apps in field experiments in the last 4 years. Most studies only used apps as an experiment treatment instead of an experiment platform; therefore, researchers have yet to fully leverage the advantages. Almost all studies were from the health research domain and 77.2% used randomized controlled trial design. Only 7 studies utilized smartphone sensors for collecting data. Only one study reported cost and ethical concerns regarding using apps for the experiment. Given these findings, we reported a case study that targeted a minority racial group and leveraged the advantages of apps as an experiment platform and as a data collection tool to illustrate practical challenges and lessons learned regarding time, financial cost, and technical support. In conclusion, we suggest apps provide new ways to study causal mechanisms with experiment big data. Limitations of generalizability, retention, and design quality were discussed as well.

Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.

Background: Access of naloxone has been increased in recent years, yet opposition to unrestricted availability persists. Objectives: To validate a measure of opposition to the policy of nonprescrip...

Science communication scholars have debated over what factors are related to public support for science and technology. This study examines the relationship between factual knowledge of gene editing technologies, value predispositions, and general science attitudes among four major U.S. agricultural stakeholder groups: farmers, scientists, policymakers, and the general public. Understanding these factors will aid in guiding message strategies for engagement with stakeholder groups. Findings indicate that gene editing knowledge was positively associated with science attitudes for all four groups, while conservative ideology was negatively associated with science attitudes among three of the groups. Implications and limitations are discussed.

Online virality metrics have been shown to influence information processing and behavioral outcomes. This study examined how virality metrics, in terms of the number of online shares, impacted the persuasiveness of a health campaign message in influencing viewers’ evaluation of the message, their perceived injunctive norms, descriptive norms, and preventative behavioral intentions. We conducted a 4 by 2 factorial online experiment (N = 621), featuring an HIV prevention video accompanied by a virality metric (i.e., high, medium, low, and no metric) and a video poster (i.e., demographic similarity versus dissimilarity). Results showed that virality metrics did not influence message evaluation. However, the presence of metrics decreased viewers’ perceived injunctive norms supporting condom use and HIV testing, which further decreased the corresponding behavioral intentions. The similarity between the viewer and the poster did not moderate the effects of virality metrics. These findings suggest a boomerang effect of virality metrics in reducing the persuasive impact of health messages. Theoretical explanations and practical implications are discussed.

Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid–generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

We investigated the feasibility of estimating absolute tissue blood perfusion using dynamic contrast-enhanced ultrasound (CEUS) imaging in mice. We developed a novel method of microbubble administration and a model-free approach to estimate absolute kidney perfusion, and explored the kidney as a reference organ to estimate absolute perfusion of a neuroblastoma tumor. We performed CEUS on the kidneys of CD1 nude mice using the VisualSonics VEVO 2100 imaging system. We estimated individual kidney blood perfusion using the burst–replenishment (BR) technique. We repeated the kidney imaging on the mice after a week. We performed CEUS imaging of a neuroblastoma mouse xenograft tumor along with its right kidney using two sets of microbubble administration parameters to estimate absolute tumor blood perfusion. We performed statistical tests at a significance level of 0.05. Our estimated absolute kidney perfusion (425 ± 123 mL/min/100 g) was within the range of previously reported values. There was no statistical difference between the estimated absolute kidney blood perfusions from the 2 wk of imaging (paired t -test, p = 0.09). We estimated the absolute blood perfusion in the neuroblastoma tumor to be 16.49 and 16.9 mL/min/100 g for the two sets of microbubble administration parameters (Wilcoxon rank-sum test, p = 0.6). We have established the kidney as a reliable reference organ in which to estimate absolute perfusion of other tissues. Using a neuroblastoma tumor, we have determined the feasibility of estimating absolute blood perfusion in tissues using contrast-enhanced ultrasound imaging.

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients.

Cerebral microdialysis is used to study anticancer drug penetration in the central nervous system (CNS) and brain tumors in animal models. Genetically engineered murine models (GEMMs) have been recently used to study many aspects of CNS tumors since they represent a more relevant model than orthotopic brain tumor xenograft models. However, it is challenging to implant microdialysis cannula in these animals because T2-weighted magnetic resonance imaging (MRI) does not show the reference point (bregma) traditionally used to obtain stereotactic coordinates. Thus, an alternative reference point that can be visualized on MRI images is needed. In this study, a novel reference point, identified as the intersection between the olfactory bulb/frontal lobe border and the midline between cerebral hemispheres on T2-weighted MRI images, was used to calculate anterior–posterior and medial–lateral coordinates of brain tumors in a GEMM. This point overlies a visible crossover between the rostral rhinal vein and the midline suture on the mouse skull, allowing for the conversion of the MRI coordinates into surgical stereotactic coordinates. Postmortem MRI and histological examination confirmed accurate probe placement. This procedure will facilitate the accurate and precise implantation of microdialysis probes for the study of anticancer drug penetration in brain tumors of GEMMs. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4210–4214, 2011

Purpose Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials Orthotopic U87 xenografts were treated with either continuous interferon-β (IFN-β) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-β or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab or 5 days after bevacizumab. Conclusion Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

Contains fulltext : 88045.pdf (Publisher’s version ) (Open Access) Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-β on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-β delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-β was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-β–mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling—continuous delivery of IFN-β. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy. (Mol Cancer Res 2007;5(6):531–42)

Mice lacking p53 and one or two alleles of the cyclin D–dependent kinase inhibitor p18Ink4c are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1+/− mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild-type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c−/−, p53−/− mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These “engineered” tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation. [Cancer Res 2007;67(6):2676–84]