tbuckley/cabot-search huggingface dataset:
Abstract 4577: Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia
Authors: Sumit Mukherjee, Angela Fried, Rahman Hussaini, Richard White, Aheli Chatterjee, Probal Banerjee
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most insidious form of primary adult brain tumor with a mean life expectancy of 12-24 months. Previously, we have used the non-invasive strategies of (1) intranasal delivery of a glioblastoma-directed curcumin (CC) adduct (CC-CD68Ab) and (2) the intraperitoneal (i.p.) infusion of a lipid-encapsulated formulation of CC-phytosome to rescue orthotopically GL261-implanted GBM mice and study the effect of CC on the phenotype of the tumor-associated microglial cells (TAMs). Both treatment regimens not only caused tumor remission in 50-60% of GL261-implanted GBM mice, but also induced a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high, IL10high, iNOSlow, IL12low M2-type TAMs, while simultaneously inducing the Arginase1low, IL10low, iNOShigh, IL12high M1-type TAMs. Concurrently, we observed a marked induction and phosphorylation-mediated activation of microglial p65 NF-kB and STAT1, with concomitant suppression and inactivation of STAT3. p-STAT1high, p-STAT3low M1 microglia are known to cause IL12-dependent recruitment/activation of tumoricidal NKp46high natural killer (NK) cells. In determining the kinetics of CC-induced M1 repolarization of M2-TAMs, we observed that five days of CCP treatment (i.p.) was sufficient to induce a dramatic change in the tumor-associated Iba1+ TAMs, inhibiting the tumor-promoting M2-type TAM population, while activating M1-type microglia. As expected, we observed a concomitant recruitment of NKp46high NK cells into the GBM tumor. Cognizant of the fact that NK cells activate and stabilize the M1-microglia, we eliminated the NK cells in these GBM mice using the NK cell-targeted antibody NK1.1 Ab to observe a significant reduction in CC-evoked repolarization of TAMs. Our results demonstrate a unique oncoimmunotherapeutic function of CC, which when appropriately delivered, not only eliminates GBM directly, but also indirectly elicits recruitment and activation of tumoricidal NK cells and M1-TAMs. Furthermore, maintenance of this CC-evoked M1 phenotype is contingent upon CC-induced recruitment and activation of NK cells. Thus, when delivered appropriately, CC functions on GBM both directly as well as by stimulating and recruiting an army of immune cells that eliminate both GBM and GBM-initiating cells. Citation Format: Sumit Mukherjee, Angela Fried, Rahman Hussaini, Richard White, Aheli Chatterjee, Probal Banerjee. Appropriately delivered curcumin causes recruitment of natural killer cells into glioblastoma brain, stabilizing M1 polarization of tumor-associated microglia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4577. doi:10.1158/1538-7445.AM2017-4577
Abstract P324: Unhealthy Diet and Air Pollution Compromise Human Cardiovascular Cell Functions: A First Mechanistic Analysis
Authors: Niloofar Ale-Agha, Nicole Buechner, Ulrich Sydlik, Klaus Unfried, Joachim Altschmied, Judith Haendeler
Journal: Circulation Research (2011)

Diet and pollution are environmental factors known to compromise ″healthy cardiovascular aging″. The molecular consequences of the permanent burden for aging of the cardiovascular system are unknown, since they have never been examined in primary, adult human cells. Therefore, this study investigates the impact of unhealthy diet on aging-related signaling pathways of human, primary cardiovascular cells and of airborne particles on human endothelial cells, as several studies demonstrated that ultrafine particles can enter the circulation and thus may interact with endothelial cells directly. Nutrition health reports have shown that the diet in industrialized countries contains more than 100 mg/dl low density lipoprotein (LDL) and a too high fraction of monosaccharides, especially fructose, which is metabolized insulin-independently. Both components have been shown to increase the risk for cardiovascular diseases. To simulate unhealthy diet we supplemented cell culture media of human, primary endothelial cells (EC), smooth muscle cells (SMC) and cardiomyocytes (CM) with 100 mg/dl LDL and replaced 1/3 of the glucose with fructose for one week. This treatment did not induce cell death in any of the cell types. However, we observed increased senescence, loss of endothelial nitric oxide synthase and increased nuclear localization of Foxo3 in EC, increased proliferation in SMC and hypertrophy in CM. With respect to pollution we have used ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, in concentrations our vessels are constantly exposed to. These concentrations of ufCB are non-toxic and non-inflammatory for EC. Despite these missing immediate effects, ufCB dramatically reduced the S-NO content, a marker for NO-bioavailability in EC and increased reactive oxgen species formation. As a consequence, ufCB dramatically increased senescence of EC after two weeks. Thus, unhealthy diet and a high burden of ultrafine carbon black nanoparticles, to which we are exposed every day, seem to induce a ″cardiovascular aging″ phenotype and can lead to severe cardiovascular diseases.
Abstract 5931: Effect of necrosis on the migration, invasion and miRNA-mRNA association in glioblastoma cells
Authors: So-Hee Ahn, Hyunju Park, Jeong Seon Kim, Young-Ho Ahn, Sewha Kim, Min-Sun Cho, Jihee Lee Kang, Youn-Hee Choi
Journal: Cancer Research (2017)

Abstract Grade IV astrocytoma, also called glioblastoma multiforme (GBM), is considered the most malignant glial tumor. The purpose of our study is to understand the molecular mechanisms underlying the signaling network between necrotic tissues and GBM cells by exploring the effect of necrosis on GBM migration, invasion and miRNA-mRNA association. The migration and invasion of the CRT-MG human astroglioma cells were significantly enhanced by treatment with necrotic cells, as shown by assays for scratch wound healing and spheroid invasion. Incubation with necrotic cells induced IL-8 secretion in CRT-MG in dose-dependent manner. Immunohistochemical and immunoflurorescence analysis for IL-8 in human GBM tissues showed that positively stained cells were mainly distributed in perinecrotic region. Necrotic cells induced NF-κB and AP-1 activation and their DNA binding to IL-8 promoter, leading to enhanced IL-8 production and secretion in GBM cells. To determine the effect of necrosis on the miRNA profiles and regulatory relationship, the expression profiles of miRNA and mRNA and association between mRNA and their corresponding miRNAs were analyzed by next-generation sequencing (NGS). Our results demonstrate that necrotic cells enhance the migration and invasion of GBM cells through NF-κB/AP-1/IL-8 signaling pathway and induce dysregulation of miRNA and mRNA expression profiles in GBM cells. Citation Format: So-Hee Ahn, Hyunju Park, Jeong Seon Kim, Young-Ho Ahn, Sewha Kim, Min-Sun Cho, Jihee Lee Kang, Youn-Hee Choi. Effect of necrosis on the migration, invasion and miRNA-mRNA association in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5931. doi:10.1158/1538-7445.AM2017-5931
Abstract 2770: Bcl-2 overexpression is a predictive biomarker for the combination of ABT-199 with chemotherapy in diffuse large B-cell lymphoma cell lines
Authors: Ian McConnell, Elyse Anderson, Victor Yazbeck
Journal: Cancer Research (2017)

Abstract Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin’s Lymphoma. The anti-apoptotic Bcl-2 protein is expressed in certain DLBCL subtypes such as “Double-Hit” where it mediates resistance to chemotherapy. ABT-199 is a BH3-mimetic that specifically targets Bcl-2, and has shown excellent clinical activity in several hematological malignancies. The anti-apoptotic protein Mcl-1 mediates resistance to ABT-199, and can be inhibited with chemotherapy. However, despite variability in the Bcl-2 expression levels, current clinical trials involving combinations of ABT-199 and chemotherapy for the treatment of patients with DLBCL use a one-size-fits-all approach regardless of Bcl-2 expression levels. We hypothesized that high Bcl-2 expression levels correlates with sensitivity to the combination of ABT-199 and chemotherapy in DLBCL. We examined the activity of ABT-199 in four DLBCL cell lines with varying Bcl-2 levels (CARNAVAL, OCI-ly18, SU-DHL-4 and SU-DHL-8) as determined by cell viability (Cell Titer Glo Assay) and apoptosis (Annexin-V/PI staining and FACS) analyses. CARNAVAL and SU-DHL-8 have the highest and lowest Bcl-2 expression levels, respectively, as revealed by immunoblotting. Of the four cell lines, CARNAVAL displayed the highest sensitivity (IC50 = ~7 nM) while SU-DHL-8 was resistant (IC50 = &amp;gt;10 µM) with the other 2 cell lines exhibiting intermediate sensitivity (45.9 nM for OCI-ly18 and 2.6 µM for SU-DHL-4). We then selected CARNAVAL and SU-DHL-8 in order to further examine the effect of the combination of ABT-199 with classic chemotherapy agents (etoposide and doxorubicin) used in DLBCL treatment. In CARNAVAL cells, the combination of either chemotherapy with ABT-199 led to a significant decrease in cell viability at 48 hrs compared to each single agent alone. This was associated with apoptosis induction as measured by Annexin-V/PI, caspase-3 and PARP cleavage, an increase in γ-H2AX (associated with DNA damage), and decrease in Mcl-1. Unlike CARNAVAL cells, ABT-199 did not enhance the activity of chemotherapy in SU-DHL-8 cells that lack Bcl-2 expression. These preclinical results support the use of Bcl-2 overexpression as a predictive biomarker for selecting patients that are likely to benefit from the combination of ABT-199 with chemotherapy in DLBCL. Current efforts are investigating the mechanism of resistance to the combination. Citation Format: Ian McConnell, Elyse Anderson, Victor Yazbeck. Bcl-2 overexpression is a predictive biomarker for the combination of ABT-199 with chemotherapy in diffuse large B-cell lymphoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2770. doi:10.1158/1538-7445.AM2017-2770
Abstract 5913: The impact of daily exercise on tumor perfusion
Authors: Jennifer M. Wiggins, Sharon Lepler, Christine Pampo, Lori Rice, Jennifer A. Lee, Dietmar Siemann
Journal: Cancer Research (2017)

Abstract Aberrant blood vessel networks in solid tumors lead to impaired tissue perfusion and areas of hypoxia (pO2 &amp;lt; 10 mmHg). Tumor hypoxia is associated with aggressive progression, dissemination, and therapeutic resistance. It is found in 40% of breast cancers, and can constitute a major obstacle to anticancer therapy. Exercise is associated with improvements in cardiovascular and respiratory function, aerobic capacity and overall health. In cancer patients undergoing therapy, exercise has been shown to decrease treatment related side effects and general fatigue. The goal of the present investigation was to determine whether aerobic exercise could be applied to improve tumor perfusion and oxygenation in a breast cancer model. Such modulation of the tumor physiology and host environment would be expected to lead to enhanced antitumor efficacy when combined with radiotherapy or chemotherapy. The effects of a single and daily bouts of moderate intensity treadmill running were studied in mice bearing the syngeneic murine mammary carcinoma 4T1. The exercise intensity was determined by measuring the anaerobic threshold, which was assessed by measuring the steady rise in blood lactate during exercise. Initial studies examined the effect of a single moderate bout of exercise (18 m/min) in mice bearing ~500 mm3 orthotopic tumors. In subsequent experiments mice were exercised at 18 m/min, 5 days a week, for 8 weeks prior to orthotopic injection of tumor cells and continued exercise (5 days a week) for 2 weeks during tumor growth. Controls for each treatment consisted of sedentary mice exposed to a stationary treadmill for the equivalent amount of time. At the end of each of the exercise regimen, tumors were harvested, sectioned, stained, and tile mapped to assess physiological changes by immunofluorescence. The detection of open blood vessels (Hoechst-33342) was used as an indirect indicator of perfusion. Tumor hypoxia was determined using the 2-nitroimidazole (EF5). Blood vessels were stained using the endothelial cell marker CD-31. All markers were quantified using Photoshop and ImageJ NIH software. Our results indicate that in the 4T1 breast cancer model moderate intensity exercise did not significantly alter tumor growth, oxygenation or blood vessel number. However, daily bouts of exercise did significantly increase the number of open tumor vessels indicating improved tumor perfusion. These results suggest that a daily exercise regimen may have the potential to improve drug delivery to mammary tumors Citation Format: Jennifer M. Wiggins, Sharon Lepler, Christine Pampo, Lori Rice, Jennifer A. Lee, Dietmar Siemann. The impact of daily exercise on tumor perfusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5913. doi:10.1158/1538-7445.AM2017-5913
Evidence for Health Decision Making — Beyond Randomized, Controlled Trials
Authors: Thomas R. Frieden
Journal: New England Journal of Medicine (2017)

A core principle of good public health practice is to base all policy decisions on the highest-quality scientific data, openly and objectively derived. 1 Determining whether data meet these conditions is difficult; uncertainty can lead to inaction by clinicians and public health decision makers.3][4][5][6][7][8] In this article, I describe the use of RCTs and alternative (and sometimes superior) data sources from the vantage point of public health, illustrate key limitations of RCTs, and suggest ways to improve the use of multiple data sources for health decision making.In large, well-designed trials, randomization evenly distributes known and unknown factors among control and intervention groups, reducing the potential for confounding.Despite their strengths, RCTs have substantial limitations.Although they can have strong internal validity, RCTs sometimes lack external validity; generalizations of findings outside the study population may be invalid. 2,4,6CTs usually do not have sufficient study periods or population sizes to assess duration of treatment effect (e.g., waning immunity of vaccines) or to identify rare but serious adverse effects of treatment, which often become evident during postmarketing surveillance and long-term follow-up but could not be practically assessed in an RCT.The increasingly high costs and time constraints of RCTs can also lead to reliance on surrogate markers that may not correlate well with the outcome of interest.Selection of high-risk groups increases the likelihood of having adequate numbers of end points, but these groups may not be relevant to the broader target populations.These limitations and the fact that RCTs often take years to plan, implement, and analyze reduce the ability of RCTs to keep pace with clinical innovations; new products and standards of care are often developed before earlier models complete evaluation.These limitations also affect the use of RCTs for urgent health issues, such as infectious disease outbreaks, for which public health decisions must be made quickly on the basis of limited and often imperfect available data.RCTs are also limited in their ability to assess the individualized effect of treatment, as can result from differences in surgical techniques, and are generally impractical for rare diseases.Many other data sources can provide valid evidence for clinical and public health action.Observational studies, including assessments of results from the From Atlanta, GA.
Abstract 504: Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program
Authors: Jun Fan, Raya Khanin, Hitomi Sakamoto, Yi Zhong, Chelsea Michael, Derwin Pena, Breanna Javier, Laura Wood, Christine Iacobuzio-Donahue
Journal: Cancer Research (2017)

Abstract The last decade has seen a marked rise in the use of cancer tissues obtained from research autopsies. Such resources have been invaluable for studying cancer evolution or the mechanisms of therapeutic resistance to targeted therapies. Degradation of biomolecules is a potential challenge to usage of cancer tissues obtained in the post-mortem setting and remains incompletely studied. We analysed the nucleic acid quality in 371 different frozen tissue samples collected from 80 patients who underwent a research autopsy, including eight normal tissue types, primary and metastatic tumors. Our results indicate that RNA integrity number (RIN) of normal tissues decline with the elongation of post-mortem interval (PMI) in a tissue-type specific manner. Unlike normal tissues, the RNA quality of cancer tissues is highly variable with respect to post-mortem interval. The kinetics of DNA damage also has tissue type-specific features. Moreover, while DNA degradation is an indicator of low RNA quality, the converse is not true. Finally, we show that despite RIN values as low as 5.0, robust data can be obtained by RNA sequencing that reliably discriminates expression signatures. Based on this promising pilot data, we are currently identifying samples for multiregion RNA sequencing of pancreatic cancers with divergent morphologies within the primary and/or metastatic sites. Thus far we have screened 554 RNA samples from 10 autopsy cases. These samples represent 198 geographically distinct regions of tumor with duplicate or triplicate RNA extractions. The number of samples per patient ranges from 17 to 86 with an average of 55. Our data shows that high quality RNA can be acquired from cases with long PMI (&amp;gt;48h). While extensive screening of samples is required to identify those with optimal quality, the downstream data produced is of high quality and can support novel hypotheses or validations of experimental data. Citation Format: Jun Fan, Raya Khanin, Hitomi Sakamoto, Yi Zhong, Chelsea Michael, Derwin Pena, Breanna Javier, Laura Wood, Christine Iacobuzio-Donahue. Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 504. doi:10.1158/1538-7445.AM2017-504
Abstract 4715: Protective anti-tumor immune responses in breast cancer depend on tumor mutation rate
Authors: Lance D. Miller, Eric D. Routh, Jeff W. Chou, Alexandra Thomas
Journal: Cancer Research (2017)

Abstract The relationship between tumor antigenicity and anti-tumor immune responses in breast cancer are poorly understood. Metrics that can accurately predict tumor immunogenic potential could guide therapeutic decisions for breast cancer patients. We examined the relationship between tumor immune subclasses and patient overall survival in the context of the rate of nonsynonymous mutations in breast cancers. These analyses were conducted using RNAseq and exome sequencing data from the Cancer Genome Atlas (TCGA) breast cancer cohort (n=1,098 patients). A previously described tumor-immune classification system, based on the relative abundance of infiltrating effector immune cells, was employed for assigning patients to favorable, weak or poor immunogenic dispositions (FID, WID or PID, respectively). In breast tumors exhibiting low mutation rates (LMR), no significant survival differences were observed among patients comprising the immune subclasses. By contrast, in the context of tumors with high mutation rates (HMR), the immune subclasses exhibited highly significant survival differences (p&amp;lt;0.001). Patients with FID tumors achieved 100% survival at 10 years as compared to those with PID tumors who displayed a 10-year survival rate of 44%. These survival differences were independent of molecular subtype composition, with the majority of the excellent-outcome FID subclass comprising predominantly of Basal-like, HER2-enriched and Luminal B breast tumors. In the smaller subset of HMR Luminal A breast tumors, the immune subclasses also exhibited significantly different survival outcomes (p=0.01), with patients of the poor-outcome Luminal A PID subclass experiencing a 10-year survival rate of 22%. By Cox proportional hazards regression analysis, the immune subclasses contributed significant additive prognostic information in the presence of AJCC stage (p=0.003). A mutation rate of 1.63 mutations per megabase of sequenced DNA was found to be an optimal threshold for distinguishing immune-relevant low and high mutational load. These findings fit a model where mutational burden, reflective of tumor antigenicity, is a major determinant of clinically-relevant breast tumor immunogenicity. This relationship between immunogenic tumor subclasses, overall survival and mutational burden may offer opportunities for therapeutic stratification of breast cancer patients. Citation Format: Lance D. Miller, Eric D. Routh, Jeff W. Chou, Alexandra Thomas. Protective anti-tumor immune responses in breast cancer depend on tumor mutation rate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4715. doi:10.1158/1538-7445.AM2017-4715