tbuckley/cabot-search huggingface dataset:
OS06.2 Combination RNAi therapy against glioma stem cells via sustained lipopolymeric nanoparticle delivery delays tumor progression
Authors: D. Yu, O. F. Khan, M. L. Suvà, W. K. Panek, M. Wu, Y. Han, A. U. Ahmed, I. V. Balyasnikova, D. G. Anderson, R. Langer, M. S. Lesniak
Journal: Neuro-Oncology (2017)

Background: Glioma stem cells (GSCs) have been identified as the predominant contributor to the therapy resistance, recurrence, and progression of malignant glioma, particularly glioblastoma multiforme (GBM). However, GSCs are elusive therapeutic targets across the blood brain barrier, underscoring the urgent need to develop novel therapeutic targeting strategies. Further impeding the discovery of effective anti-GSC therapies, the complex intratumoral heterogeneity, identified via single cell RNAseq and transcriptome research, as well as the genomic adaptations by GSCs that evade therapeutic pressure, limit therapeutic efficacy of individual gene targeting. With recent breakthrough discoveries of genetic and epigenetic signatures of GSC mediated tumorigenesis, RNAi emerges as a promising anti-GSC therapeutic strategy to counteract tumorigenic genetic elements. HYPOTHESIS: We hypothesize that multiplexed RNAi using GSC targeting nanoparticles are effective counter measures against genetic drivers of GSC phenotypes. Methods: Based on a panel of qPCR and Western blotting analysis, we selected 2 suitable GSC candidates from patient derived glioma as therapeutic model targets. We then identified the novel lipopolymeric nanoparticle 7C1 as a pilot siRNA encapsulation candidate, and characterized its uptake dynamics in comparison with mouse brain endothelial cells and astrocytes. 7C1 demonstrates a striking affinity for GSCs, and multiplexed siRNA encapsulation in 7C1 was achieved using a microfluidic mixing device invented in our group. Results: In this report, we establish that 7C1 nano-encapsulation of multiplexed GSC RNAi is a flexible GSC targeting strategy when delivered directly to the brain tumor microenvironment. In vitro and in vivo GSC growth arrest is accomplished via concurrent siRNA knockdown of four transcription factors that engender the proneural GSC phenotype, namely SOX2, OLIG2, SALL2, and POU3F2. The therapeutic potential was most evident when the 7C1 multiplexed RNAi was delivered to mouse models of GBM created via intracranial xenograft of candidate GSCs via an AlzetTM osmotic pump (Durect Corp., Cupertino, CA, USA), which demonstrates a significant extension of median survival in patient derived GSC xenograft mouse models of aggressive GBM (9 days, log rank test, ***p=0.003). CONCLUSION: This pilot study validates an encouraging non-viral gene therapy platform to target GSCs, and demonstrates the potential capacity to channel infinite combinations of multiplexed RNAi schemes to address the intratumoral heterogeneity championed by GSCs. Future engineering to enhance the intratumoral distribution and enable long term delivery are underway to improve performance.
P09.25 Identifying the correct patient (pt) population for ABT414: biomarker assays for epidermal growth factor receptor (EGFR) in pts with glioblastoma (GBM)
Authors: A. Lassman, H. Gan, L. Robert-Rapp, P. Ansell, R. Merrell, P. Kumthekar, E. Gomez, K. Holen, D. Reardon, M. van den Bent
Journal: Neuro-Oncology (2017)

Aim: Aberrant EGFR signaling plays a vital role in GBM oncogenesis. ABT414 comprises an EGFR targeted antibody conjugated to the toxic agent monomethylauristatin F. An open label, 3 arm, phase I study (NCT01800695) is underway to evaluate 3 different ABT414 regimens in GBM. To understand the population most suited for ABT414 therapy, assays measuring EGFR gene amplification/protein overexpression, and the presence of EGFRvIII mutation have been developed. Methods: Total EGFR and EGFRvIII expression were measured with reverse transcription polymerase chain reaction (RTPCR). EGFR gene amplification was detected with fluorescence in situ hybridization (FISH) using 2 probes: Vysis locus specific identifier EGFR probe and Vysis chromosome enumeration probe (CEP) 7 probe. FISH utilized Ratio of EGFR to CEP 7 to identify locus specific EGFR gene amplification. Total EGFR protein expression was analyzed via immunohistochemical (IHC) using Dako pharmDx™ IHC assay. Relative expression of total EGFR and presence of EGFRvIII mRNA were determined with quantitative RTPCR. Tumor tissues from 89 pts were used for these tests. Results: IHC and RTPCR confirmed expression of EGFR mRNA and protein are correlated in GBM tissue samples (Spearman correlation is -0.86, P = 0.0026). A strong association between EGFR gene amplification and mRNA overexpression was observed. EGFRvIII mRNA was detected almost exclusively in cases with EGFR amplification. Thus far, EGFR amplification has been confirmed in 23/29 pts tested. All 6/6 pts with confirmed objective radiographic responses by Response Assessment in NeuroOncology criteria displayed EGFR gene amplification, whereas only 5/6 pts had total EGFR mRNA overexpression using RTPCR. EGFRvIII expression by RTPCR was detected in 4/6 pts. Conclusions: Assays were developed to characterize EGFR gene amplification, EGFR mRNA and protein expression, EGFRvIII status, and used to characterize EGFR status of GBM samples from pts treated with ABT414 in ongoing phase I trial. When comparing EGFR status to pt outcome, EGFR amplification by FISH had strongest association with objective radiographic responses.
P09.24 The germline mutation PIK3R1Met326Ile correlates with the levels of cysteine&lt;-&gt;rich protein 61 and poor prognosis of glioblastoma
Authors: K. Kurozumi, Y. Otani, J. Ishida, T. Ichikawa, T. Oka, T. Shimizu, Y. Tomita, Y. Hattori, H. Michiue, S. Tomida, T. Matsubara, I. Date
Journal: Neuro-Oncology (2017)

Despite advances in treatment, glioblastoma remains a lethal brain tumor. Efforts to identify prognostic molecular biomarkers for glioblastoma have intensified, and we previously reported that the median progression-free survival (PFS) and overall survival (OS) of patients with high levels of cysteine-rich protein 61 (CCN1/CYR61) are significantly shorter compared with those with low levels of CCN1. To identify the molecular mechanisms that regulate the expression of CCN1 in glioblastomas, we analyzed tumor samples from 42 patients with glioblastoma. Next-generation and Sanger sequencing techniques revealed that the PIK3R1Met326Ile mutation was significantly more frequent in patients with high vs low levels of CCN1 (9/22, 40.9% vs 2/20, 10.0%; respectively). Moreover, this mutation was identified in the corresponding blood samples. Univariate analysis of Kaplan-Meier survival data revealed that high levels of CCN1 and the presence of the PIK3R1Met326Ile mutation were significantly associated with PFS (p=0.0003 and 0.0191, respectively) and that age, high levels of CCN1, and the presence of the PIK3R1Met326Ile mutation were significantly associated with OS (p=0.0016, 0.0019 and 0.0057, respectively). Multivariate analysis identified age >65 years and the presence of the PIK3R1Met326Ile mutation as prognostic factors for OS (HR=3.533 [1.519-8.220], p=0.003) and (HR=2.712 [1.187-6.198], p=0.018, respectively). We conclude that the germline mutation PIK3R1Met326Ile correlates with the levels of CCN1 and poor prognosis of glioblastoma.
Chlamydia Screening Practices of Primary-Care Providers—Wake County, North Carolina, 1996
Journal: JAMA (1997)

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Abstract P111: Rheb-mTOR Signaling Pathway Regulates Cardiomyocyte Mass During Post-Neonatal Period
Authors: Takahito Tamai, Shungo Hikoso, Tomokazu Murakawa, Jota Oyabu, Takafumi Oka, Manabu Taneike, Toshihiro Takeda, Osamu Yamaguchi, Hiroyuki Nakayama, Kazuhiko Nishida, Issei Komuro, Kinya Otsu
Journal: Circulation Research (2011)

Rheb (Ras homologue enriched in brain) is a major activator of mTOR. Rheb-mTOR pathway is a critical mechanism for maintenance of homeostasis, cell growth and stress response by regulating both protein synthesis and degradation. In this study, we attempted to clarify the role of Rheb-mTOR pathway in the heart using cardiac-specific Rheb-deficient mice (Rheb −/− ). We generated floxed Rheb mice and crossed them with transgenic mice expressing Cre recombinase in cardiac-specific mannner to generate Rheb −/− . Rheb −/− were born in Mendelian ratio, but they started to die 8 days after birth and all of them had died until 10 days after birth. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb −/− were indistinguishable from those of control mice (Rheb +/+ ) 5 days after birth. However, Rheb −/− exhibited cardiac dilatation and reduced contractility 8 days after birth (LV end diastolic dimension, Rheb −/− : 2.5±0.2 mm vs. Rheb +/+ : 2.1±0.2 mm, p&lt;0.01, fractional shortening, Rheb −/− : 19.7 ± 9.7 % vs. Rheb +/+ : 48.6 ± 8.8 %, p&lt;0.01). These suggest that Rheb −/− died of cardiac dysfunction and heart failure. Heart weight and cross-sectional area of cardiomyocytes were significantly lower in Rheb −/− 8 days after birth. Electron microscopic analysis revealed that the area of sarcomere was significantly lower in Rheb −/− cardiomyocytes. Expressions of sarcomeric proteins, such as myosin heavy chain, actin or desmin, were decreased in Rheb −/− , while the mRNA expression of desmin was significantly increased in Rheb −/− . Thus impairment of cardiomyocyte growth observed in Rheb −/− could be due to either increased degradation or decreased translation. Although autophagic activity was enhanced in Rheb −/− heart, ablation of Atg5, an essential molecule for autophagy, could not prevent premature death of Rheb −/− . On the other hand, polysome analysis revealed that the mRNA translation activity had decreased in Rheb −/− heart compared with Rheb +/+ . Thus, we concluded that Rheb-mTOR pathway in the heart is essential to regulate mRNA translation activity and protein synthesis, thereby to cardiomyocyte growth in neonatal period.
Alpha1‐antitrypsin deficiency and c‐JUN
Authors: Antonio Ponzetto, Guillermo I. Perez‐Perez, Natale Figura
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Most patients with alpha1‐antitrypsin deficiency—a genetic cause of liver disease that may lead to cirrhosis and hepatocellular carcinoma—carry the Z mutation (ATZ) in the SERPINA1 gene. Pastore et al.1 observed that ATZ‐mediated liver damage was a consequence of c‐JUN activation. In addition, transplantation of hepatocytes harboring JUN kinase inhibitor reduced c‐JUN levels and hepatocyte damage in recipient mice. The variable severity of liver damage could be due to the fluctuating c‐JUN levels, reflected in the circa 10%‐15% risk of liver failure in homozygous patients. Helicobacter pylori infection strongly activates c‐JUN,2 which, together with c‐FOS, forms the activator protein 1, which binds and activates the cyclin D1 promoter.2 High c‐JUN levels, associated with hepatocyte damage and increased replication, could amplify the risk of cirrhosis and hepatocellular carcinoma. We hypothesize that patients infected by H. pylori strains expressing the oncoprotein CagA would have more abundant intracellular c‐JUN and therefore higher risk of developing early cirrhosis and possibly also hepatocellular carcinoma. Shimoda et al.3 recently showed that CagA circulates within exosomes, structures resembling small liposomes, made by mucocytes following CagA translation, and the liver parenchyma is effective in taking up small liposomes. Thus, it is conceivable that CagA could be internalized into hepatocytes, where it may elicit proinflammatory4 and procarcinogenic effects.5 We wonder if patients infected with H. pylori have higher risk to develop cirrhosis and hepatocellular carcinoma and whether eradicating H. pylori infection might slow the progression of ATZ‐related liver disease.
OS04.6 DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy
Authors: Y. Umemura, D. Wang, K. Peck, W. Shi, Z. Zhang, R. Fatovic, E. Anderson, K. Beal, T. Kaley, R. Young
Journal: Neuro-Oncology (2017)

Objective: To assess the ability of dynamic contrast enhanced T1 magnetic resonance imaging (DCE-MRI) to identify pseudoprogression in melanoma brain metastases. BACKGROUND: Immunotherapy is the emerging standard of care for metastatic melanoma. Pseudoprogression is the transient worsening of enhancing lesions that can result from activated tumor directed immunity, and may be misclassified as progression. We hypothesize DCE-MRI can be applied to identify pseudoprogression in patients with melanoma brain metastases. METHODS: Retrospectively, 44 patients with melanoma brain metastases were identified to have received immunotherapy and DCE-MRI from 1/2011 to 6/2016 at Memorial Sloan Kettering Cancer Center. We analyzed total of 64 enhancing lesions ≥ 5 mm diameter, new or increased while on immunotherapy. Lesion classification was determined by histopathology, or by follow up with pseudoprogression defined as neurological and radiographic stability or improvement without any new treatment for ≥ 2 months. Results: Most patients received ipilimumab monotherapy (64%). The median duration of immunotherapy was 9 weeks (range 0–138). Histopathology was available in 13/55 progression and 1/9 pseudoprogression lesions. Twelve progression and 8 pseudoprogression lesions were previously irradiated. Fourty-four progression lesions and 8 pseudoprogression lesions were hemorrhagic. The median lesion volume was not statistically different between the pseudoprogression group at 2.3cm3 and the progression group at 3.2cm3 (p=0.82). The median 90%tile plasma volume (Vp90) was smaller in pseudoprogression at 2.2cm3 than in POD at 5.3cm3 (p=0.02), and it remained significant after false discovery rate adjustment (p=0.04). Conclusions: We found that pseudoprogression has significantly lower Vp90 on DCE-MRI compared to progression, which can be useful in radiographic follow up of brain metastases in melanoma patients receiving immunotherapy. Better differentiation of pseudoprogression and progression is needed to provide appropriate clinical interventions in these patients. STUDY SUPPORT: Diane Wang was supported by the Memorial Sloan Kettering Cancer Center Medical Student Summer Fellowship. This work was partially supported by NIH Core Grant P30 CA008748.
A Branching Evolution Model at Relapse Characterizes Multiple Myeloma Patients Who Responded to up-Front Combination Therapy Including New Drugs
Authors: Carolina Terragna, Marina Martello, Barbara Santacroce, Vincenza Solli, Lucia Pantani, Elena Zamagni, Paola Tacchetti, Beatrice Anna Zannetti, Katia Mancuso, Giulia Marzocchi, Nicoletta Testoni, Gaia Ameli, Rosalinda Termini, Flores A Dico, Enrica Borsi, Giovanni Martinelli, Michele Cavo
Journal: Blood (2016)
Emerging Affinity-Based Proteomic Technologies for Large-Scale Plasma Profiling in Cardiovascular Disease
Authors: J. Gustav Smith, Robert E. Gerszten
Journal: Circulation (2017)

Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the proteome, and the broad range of abundance levels, as well. Proteome-wide, untargeted profiling can be performed in tissues and cells with tandem mass spectrometry. However, applications to plasma are limited by the need for complex preanalytical sample preparation stages limiting sample throughput. Multiplexing of targeted methods based on capture and detection of specific proteins are therefore receiving increasing attention in plasma proteomics. Immunoaffinity assays are the workhorse for measuring individual proteins but have been limited for proteomic applications by long development times, cross-reactivity preventing multiplexing, specificity issues, and incomplete sensitivity to detect proteins in the lower range of the abundance spectrum (below picograms per milliliter). Emerging technologies to address these issues include nucleotide-labeled immunoassays and aptamer reagents that can be automated for efficient multiplexing of thousands of proteins at high sample throughput, coupling of affinity capture methods to mass spectrometry for improved specificity, and ultrasensitive detection systems to measure low-abundance proteins. In addition, proteomics can now be integrated with modern genomics tools to comprehensively relate proteomic profiles to genetic variants, which may both influence binding of affinity reagents and serve to validate the target specificity of affinity assays. The application of deep quantitative proteomic profiling to large cohorts has thus become increasingly feasible with emerging affinity methods. The aims of this article are to provide the broad readership of Circulation with a timely overview of emerging methods for affinity proteomics and recent progress in cardiovascular medicine based on such methods.
Outlier Practice Patterns in Mohs Micrographic Surgery
Authors: Aravind Krishnan, Tim Xu, Susan Hutfless, Angela Park, Thomas Stasko, Allison T. Vidimos, Barry Leshin, Brett M. Coldiron, Richard G. Bennett, Victor J. Marks, Rebecca Brandt, Martin A. Makary, John G. Albertini
Journal: JAMA Dermatology (2017)

Outlier physician practices in health care can represent a significant burden to patients and the health system.
Influence of Pravastatin and Plasma Lipids on Clinical Events in the West of Scotland Coronary Prevention Study (WOSCOPS)
Authors: All 6595 randomized patients were used to calculate quintiles of baseline LDL cholesterol, HDL cholesterol, and plasma triglyceride. The Kaplan-Meier 5-year risk of any cardiovascular event was then determined separately for each quintile of the placebo and pravastatin groups. Baseline lipids as continuous variables were related to risk of any cardiovascular event in the two groups separately by Cox regression, both univariately and then multivariately with other baseline covariates (as described in Reference 16, ) to test their independence as predictors. The covariates used in the adjustment were age, smoking, blood pressure, ECG abnormality, self-reported angina, self-reported hypertension, diabetes, family history of premature death from CHD, and nitrate use.
Journal: Circulation (1998)

Background —The West of Scotland Coronary Prevention Study was a primary prevention trial that demonstrated the effectiveness of pravastatin (40 mg/d) in reducing morbidity and mortality from coronary heart disease (CHD) in moderately hypercholesterolemic men. The present analysis examines the extent to which differences in LDL and other plasma lipids both at baseline and on treatment influenced CHD risk reduction. Methods and Results —Relationships between baseline lipid concentrations and incidence of all cardiovascular events and between on-treatment lipid concentrations and risk reduction in patients taking pravastatin were examined by use of Cox regression models and by division of the cohort into quintiles. Variation in plasma lipids at baseline did not influence the relative risk reduction generated by pravastatin therapy. Fall in LDL level in the pravastatin-treated group did not correlate with CHD risk reduction in multivariate regression. Furthermore, maximum benefit of an ≈45% risk reduction was observed in the middle quintile of LDL reduction (mean 24% fall); further mean decrements in LDL (up to 39%) were not associated with a greater decrease in CHD risk. Comparison of event rates between placebo- and pravastatin-treated subjects with the same LDL cholesterol level provided evidence for an apparent treatment effect that was independent of LDL. Conclusions —We conclude that the treatment effect of 40 mg/d of pravastatin is proportionally the same regardless of baseline lipid phenotype. There is no CHD risk reduction unless LDL levels are reduced, but a fall in the range of 24% is sufficient to produce the full benefit in patients taking this dose of pravastatin. LDL reduction alone does not appear to account entirely for the benefits of pravastatin therapy.