tbuckley/cabot-search huggingface dataset:
MEDU-35. Nox4 MEDIATED HIF1a STABILIZATION IN SONIC HEDGEHOG MEDULLOBLASTOMA TUMOR REPOPULATING CELLS
Authors: Chad Potts, Hope Robinson, Nicholas Eyrich, Anshu Malhotra, Abhinav Dey, Anna Marie Kenney
Journal: Neuro-Oncology (2019)

Investigating mechanisms promoting maintenance and survival of medulloblastoma tumor repopulating cells is key to gaining insight into how to prevent tumor recurrence and improve effectiveness of radiation and chemotherapy. Tumor recurrence is typically fatal and there are no standard effective salvage therapies. Using primary cultures of neonatal cerebellar granule neuron progenitors (CGNPs), putative cells-of-origin for the Sonic Hedgehog (SHH) molecular subclass of medulloblastoma, and genetically engineered mouse models for SHH medulloblastoma, we have examined cell biological mechanisms underlying “stemness”/inhibition of differentiation and evasion of apoptosis. We have observed that hypoxia-inducible factor 1a(HIF1a) protein is up-regulated in CGNPs exposed to SHH, their obligate mitogen. This up-regulation occurs under normoxia and post-translational, mediated in part by NADPH oxidase 4 (Nox4)-mediated stabilization. Nox4 is most highly expressed in the human SHH patient population, which also feature increased levels of HIF1aprotein but do not show elevated HIF1amRNA expression, consistent with a conserved stabilization mechanism. In mouse SHH medulloblastomas, HIF1aand Nox4 localized to the radiation resistant cells occupying the perivascular niche, which have been proposed to possess tumor repopulating capacity. Using organotypic slice cultures, we find that pharmacologic inhibition or lentivirus-mediated knockdown of Nox4 restores radiation-induced apoptosis in these cells, elimination of the stem cell niche, and down-regulation of HIF1a. In SHH-treated primary CGNPs, Nox4 knockdown also resulted in reduced HIF1a and proliferation markers, as well as increased cleaved caspase 3. Taken together, our findings suggest that a novel HIF1a:Nox4 axis downstream of activated SHH signaling promotes CGNP survival and tumor stem cell maintenance and radiation resistance. In the future, these findings could be leveraged to include Nox4 inhibition in SHH medulloblastoma patients to improve response to radiation, permit lower doses of radiation, and prevent tumor recurrence.
Low Dose Ara-C Versus Low Dose Ara-C and Arsenic Trioxide: the UK NCRI AML16 “Pick a Winner” Comparison.
Authors: Nigel H. Russell, Robert K Hills, Ann E. Hunter, Donald Milligan, William J. Kell, Keith Wheatley, Mary Frances McMullin, John AL Yin, David T. Bowen, A. Burnett
Journal: Blood (2009)
Abstract #4865: Long-term postmenopausal hormone therapy and endometrial cancer
Authors: Pedram Razavi, Malcolm Pike, Pamela Horn-Ross, Leslie Bernstein, Giske Ursin
Journal: Cancer Research (2009)

Background: Postmenopausal hormone treatment (HT) with estrogen alone (ET) or estrogen and progestin treatment (EPT) has been commonly used to alleviate menopausal symptoms. Treatments that contain 10 or more days of progestin per month have been considered relatively safe with respect to endometrial cancer risk. However, the endometrial safety of long-term use of EPT regimens is uncertain. Methods: We conducted a case-control study of 401 invasive endometrial cancer cases and 675 controls, nested within the California Teachers Study (CTS) cohort. We used unconditional multivariable logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs) for the association between long term use of hormone therapy and the risk of endometrial cancer and to examine the modifying effect of body mass index. Results: ET and sequential EPT treatments with less than 10 days of progestin per month were associated with a statistically significant elevated risk of endometrial cancer. Compared to HT never users, the ORs for 10 years or more use of these regimens were 4.4 (95% CI: 2.4 - 8.3) and 5.0 (95% CI: 1.9 - 13.4), respectively (both Ptrend  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4865.
Disabling ocular sequelae of epidermal necrolysis: risk factors during the acute phase and associated sequelae
Authors: C. Hajj, K. Ezzedine, D. Thorel, A. Delcampe, G. Royer, C. Hua, A. Colin, N. Prost, M. Muraine, O. Chosidow, P. Wolkenstein, J. Gueudry, S. Ingen‐Housz‐Oro
Journal: British Journal of Dermatology (2019)
Trends in Blood Infection Rates
Authors: Bridget Kuehn
Journal: JAMA (2019)

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A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer
Authors: Thoudam Debraj Singh, Jaeyoung Song, Jina Kim, Jungwook Chin, Hyun Dong Ji, Jae-Eon Lee, Sang Bong Lee, Heeseok Yoon, Ji Hoon Yu, Sang Kyoon Kim, Ghil Suk Yoon, Hayoung Hwang, Ho Won Lee, Ji Min Oh, Sang-Woo Lee, Jaetae Lee, Hueng-Sik Choi, Soon-Young Na, Won-Il Choi, Young Joo Park, Young Shin Song, Young A. Kim, In-Kyu Lee, Sung Jin Cho, Yong Hyun Jeon
Journal: Clinical Cancer Research (2019)

Abstract Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered 131I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively. Results: DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.
HGG-03. EVEROLIMUS TREATMENT IMPROVES THE CNS PENETRATION AND EFFICACY OF DASATINIB IN THE TREATMENT OF PDGFRA-DRIVEN PEDIATRIC HIGH-GRADE GLIOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Zachary Miklja, Brendan Mullan, Stefanie Stallard, Viveka Nand Yadav, Amy K Bruzek, Taylor Garcia, Marcia Leonard, Patricia L Robertson, Alyssa Paul, Manjunath P Pai, Timothy Phoenix, Bernard Marini, Carl Koschmann
Journal: Neuro-Oncology (2019)

Pediatric high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG) frequently harbor alterations in PDGFRA. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp in non-tumor models, would increase CNS penetration and efficacy of dasatinib in PDGFRA-driven HGG and DIPG. Dasatinib effectively treated mouse DIPG cells generated from an intra-uterine electroporation (IUE) model (TP53, PDGFRA and H3K27M mutations), with an IC50 of 100 nM and a dose-dependent reduction in PDGFRA and pPDGFRA by western blot. Using an in vitro P-gp inhibitor assay, we confirmed that everolimus strongly blocks P-gp activity at 1 uM (p=0.0028 vs untreated, and NS vs complete P-gp block). Treatment studies using the IUE model are ongoing. Brief treatment with everolimus resulted in sub-IC50 dasatinib average mouse cortex (23 nM) and tumor (65 nM) concentrations by mass spectroscopy, but prolonged (>24 hours) everolimus exposure resulted in improved average cortex (288 nM) and brainstem tumor (360 nM) concentrations. Based on this promising pre-clinical data, we established a phase 2 trial employing dasatinib and everolimus in children with HGG and DIPG that contain PDGFRA alterations (NCT03352427). The first two patients (a recurrent PDGFRA-amplified HGG and a recurrent PDGFRA D842V-mutated DIPG) treated with dasatinib and everolimus after re-irradiation survived 6 months and 9 months (ongoing), respectively, after progression, which compares very favorably to historical controls. Paired CSF samples (before and after addition of everolimus) from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. In summary, we demonstrate that dasatinib treatment of PDGFRA-driven pediatric HGG and DIPG is improved with everolimus blockade of P-gp. This represents a novel route for improving the CNS penetration and efficacy of precision therapies for pediatric HGG.
The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC
Authors: Yueping Jin, Hui Dong, Liliang Xia, Yi Yang, Yongqiang Zhu, Yan Shen, Huajun Zheng, Chengcheng Yao, Ying Wang, Shun Lu
Journal: Journal of Thoracic Oncology (2019)

Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types
Authors: William S. Chen, Mohammed Alshalalfa, Shuang G. Zhao, Yang Liu, Brandon A. Mahal, David A. Quigley, Ting Wei, Elai Davicioni, Timothy R. Rebbeck, Philip W. Kantoff, Christopher A. Maher, Karen E. Knudsen, Eric J. Small, Paul L. Nguyen, Felix Y. Feng
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale. Experimental Design: We utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort. Results: RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P = 0.008) and gene body hypomethylation (P = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P &amp;lt; 0.00001), overall (P = 0.0004), and disease-specific (P &amp;lt; 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P = 0.03) and of shorter overall survival in mCRPC (P = 0.004) independently of the number of DNA alterations in RB1. Conclusions: Our study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption. See related commentary by Choudhury and Beltran, p. 4199
TMOD-21. EXPANDING A PEDIATRIC GLIOMA TOOLKIT OF GENETIC MANIPULATION TO GENERATE TERTIARY MODES OF INDUCIBLE RECOMBINASE EXPRESSION
Authors: Katie B Grausam, David Rincon Fernandez Pacheco, Kruttika Dabke, Joshua J Breunig
Journal: Neuro-Oncology (2019)

Modeling gliomas in genetically engineered mouse models (GEMMs) is the gold standard for recapitulation of the human disease. However, with its heterogeneity and myriad genetic mutations, this becomes a difficult, if not impossible task. Our lab has recently developed an in vivo method of transgenesis called mosaic analysis by dual recombinase-mediated cassette exchange (MADR) that involves genetic recombination at the Rosa26 locus, allowing for consistent transgenic expression in mutant cells. Using electroporation-mediated delivery, DNA plasmids are injected into the lateral ventricle of the brain, followed by application of an electric current that allows the DNA to be taken up by the shocked cells. MADR donor plasmids are then inserted into this locus using FlpO and Cre recombinases. The MADR donor plasmid is a promoter-less vector with a cistron encoding transgenes (e.g., tumor driver genes and/or reporter genes separated by P2A self-cleaving peptides in order to generate multiple proteins from a single cistron) flanked by loxP and FRT sites. For tertiary recombinase expression, VCre is added (with an additional P2A) to the donor. Further, for inducible control of VCre expression, we have developed three separate plasmids: (1) VCre preceded by destabilized domain (DD), as well as dual flanking domains of (2) estrogen ligand binding domain (ERT2) and (3) progesterone receptor (PR). Finally, a flip excision (FlEx) cistron is co-electroporated which can be induced by VCre. Induction of any number of additional transgenes can thus be included such as genes associated with tumor progression or candidate elements for therapeutic mimicry. Incorporating a tertiary level of inducible recombinase expression through VCre, therefore, substantially widens the utility of this method to not only recapitulate the clinical profile of tumor progression, but also to explore different temporal and spatial cells of origin by regulation of this tertiary recombinase.
Hydrogen peroxide regulates the PI3K signaling cascade via oxidation of the tumor suppressor PTEN.
Authors: Sreenivasa R. Chinni, Sivasakthy Sivalogan, Zhong Dong, J. Carlos Trindade Filho, Sunita Bhagat, R. Daniel Bonfil, Michael L. Cher
Journal: Cancer Research (2004)

3535  We showed previously that broad-spectrum inhibition of matrix metalloprotease (MMP) activity diminishes bone matrix turnover and proliferation of prostate cancer (PC) cells in bone (JNCI 94:17, 2002). Using specific tissue-based enzymatic activity assays, we recently demonstrated an increase in net MMP-9 activity, but not MMP-2 or MT1-MMP activity, in bone tissues colonized by cancer cells in vivo. The MMP-9 protein immunolocalized to prostate cancer cells and osteoclasts (Proc AACR 44:3269A, 2003). Herein, we sought to characterize intracellular signaling pathways that lead to the secretion of MMP-9 by cancer cells exposed to the bone microenvironment. The PI3K/Akt signaling pathway is known to be activated in variety of cancer cells following interaction with extracellular matrix components and/or autocrine/paracrine growth factors; thus, we analyzed this pathway during co-culture of PC cells with human bone marrow stromal cells or intact bone tissue. Using a variety of methods including confocal analysis, western blot, and gelatin zymography, we showed that (a) secretion of pro-MMP-9 by PC-3 cells is induced by co-culture with bone stromal cells; (b) the Akt pathway is selectively activated in PC-3 cells during co-cultures; (c) secretion of pro-MMP-9 by PC-3 cells is sensitive to the PI3K inhibitor, LY294002; (d) proteolytic activation of latent pro-MMP-9 to active MMP-9 occurs when PC-3 cells are cultured together with intact bone tissue; and (e) the activation of MMP-9 is sensitive to PI3K inhibition by LY294002. Western blot analysis of experimental in vivo PC bone tumor tissue showed activation of Akt and its downstream molecules. These data suggest that activation of tumor cell-associated Akt kinase and downstream molecules in the Akt pathway play a key role in bone stromal-tumor interactions leading to the secretion of MMP-9 by tumor cells. Neutralization strategies involving dominant negative Akt constructs and isoform-specific Akt siRNA are under progress to delineate the mechanisms underlying Akt signaling and MMP-9 expression and activation.
Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion
Authors: Karuna S. Meda, Tosha Patel, Joao M. Braz, Ruchi Malik, Marc L. Turner, Helia Seifikar, Allan I. Basbaum, Vikaas S. Sohal
Journal: Neuron (2019)
Wilson and Jungner would not approve of screening for atrial fibrillation
Authors: Trygve Berge
Journal: BMJ (2019)

We simply do not know how or who we should screen for atrial fibrillation to reach the desired outcomes (reduced stroke incidence or mortality).1 Only randomised controlled trials (RCTs), such as the Strokestop and SAFER studies, can provide answers.23 As in these studies, we used a handheld electrocardiography (ECG) monitor (for 30 seconds, twice daily and when symptoms occurred, over two weeks) to screen 65 year olds at increased stroke risk (CHA2DS2-VASc score ≥2 for …
Stewart Sinclair Jessamine
Authors: Peter Abernethy, Linda Stephen
Journal: BMJ (2019)

Stewart Jessamine was a world leading medicines expert and public servant. Raised in Cumbernauld, Lanarkshire, he studied medicine at the University of Glasgow, where he met his Malaysian wife, Siew Gueh. After the birth of their daughter, Kathryn, Stewart and Siew Gueh emigrated to New Zealand in 1987, where Stewart started his professional career as a GP in a series of small towns. At a GP conference in the early 1990s he heard an appeal for GPs to consider switching from “poachers” to “gamekeepers,” and in 1993 he joined the New Zealand Ministry of Health, where he was a dedicated and innovative leader for 25 years.

The therapeutics section he joined at the ministry soon morphed into Medsafe, responsible for medicine regulation, and Stewart went from providing resources and liaising with GPs to managing the unit. He moved higher in the ministry and picked up broader public health and regulatory work, with more staff and a …
MicroRNA-92 Expression in CD133+ Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ
Authors: Chris Shidal, Narendra P. Singh, Prakash Nagarkatti, Mitzi Nagarkatti
Journal: Cancer Research (2019)

In addition to being refractory to treatment, melanoma cancer stem cells (CSC) are known to suppress host antitumor immunity, the underlying mechanisms of which need further elucidation. In this study, we established a novel role for miR-92 and its associated gene networks in immunosuppression. CSCs were isolated from the B16-F10 murine melanoma cell line based on expression of the putative CSC marker CD133 (Prominin-1). CD133+ cells were functionally distinct from CD133- cells and showed increased proliferation in vitro and enhanced tumorigenesis in vivo. CD133+ CSCs also exhibited a greater capacity to recruit immunosuppressive cell types during tumor formation, including FoxP3+ Tregs, myeloid-derived suppressor cells (MDSC), and M2 macrophages. Using microarray technology, we identified several miRs that were significantly downregulated in CD133+ cells compared with CD133- cells, including miR-92. Decreased expression of miR-92 in CSCs led to higher expression of target molecules integrin αV and α5 subunits, which, in turn, enhanced TGFβ activation, as evidenced by increased phosphorylation of SMAD2. CD133+ cells transfected with miR-92a mimic and injected in vivo showed significantly decreased tumor burden, which was associated with reduced immunosuppressive phenotype intratumorally. Using The Cancer Genome Atlas database of patients with melanoma, we also noted a positive correlation between integrin α5 and TGFβ1 expression levels and an inverse association between miR-92 expression and integrin alpha subunit expression. Collectively, this study suggests that a miR-92-driven signaling axis involving integrin activation of TGFβ in CSCs promotes enhanced tumorigenesis through induction of intratumoral immunosuppression. SIGNIFICANCE: CD133+ cells play an active role in suppressing melanoma antitumor immunity by modulating miR-92, which increases influx of immunosuppressive cells and TGFβ1 expression.