tbuckley/cabot-search huggingface dataset:
Delivery of Anti-miRNA for Triple-Negative Breast Cancer Therapy Using RNA Nanoparticles Targeting Stem Cell Marker CD133
Authors: Hongran Yin, Gaofeng Xiong, Sijin Guo, Congcong Xu, Ren Xu, Peixuan Guo, Dan Shu
Journal: Molecular Therapy (2019)

Triple-negative breast cancer (TNBC) is an aggressive disease with a short median time from relapse to death. The increased aggressiveness, drug resistance, disease relapse, and metastasis are associated with the presence of stem cells within tumors. Several stem cell markers, such as CD24, CD44, CD133, ALDH1, and ABCG2, have been reported, but their roles in breast cancer tumorigenesis remain unclear. Herein, we apply RNA nanotechnology to deliver anti-microRNA (miRNA) for TNBC therapy. The thermodynamically and chemically stable three-way junction (3WJ) motif was utilized as the scaffold to carry an RNA aptamer binding to CD133 receptor and a locked nuclei acid (LNA) sequence for miRNA21 inhibition. Binding assays revealed the specific uptake of the nanoparticles to breast cancer stem cells (BCSCs) and TNBC cells. Functional assays showed that cancer cell migration was reduced, miR21 expression was inhibited, and downstream tumor suppressor PTEN and PDCD4 expressions were upregulated. In vitro and in vivo studies revealed that these therapeutic RNA nanoparticles did not induce cytokine secretion. Systemic injection of these RNA nanoparticles in animal trial demonstrated high specificity in TNBC tumor targeting and high efficacy for tumor growth inhibition. These results revealed the clinical translation potential of these RNA nanoparticles for TNBC therapy.
Post Hoc Bayesian Analyses—Reply
Authors: Ewan C. Goligher, George Tomlinson, Arthur S. Slutsky
Journal: JAMA (2019)

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Additive Traits Lead to Feeding Advantage and Reproductive Isolation, Promoting Homoploid Hybrid Speciation
Authors: Juan F Masello, Petra Quillfeldt, Edson Sandoval-Castellanos, Rachael Alderman, Luciano Calderón, Yves Cherel, Theresa L Cole, Richard J Cuthbert, Manuel Marin, Melanie Massaro, Joan Navarro, Richard A Phillips, Peter G Ryan, Lara D Shepherd, Cristián G Suazo, Henri Weimerskirch, Yoshan Moodley
Journal: Molecular Biology and Evolution (2019)

Speciation through homoploid hybridization (HHS) is considered extremely rare in animals. This is mainly because the establishment of reproductive isolation as a product of hybridization is uncommon. Additionally, many traits are underpinned by polygeny and/or incomplete dominance, where the hybrid phenotype is an additive blend of parental characteristics. Phenotypically intermediate hybrids are usually at a fitness disadvantage compared with parental species and tend to vanish through backcrossing with parental population(s). It is therefore unknown whether the additive nature of hybrid traits in itself could lead successfully to HHS. Using a multi-marker genetic data set and a meta-analysis of diet and morphology, we investigated a potential case of HHS in the prions (Pachyptila spp.), seabirds distinguished by their bills, prey choice, and timing of breeding. Using approximate Bayesian computation, we show that the medium-billed Salvin's prion (Pachyptila salvini) could be a hybrid between the narrow-billed Antarctic prion (Pachyptila desolata) and broad-billed prion (Pachyptila vittata). Remarkably, P. salvini's intermediate bill width has given it a feeding advantage with respect to the other Pachyptila species, allowing it to consume a broader range of prey, potentially increasing its fitness. Available metadata showed that P. salvini is also intermediate in breeding phenology and, with no overlap in breeding times, it is effectively reproductively isolated from either parental species through allochrony. These results provide evidence for a case of HHS in nature, and show for the first time that additivity of divergent parental traits alone can lead directly to increased hybrid fitness and reproductive isolation.
Combination therapy of sofosbuvir and ribavirin fails to clear chronic hepatitis E infection in a multivisceral transplanted patient
Authors: Marten Schulz, C. Patrick Papp, Claus-Thomas Bock, Jörg Hofmann, Undine A. Gerlach, Max Magnus Maurer, Dennis Eurich, Tobias Mueller
Journal: Journal of Hepatology (2019)
Letter by Wu and Ballantyne Regarding Article, “Protein Kinase Cθ via Activating Transcription Factor 2–Mediated CD36 Expression and Foam Cell Formation of Ly6C <sup>hi</sup> Cells Contributes to Atherosclerosis”
Authors: Huaizhu Wu, Christie M. Ballantyne
Journal: Circulation (2019)

CD36, and greater lipid uptake by Ly-6C high monocytes, are markedly different from reports from other studies 2-5 and need further investigation and validation.
Effects of Proton Pump Inhibitors on the Gastrointestinal Microbiota in Gastroesophageal Reflux Disease
Authors: Yi-Chao Shi, Shun-Tian Cai, Ya-Ping Tian, Hui-Jun Zhao, Yan-Bing Zhang, Jing Chen, Rong-Rong Ren, Xi Luo, Li-Hua Peng, Gang Sun, Yun-Sheng Yang
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract Proton pump inhibitors (PPIs) are commonly used to lessen symptoms in patients with gastroesophageal reflux disease (GERD). However, the effects of PPI therapy on the gastrointestinal microbiota in GERD patients remain unclear. We examined the association between the PPI usage and the microbiota present in gastric mucosal and fecal samples from GERD patients and healthy controls (HCs) using 16S rRNA gene sequencing. GERD patients taking PPIs were further divided into short-term and long-term PPI user groups. We showed that PPI administration lowered the relative bacterial diversity of the gastric microbiota in GERD patients. Compared to the non-PPI-user and HC groups, higher abundances of Planococcaceae, Oxalobacteraceae, and Sphingomonadaceae were found in the gastric microbiota from the PPI-user group. In addition, the Methylophilus genus was more highly abundant in the long-term PPI user group than in the short-term PPI-user group. Despite the absence of differences in alpha diversity, there were significant differences in the fecal bacterial composition of between GERD patients taking PPIs and those not taking PPIs. There was a higher abundance of Streptococcaceae, Veillonellaceae, Acidaminococcaceae, Micrococcaceae, and Flavobacteriaceae present in the fecal microbiota from the PPI-user group than those from the non-PPI-user and HC groups. Additionally, a significantly higher abundance of Ruminococcus was found in GERD patients on long-term PPI medication than that on short-term PPI medication. Our study indicates that PPI administration in patients with GERD has a significant effect on the abundance and structure of the gastric mucosal microbiota but only on the composition of the fecal microbiota.
A Novel Glycomimetic Compound (GMI-1757) with Dual Functional Antagonism to E-Selectin and Galectin-3 Demonstrates Inhibition of Thrombus Formation in an Inferior Vena Cava Model
Authors: John Peterson, Yusuf Vohra, Daniel Durant Myers, Silvia Locatelli-Hoops, Ji-Won Lee, Lingquan Deng, Theodore AG Smith, William E Fogler, John L Magnani
Journal: Blood (2018)
MEDU-47. A NOVEL TGF-BETA/MYC-DRIVEN MEDULLOBLASTOMA MODEL TO STUDY IMMUNE-TUMOR INTERACTIONS
Authors: Jacob Henderson, Jianya Huang, Nadav Lelkes, Matt Wood, Andrew Weinberg, Yoon-Jae Cho
Journal: Neuro-Oncology (2019)

Developing authentic mouse models of medulloblastoma (MB) is vitally important for understanding MB biology and developing novel treatments for patients with this disease. In particular, models with a native immune system are critical for deciphering the complex roles that immune escape and surveillance play in MB formation and eradication, respectively. We previously reported that components of the TGFb signaling pathway are necessary for Group 3 MYC-amplified MB proliferation and survival. We have also observed that small molecule inhibition of the TGFb pathway primes MB for immune checkpoint allowing for increased T cell infiltration in an otherwise “immunodepleted” tumor. Here, we sought to determine whether TGFb signaling in cooperation with MYC was sufficient to transform cells into MB. Toward this end, we isolated cerebellar stem cells from 4–6 week old mice and transduced them with lentiviral vectors expressing either a constitutively active TGFbR1 (ALK5) or MYC, or both. Cells transduced with both ALK5 and MYC, but not each individually, quickly formed dense neurospheres in vitro that propagated ad infinitum. When allografted into either immunodeficient or syngeneic immune competent mice, these transformed cells formed large, infiltrating tumors, that displayed nuclear atypia and other features reminiscent of anaplastic MB. Gene expression microarray analysis further confirmed an expression signature consistent with previously published Group 3 MYC-amplified MB mouse models (GTML; MYC-DNp53) as well as human primary Group 3 MB. Interestingly, tumors generated from TGFb/MYC-transformed cells allografted into syngeneic immune competent mice lacked T cell infiltration and had dysfunctional neoantigen presenting machinery consistent with the human condition. Thus, we provide a novel Group 3 TGFb/MYC-driven MB model that closely recapitulates the human condition and will serve as a useful resource to better understand mechanisms of tumor-immune interactions in MB. SIGNALING
Pulmonary arterial pressure at rest and during exercise in chronic mountain sickness: a meta-analysis
Authors: Rodrigo Soria, Matthias Egger, Urs Scherrer, Nicole Bender, Stefano F. Rimoldi
Journal: European Respiratory Journal (2019)

Up to 10% of the more than 140 million high-altitude dwellers worldwide suffer from chronic mountain sickness (CMS). Patients suffering from this debilitating problem often display increased pulmonary arterial pressure (PAP), which may contribute to exercise intolerance and right heart failure. However, there is little information on the usual PAP in these patients. We systematically reviewed and meta-analysed all data published in English or Spanish until June 2018 on echocardiographic estimations of PAP at rest and during mild exercise in CMS patients. Nine studies comprising 287 participants fulfilled the inclusion criteria. At rest, the point estimate from meta-analysis of the mean systolic PAP was 27.9 mmHg (95% CI 26.3–29.6 mmHg). These values are 11% (+2.7 mmHg) higher than those previously meta-analysed in apparently healthy high-altitude dwellers. During mild exercise (50 W) the difference in mean systolic PAP between patients and high-altitude dwellers was markedly more accentuated (48.3 versus 36.3 mmHg) than at rest. These findings indicate that in patients with CMS PAP is moderately increased at rest, but markedly increased during mild exercise, which will be common with activities of daily living.
Abstract 15806: Decoding Gene Regulatory Networks Governing Differentiation of Human Induced Pluripotent Stem Cell to Cardiovascular Lineages by Single Cell RNA-seq
Authors: Wuming Gong, Naoko Koyano-Nakagawa, Wei Pan, Daniel J Garry
Journal: Circulation (2016)

Background: Human induced pluripotent stem cells (hiPSCs) offer a unique platform to investigate the regulation of human genes implicated in congenital heart diseases. However, due the heterogeneit...
Cardioprotective Effects of <i>MTSS1</i> Enhancer Variants
Authors: Michael P. Morley, Xiao Wang, Ray Hu, Jeffrey Brandimarto, Nathan R. Tucker, Janine F. Felix, Nicholas L. Smith, Pim van der Harst, Patrick T. Ellinor, Kenneth B. Margulies, Kiran Musunuru, Thomas P. Cappola
Journal: Circulation (2019)
IIc or not IIc: a question for meticulous optical evaluation
Authors: Neal Shahidi, Mayenaaz Sidhu, Iddo Bar-Yishay, Michael J Bourke
Journal: Gut (2019)

A middle-aged man was referred to assess the feasibility of endoscopic removal of a 35 mm laterally spreading lesion within the sigmoid colon. The referring endoscopist appreciated a central depression (0–IIc Paris morphology) and raised the concern for submucosal invasive cancer.

Using an Olympus 190 series high-definition colonoscope (Olympus, Tokyo, Japan), the lesion was carefully examined under white light and narrow-band imaging (NBI) (figure 1A). The central aspect of the …
High prevalence of hepatitis B and syphilis in illegal gold miners in French Guiana
Authors: M. Douine, R. Schaub, H. Jardin, A. Adenis, M. Nacher, L. Hureau-Mutricy, S. Vreden, E. Mosnier, A. Pisoni, E. Tuaillon
Journal: Clinical Microbiology and Infection (2019)
Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2
Authors: Carmelo Carmona-Rivera, Sami S. Khaznadar, Kyawt W. Shwin, Jorge A. Irizarry-Caro, Liam J. O’Neil, Yudong Liu, Kenneth A. Jacobson, Amanda K. Ombrello, Deborah L. Stone, Wanxia L. Tsai, Daniel L. Kastner, Ivona Aksentijevich, Mariana J. Kaplan, Peter C. Grayson
Journal: Blood (2019)
SPED.live 2019
Authors: P Bastos, F Vilas-Boas, M Dinis-Ribeiro, G Macedo
Journal: Endoscopy (2019)

The Portuguese Society of Endoscopy (SPED) has organized in this early spring its first course with transmission of live endoscopic cases: the SPED.live. The course had some groundbreaking aspects in the portuguese endoscopic milieu, since it was a joint-venture between two distinct medical institutions: Hospital S. João and the Portuguese Institute of Oncology (IPO Porto) and was streamed online through a dedicated YouTube channel.
Abstract 15976: CPVT Arrhythmic Phenotype in KCNJ2-R67Q KI Mouse With Decreased Repolarization Reserve and Increased Triggered Activity
Authors: Louise Reilly, Di Lang, Cordell Spellman, Sara Abozeid, Hanora van Ert, Jarrett Warden, Elise McCune, Manasa Kalluri, Chris Mann, Alexey V Glukhov, Lee L Eckhardt
Journal: Circulation (2017)

Introduction: KCNJ2 mutations are associated with Anderson-Tawil Syndrome (ATS), Short QT Syndrome 3 (SQT3) and in CPVT. We previously reported KCNJ2 mutation R67Q from a patient with adrenergic-in...
ATRT-09. INTEGRATIVE ANALYSES OF GENE REGULATORY LANDSCAPES REVEAL RHABDOID TUMOR SUBGROUPS WITH POSSIBLE IMMUNE MODULATION THROUGH EPIGENETIC DYSREGULATION
Authors: Pascal Johann, Hye-Jung Chun, Serap Erkek, Murat Iskar, Elizabeth Perlman, Martin Hasselblatt, Stefan M Pfister, Marco Marra, Marcel Kool
Journal: Neuro-Oncology (2019)

chromatin-associated molecules in patient-derived ATRT cell lines.This unbiased screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability.We hypothesized that BMI1 promotes ATRT tumorigenesis by co-operating with SMARCB1 loss to suppress scheduled transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells.We found that BMI1 expression is elevated in ATRT patient samples and cell lines compared to the normal pediatric cerebellum.Genetic depletion of BMI-1 suppressed ATRT cell clonogenicity and decreased in vitro stem cell maintenance.Using RNA-seq-based gene set enrichment analysis we show that BMI1 depletion decreases c-MYC driven transcriptomic programs and induces p53 driven apoptotic programs.This suggests that BMI-1 drives ATRT tumorigenesis by promotingc-Myc driven tumor stem cell self-renewal and driving resistance to therapy by inactivating p53 mediated apoptotic pathways.Finally, we sought to evaluate whether BMI1 is a therapeutic vulnerability in ATRT.We found that PTC596, the clinical lead compound inhibitor of BMI-1, significantly inhibited clonogenic potential, decreased S-phase length and induced apoptosis in ATRT cells in vitro.Furthermore, using ChIP-seq we show that PTC596 alters chromatin occupancy of BMI1 away from differentiation associated gene promoters in ATRT cells.In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors compared to control animals as evaluated by MRI imaging.Moreover, treated mice survived significantly longer than control animals.These studies are the first pre-clinical validation of PRC1/BMI1 inhibition as a novel therapeutic approach in ATRT.
MEDU-21. LOSS OF THE TRANSCRIPTIONAL CO-REPRESSOR BCOR LEADS TO OVEREXPRESSION OF THE GROWTH FACTOR IGF2 AND SHH MEDULLOBLASTOMA TUMOR FORMATION
Authors: Lena Kutscher, Nadja Batora, Konstantin Okonechnikov, Jessica Clark, Mikaella Vouri, Sjoerd van Rijn, Micah Gearhart, Brent Orr, Andrey Korshunov, Marcel Kool, Vivian Bardwell, Stefan M Pfister, Paul A Northcott, Daisuke Kawauchi
Journal: Neuro-Oncology (2019)

Sonic hedgehog (SHH) medulloblastoma (MBSHH) accounts for approximately 25% of all MB diagnoses and is the predominant disease subgroup in infants and adults. Pediatric MBSHH is caused by an abnormal activation of the SHH pathway in granule cell progenitors (GNPs) in the developing cerebellum, but also requires additional secondary lesions. These secondary genetic hits often occur in chromatin modifying genes, but functional evidence for a role of these mutations in MBSHH progression is lacking. We have identified the transcriptional co-repressor BCOR, a subunit of the PRC1.1 complex, as recurrently mutated in approximately 10% of MBSHH patients and likely to function as a suppressor of MBSHH tumor formation. Conditional genetic ablation of Bcor in GNPs strongly accelerated tumor formation in Ptch1+/- mice in a cell-autonomous manner. Moreover, we found that the growth factor Igf2 is 100-fold upregulated in Bcor-deficient Ptch1+/- MBs compared to control tumors. This upregulation was observed in neoplastic lesions but not in normally differentiating GNPs, suggesting potential epigenetic regulation of Igf2 by Bcor during tumorigenesis. Overexpression of Igf2 in Ptch1+/- GNPs was sufficient to generate tumors with 100% penetrance. Intriguingly, in a small subset of human MBSHH, we observed an association between deleterious BCOR mutations and high IGF2 expression. Our data suggest that loss of Bcor cooperates with aberrant SHH signaling to promote Igf2-dependent tumor growth.
A Temporizing Solution to “Artemisinin Resistance”
Authors: Jigang Wang, Chengchao Xu, Fu Long Liao, Tingliang Jiang, Sanjeev Krishna, Youyou Tu
Journal: New England Journal of Medicine (2019)

A Temporizing Solution to “Artemisinin Resistance” Three-day therapeutic courses are losing their efficacy against malarial parasites in the Greater Mekong Subregion. But continued rational and strategic use of artemisinin combination treatments is the best, and possibly the only, solution for the foreseeable future.
Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment
Authors: Xingzhe Ma, Enguang Bi, Yong Lu, Pan Su, Chunjian Huang, Lintao Liu, Qiang Wang, Maojie Yang, Matthew F. Kalady, Jianfei Qian, Aijun Zhang, Anisha A. Gupte, Dale J. Hamilton, Chengyun Zheng, Qing Yi
Journal: Cell Metabolism (2019)
A sensitive array-based assay to identify multiple TMPRSS2:ERG fusion variants in prostate cancer
Authors: Qing Lu, Kimberly Christensen, Tracy Downs, Dennis Carson, Jessica Wang-Rodriguez, Yu-Tsueng Liu
Journal: Cancer Research (2008)

3653  The presence of the TMPRSS2:ERG fusion gene has been demonstrated in approximately half of all prostate cancers. This genomic rearrangement is very likely associated with prostate cancer development. The majority of TMPRSS2:ERG fusion junctions are between exons 1 or 2 of TMPRSS2, and exons 2-5 of ERG. It has been suggested that certain fusion variants are associated with disease progression. In addition, it is common to find multiple fusion variants in prostate tumor samples. We have established a simple and sensitive microarray-based assay that is able to simultaneously determine multiple fusion variants using a single RT-PCR reaction. The assay detected TMPRSS2:ERG fusion transcripts with a detection sensitivity of 32 pg of total RNA (an equivalent to 1-3 cells) from the VCaP cell line in the presence of more than 3000 fold (100 ng of total RNA) excess of HeLa RNA. To test the ability of the exon mapping array to detect and characterize TMPRSS2:ERG fusion transcripts in clinical samples, we isolated total RNA from frozen unpurified primary prostate tissues obtained during surgery. Total RNA (5-50 ng) from prostate cancers (n = 20) and non-malignant hyperplastic prostate tissues (n = 10) were subjected to RT-PCR labeling and array hybridization. The results showed that 7/20 cancer but 0/10 non-malignant samples had TMPRSS2:ERG fusion genes. Many of these tumors samples contained a substantial fraction of normal stromal cells. One of the 7 positive tumor samples contained only 1% cancer cells. Multiple fusion variants were found in 4/7 positive samples. To confirm the presence of the gene fusion, direct sequencing was performed on the 7 fusion positive samples. The sequencing data confirmed the findings revealed by the array assay. The same strategy can be applied to detect other less prevalent fusion transcripts (TMPRSS2:ETV1 and TMPRSS2:ETV4) in prostate cancer. Eventually, they can be integrated into a single assay. The technology described here should allow larger scale investigation to determine whether there is a correlation between the aggressiveness of the disease and the presence of various fusion genes.
MEDU-31. IDENTIFICATION AND CHARACTERIZATION OF A NOVEL PATIENT-SPECIFIC GENE COMBINATION TO MODEL GROUP3 MEDULLOBLASTOMA
Authors: Claudio Ballabio, Marica Anderle, Matteo Gianesello, Giuseppe Aiello, Luca Tiberi
Journal: Neuro-Oncology (2019)

Brain cancer is now the deadliest form of childhood cancer in the United States. In particular, Group3 Medulloblastoma (MB) is the pediatric brain tumor with the highest morbidity and mortality. Patients with Group3 MB currently have the worst outcome and nearly 50% are metastatic at the time of diagnosis. However, the cellular and molecular mechanisms underlying Group3 MB are still unknown. What is still lacking in the field is the possibility to obtain tumors by direct genetic modification of mice and to be able to recapitulate the growth and metastasis formation of Group3 MB. Exploiting in-vivo transfection of mouse cerebellar cells with CRISPR-Cas9 and PiggyBac transposase systems, we tested different combinations of putative oncosuppressors and putative oncogenes, derived from human Medulloblastoma NGS data, for their ability to induce Group3 MB in mice. Surprisingly, concomitant overexpression of c-Myc and other transcription factors in mouse cerebellum is able to induce MB in a few months. The newly generated mouse model is able to fully recapitulate human Group 3 MB. Using this proposed patient-specific model, we were able to unravel the molecular aspects of Group 3 medulloblastoma tumorigenesis and identify molecules inhibiting tumor growth in a targeted manner.