tbuckley/cabot-search huggingface dataset:
Is colonic propionate delivery a novel solution to improve metabolism and inflammation in overweight or obese subjects?
Authors: Patrice D Cani
Journal: Gut (2019)

Increased intake of dietary fibre has been linked to beneficial impacts on health for decades. Strikingly, the exact mechanisms of action are not yet fully understood. Among the different families of fibres, prebiotics have gained attention mainly because of their capacity to selectively modulate the gut microbiota composition and promote health benefits.1 Prebiotics are fermented by gut bacteria into short-chain fatty acids (SCFA) such as acetate, butyrate and propionate, but multiple other metabolites have also been described.2 SCFAs have been connected with different physiological processes including the regulation of glucose and lipid metabolism but also energy, immunity and inflammation. Therefore, the gut microbiota has been suggested as a potential target to mitigate cardiometabolic disorders associated with obesity (for review, see ref 3).

Among the different SCFAs, propionate has attracted the most attention because of its capacity to bind to specific receptors and trigger the secretion of gut peptides such as glucagon-like peptide-1 and peptide YY which are involved in the regulation of appetite and glucose metabolism.3 In addition, propionate has been found to enhance the development of regulatory T cells and to reduce the expansion of proinflammatory Th17 cells.4 Therefore, increasing the endogenous production of propionate or its delivery in the colon is an attractive solution to improve metabolic disorders.

Pioneering work by Chambers and colleagues has shown that …
MEDU-17. HIGH IMPACT OF miRNA-4521 ON FOXM1 EXPRESSION IN MEDULLOBLASTOMA
Authors: Sibylle Madlener, Daniel Senfter, Mahzeiar Samadaei, Robert M Mader, Johannes Gojo, Andreas Peyrl, Georg Krupitza, Marcel Kool, Martin Sill, Christine Haberler, Gerda Ricken, Thomas Czech, Irene Slavc
Journal: Neuro-Oncology (2019)

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although knowledge of genetic variants increased over recent years and starts to be reflected in treatment stratification, survival of high-risk patients with leptomeningeal dissemination, TP53 mutation or MYC amplification is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is dysregulated in many different solid tumors, including medulloblastoma, and triggers proliferation, migration and genomic instability in the cells. We investigated the effect of miRNA-4521, located on chromosome 17p, on the expression of FOXM1 in medulloblastoma cell lines and describe a link between the downregulated miRNA-4521 and the dysregulated transcription factor FOXxM1 in medulloblastoma. Our results indicate a high impact of miRNA-4521 on FOXM1 protein expression. Transfection of this miRNA reduced the proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through the activation of the caspase 3/7. Further, the downstream targets of FOXM1 such as PLK1 and cyclin B were significantly reduced and affected the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may provide a targeted approach for medulloblastoma therapy.
ATRT-10. HETEROGENEITY OF BAF AND PBAF SWI/SNF COMPLEX SUBUNITS IN MALIGNANT RHABDOID TUMORS RELATES WITH POLYPHENOTYPIC DIFFERENTIATION AND THE IMMUNE MICROENVIRONMENT
Authors: Sriram Venneti, Pooja Panwalkar, Drew Pratt, Chan Chung, Daniel Martinez, Derek Dang, Jill Bayliss, Paul Le, Ashley Margol, Bruce Pawel, Alexander Judkins
Journal: Neuro-Oncology (2019)

Malignant Rhabdoid Tumors (MRT’s) are aggressive tumors characterized by loss of the SWI/SNF complex protein SMARCB1. They occur in the CNS (atypical teratoid/rhabdoid tumors-AT/RT) or outside (extra-CNS, eCNS). MRTs are defined by tumor cells that exhibit varying cell lineage phenotypes including neuroglial, mesenchymal and epithelial differentiation. The mechanisms that regulate polyphenotypic differentiation are not known. Because the SWI/SNF complex regulates differentiation, we hypothesized that heterogeneity in expression of various SWI/SNF components regulate multiple lineage differentiation. We examined expression of various BAF and PBAF SWI/SNF complex proteins in MRTs (24 AT/RT and 19 eCNS MRT) in relation to neuroglial, mesenchymal and epithelial differentiation. Surprisingly, we found that a subset of tumors co-expressed the mutually exclusive BAF complex components: ACTL6A and ACTL6B in eCNS MRTs and ARID1A and ARID1B in AT/RTs. ACTL6A and ACTL6B are critical regulators of neuronal differentiation. Accordingly, MRTs that co-expressed ACTL6A/ACTL6B exhibited greater neuronal differentiation. In contrast, tumors that did not express both ACTL6A/ACTL6B showed more epithelial and mesenchymal differentiation. Conversely, ARID1A and ARID1B are known to regulate epithelial differentiation and AT/RTs that showed expression of both ARID1A and ARID1B demonstrated greater epithelial and mesenchymal differentiation in comparison to tumors that did not. These data suggest that aberrant co-expression of specific mutually exclusive subunits may govern lineage differentiation in MRT. Finally, the SWI/SNF-PBAF subunits - ARID2, PBRM1 and BRD7 also showed heterogeneity in MRTs. PBRM1 regulates the immune tumor microenvironment and accordingly PBRM1 expression related inversely with cytotoxic CD8+-T cell levels and overall prognosis. Finally, tumors with high PBAF expression exhibited cell-cycle deregulation and worse prognosis. Together, our data suggest in addition to SMARCB1 deletion, the composition of residual BAF and PBAF subunits govern the biology of MRTs in relation to polyphenotypic differentiation and the immune tumor microenvironment.
The role of ENPP1/PC-1 in osteoinduction by calcium phosphate ceramics
Authors: Ziryan Othman, Hugo Fernandes, Arjan J. Groot, Theo M. Luider, Alessandro Alcinesio, Daniel de Melo Pereira, Alexander P.M. Guttenplan, Huipin Yuan, Pamela Habibovic
Journal: Biomaterials (2019)
Stereotypes About Enterotype: The Old and New Ideas
Authors: Mingyue Cheng, Kang Ning
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract In 2011, the term “enterotype” first appeared to the general public in Nature, which refers to stratification of human gut microbiota. However, with more studies on enterotypes conducted nowadays, doubts about the existence and robustness of enterotypes have also emerged. Here we reviewed current opinions about enterotypes from both conceptual and analytical points of view. We firstly illustrated the definition of the enterotype and various factors influencing enterotypes, such as diet, administration of antibiotics, and age. Then we summarized lines of evidence that pose the concept against the enterotype, and described the current methods for enterotype analysis. Finally, we showed that the concept of enterotype has been extended to other ecological niches. Based on current studies on enterotypes, it has been clear that more studies with larger sample sizes are needed to characterize the enterotypes. Improved computational methods are also required to build sophisticated models, reflecting the dynamics and resilience of enterotypes.
MEDU-42. ELUCIDATING THE ROLE OF STRESS GRANULE FORMATION IN MEDULLOBLASTOMA
Authors: Sofya Langman, Michael Lizardo, Antoine Forget, Olivier Ayrault, Poul Sorensen
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common pediatric brain malignancy, accounting for 20% of diagnosed brain tumors in children. The Group 3 (G3) MB subtype is found to be especially malignant and is commonly associated with MYC over-expression. Current G3 MB treatment regimens provide for 50% 5-year survival rates and are associated with severe side effects, including hearing loss and neurocognitive deficits. High expression of stress granule (SG) proteins such as G3BP1 and PAPBPC1 correlates with poor survival outcome in G3 MB patients. We propose that formation of SGs, mRNP granules assembled under cellular stress, is integral for MB tumor progression, and suggest that inhibition of SG formation is a novel therapeutic strategy. In order to identify key proteins for SG formation we set up a siRNA screen for 95 genes that have previously been linked to SG formation, and that are highly expressed in MB G3 tumors. The screen has been done in two G3 MB cell lines: MED8A and HDMB03. EIF2AK1, also known as HRI, was identified as one of the hits in the screen; it is an eIF2a kinase responsible for cellular response to oxidative stress. Phosphorylation of eIF2a is essential for canonical SG formation and global translation inhibition. We therefore used ISRIB, a known inhibitor of the integrated stress response, to block the effects of eIF2a phosphorylation, thus maintaining active global translation under stress conditions and preventing SG assembly. MB cells exposed to ISRIB combined with vincristine exhibited significantly decreased proliferation as well as increased apoptosis markers compared to cells exposed to vincristine alone. We show that combining SG inhibition with chemotherapy enhances the effects of the latter, which is increasingly relevant for patients suffering from therapy side effects and high chances of metastasis associated with G3 MB.
Michael O’Donnell: medical journalist, author, broadcaster, and GMC reformer
Authors: John Illman
Journal: BMJ (2019)

As editor of World Medicine , Michael O’Donnell was an outstanding radical journalist. Stephen Lock, a former editor of The BMJ , ranked him alongside William Cobbett (1763-1835), Thomas Wakley (1795-1862), William Morris (1834-96), and George Orwell (1903-50) in terms of zest, wit, readability, and purpose.

Wakley is perhaps the most appropriate comparator. Founder editor of the Lancet in 1823, Wakley attacked nepotism, malpractice, and quackery—“the canker worm which eats into the heart of the medical body.” O’Donnell’s canker worm was the General Medical Council and a profession where power was exerted largely through “a mixture of patronage and politesse.”

Both men were renowned innovators. While the Lancet was—among other things—the first periodical with a chess column, World Medicine —medicine’s Private Eye —broke new ground by reflecting “the uncertainties, the paradoxes, and the black comedy that make practising our craft so rewarding.”

O’Donnell began his 16 year tenure at World Medicine in 1966. There was no better time for a radical. This was the “swinging sixties,” symbolised by the Beatles, the Rolling Stones, the civil rights movement, the Campaign for Nuclear Disarmament, the anti-Vietnam war movement, women’s liberation, satire, and the advent of the contraceptive pill.

O’Donnell already had a formidable reputation. While studying natural sciences at Cambridge, he appeared in La Vie Cambridgienne , the first …
Physician perspectives on integration of artificial intelligence into diagnostic pathology
Authors: Shihab Sarwar, Anglin Dent, Kevin Faust, Maxime Richer, Ugljesa Djuric, Randy Van Ommeren, Phedias Diamandis
Journal: npj Digital Medicine (2019)

Abstract Advancements in computer vision and artificial intelligence (AI) carry the potential to make significant contributions to health care, particularly in diagnostic specialties such as radiology and pathology. The impact of these technologies on physician stakeholders is the subject of significant speculation. There is however a dearth of information regarding the opinions, enthusiasm, and concerns of the pathology community at large. Here, we report results from a survey of 487 pathologist-respondents practicing in 54 countries, conducted to examine perspectives on AI implementation in clinical practice. Despite limitations, including difficulty with quantifying response bias and verifying identity of respondents to this anonymous and voluntary survey, several interesting findings were uncovered. Overall, respondents carried generally positive attitudes towards AI, with nearly 75% reporting interest or excitement in AI as a diagnostic tool to facilitate improvements in workflow efficiency and quality assurance in pathology. Importantly, even within the more optimistic cohort, a significant number of respondents endorsed concerns about AI, including the potential for job displacement and replacement. Overall, around 80% of respondents predicted the introduction of AI technology in the pathology laboratory within the coming decade. Attempts to identify statistically significant demographic characteristics (e.g., age, sex, type/place of practice) predictive of attitudes towards AI using Kolmogorov–Smirnov (KS) testing revealed several associations. Important themes which were commented on by respondents included the need for increasing efforts towards physician training and resolving medical-legal implications prior to the generalized implementation of AI in pathology.
THER-33. TOCILIZUMAB AS A POTENTIAL NOVEL THERAPY IN PATIENTS DIAGNOSED WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Sydney Grob, Andrew Donson, Eric Prince, Trinka Vijmasi, Nicholas Foreman, Nathan Dahl, Rajeev Vibhakar, David Mirsky, Todd Hankinson, Jean Mulcahy Levy
Journal: Neuro-Oncology (2019)

Adamantinomatous craniopharyngioma (ACP) makes up between 6–8% of pediatric brain tumors and is the most common pediatric tumor arising in the sellar/suprasellar region of the brain. The 10-year survival for patients diagnosed with craniopharyngioma ranges between 64–92%, but given complicating factors such as its location, common cyst formation, and potential hypothalamic infiltration, there is significant morbidity in this population. There are a number of therapy options for children with craniopharyngioma including surgery, radiation, and cyst-directed therapies such as Interferon and Bleomycin. Research has raised concerns regarding efficacy and morbidity induced side effects with these conventional therapies and with difficulty in treating recurrent primary cystic ACP. Evidence from our group and others have shown that the cystic and solid tumor components of craniopharyngioma have high levels of IL-6R and IL-6, providing a potential target for therapy. Tocilizumab acts against soluble and membrane bound IL-6R, leading to the possibility that it may offer benefit for some patients with ACP. Two patients with recurrent primary cystic craniopharyngiomas treated at Children’s Hospital Colorado were offered systemic administration of the IL-6R antagonist, tocilizumab or a combination of tocilizumab and bevacizumab on a compassionate use basis. Both patients’ tumors had a significant response, with decreased cystic burden, supporting the assertion that tocilizumab and bevacizumab may be an option for patients suffering from cystic craniopharyngioma.
IMMU-02. LOCOREGIONAL HER2CAR T CELLS FOR PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS: PRECLINICAL EFFICACY TO TOLERABILITY IN FIRST PATIENT
Authors: Nicholas Vitanza, Adam Johnson, Adam Beebe, Juliane Gust, Jason Hauptman, Corrine Hoeppner, Ashley Wilson, Francisco Perez, Navin Pinto, Rimas Orenta, Laura Finn, Rebecca Gardner, Julie Park, Michael Jensen
Journal: Neuro-Oncology (2019)

Chimeric antigen receptor (CAR) T cell therapy provides a broadly applicable, targeted, yet pathway-independent, intervention for pediatric central nervous system (CNS) tumors. We have optimized the efficacy and specificity of a HER2-targeted CAR with an extracellular target-specific scFv domain derived from trastuzumab (a HER2 targeting antibody), a co-expressed truncated EGFR (EGFRt) to evaluate transduction efficacy and as a potential suicide mechanism with cetuximab treatment, and a medium-length spacer coupled to an intracellular 4-1BBζ domain. In vitro studies revealed antigen specific cytotoxicity and cytokine release against HER2-positive CNS tumors; and the HER2CAR significantly improved survival (p=0.003) in vivo at 90 days in a xenograft CNS model relative to Mock-treated controls. BrainChild-01 is a first-in-human trial evaluating locoregional infusion of HER2CAR T cells for children and young adults with HER2-positive progressive or recurrent CNS tumors. Autologous T cells are apheresed, engineered to express the second-generation HER2CAR, and expanded ex vivo. They are delivered via indwelling CNS catheter into either the tumor cavity (Arm A) or ventricular system (Arm B) using an intra-patient dose-escalation regimen with weekly dosing for 3 of every 4 weeks per course. The study period is two courses though subjects may receive up to six. Subject 001, a 19-year-old female with a parietal lobe hypermutated HER2-positive anaplastic astrocytoma (WHO grade III), enrolled on Arm A following third progression, underwent apheresis and successful production of 1.9 x 109 HER2CAR T cells. She tolerated the study-prescribed six CAR T cell doses over two courses at doses of 1 x 107 to 2.5 x 107 without dose limiting toxicity. Acute local inflammation and CRP elevation followed each dose. MRI brain/spine obtained after Course 2 revealed increased enhancement and T2/FLAIR hyperintensity surrounding the tumor cavity with mildly increased mass effect, indeterminate for treatment-related inflammatory changes/pseudoprogression versus tumor progression. Enrollment is ongoing.
DIPG-05. A RATIONAL COMBINATION STRATEGY TARGETING ATM KINASE IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Jia Xie, Chen He, Brandon Bianski, Nathaniel Twarog, Suzanne Baker, Anang Shelat, Christopher Tinkle
Journal: Neuro-Oncology (2019)

Radiation therapy (RT) is a standard component of postoperative management of children with malignant gliomas and the definitive therapy for patients with inoperable high-grade glioma (HGG), yet the duration of benefit is generally measured in months to several years. Therefore, it is important to identify novel systemic therapy agents that enhance the therapeutic efficacy of standard of care RT. We screened a custom library of 24 FDA approved drugs and late stage clinical candidates with reported radiosensitizing activity and central nervous system (CNS) penetration, including direct inducers of DNA damage and inhibitors of the DNA damage response, in combination with a dose-response of ionizing radiation (IR) in three diffuse intrinsic pontine glioma (DIPG) cell lines using the CellTiter-Glo assay, clonogenic assay, and/or live cell confluence assay. DNA damage was interrogated by measuring the formation of γ-H2AX foci and micronuclei using immunoflourescence microscopy. DNA repair efficiency was measured using the EJ-DR reporter system. Cellular senescence was quantified by senescence-associated β-galactosidase staining. The CNS penetrant ATM inhibitor, AZD1390, emerged as the best potentiator of IR across all three DIPG models. Preliminary results indicated that AZD1390 inhibited the formation of γ-H2AX foci immediately after the application of IR, but led to persistence of foci at longer timepoints. Drug treatment enhanced IR-induced cellular senescence and increased mutagenic non-homologous end joining (mNHEJ). Furthermore, the PARP inhibitor olaparib and the topoisomerase I inhibitor topotecan strongly potentiated with AZD1390 independently of IR. Taken together, our work provides strong rationale for the in vivo evaluation of combination therapy incorporating ATM inhibition with conventional DNA damaging therapy in pediatric (p)HGG xenograft models. To this end, ongoing work includes in vivo RT dose-response and CNS pharmacodynamics following AZD1390 treatment of pHGG xenografts.
Textbook Outcome Nomograms as Multivariate Clinical Tools for Building Cancer Treatment Pathways and Prognosticating Outcomes
Authors: Yuman Fong
Journal: JAMA Surgery (2019)

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Associations of Fetal and Infant Weight Change With General, Visceral, and Organ Adiposity at School Age
Authors: Suzanne Vogelezang, Susana Santos, Liza Toemen, Edwin H. G. Oei, Janine F. Felix, Vincent W. V. Jaddoe
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Both fetal and infant growth influence obesity later in life. The association of longitudinal fetal and infant growth patterns with organ fat is unknown. <h3>Objective</h3> To examine the associations of fetal and infant weight change with general, visceral, and organ adiposity at school age. <h3>Design, Setting, and Participants</h3> This cohort study was embedded in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Pregnant women with a delivery date between April 2002 and January 2006 were eligible to participate. Follow-up measurements were performed for 3205 children. Data analysis of this population was performed from July 26, 2018, to February 7, 2019. <h3>Exposures</h3> Fetal weight was estimated in the second and third trimester of pregnancy. Infant weight was measured at 6, 12, and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change in standard deviation scores greater than 0.67 between 2 ages. <h3>Main Outcomes and Measures</h3> Visceral fat index, pericardial fat index, and liver fat fraction were measured by magnetic resonance imaging. <h3>Results</h3> The sample consisted of 3205 children (1632 girls [50.9%]; mean [SD] age, 9.8 [0.3] years). Children born small for gestational age had the lowest median body mass index compared with children born appropriate for gestational age and large for gestational age (16.4 [90% range, 14.1-23.6] vs 16.9 [90% range, 14.4-22.8] vs 17.4 [90% range, 14.9-22.7]). Compared with children with normal fetal and infant growth (533 of 2370 [22.5%]), those with fetal weight deceleration followed by infant weight acceleration (263 of 2370 [11.1%]) had the highest visceral fat index (standard deviation scores, 0.18; 95% CI, 0.03-0.33;<i>P</i> = .02) and liver fat fraction (standard deviation scores, 0.34; 95% CI, 0.20-0.48;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Fetal and infant weight change patterns were both associated with childhood body fat, but weight change patterns in infancy tended to have larger effects. Fetal growth restriction followed by infant growth acceleration was associated with increased visceral and liver fat.