tbuckley/cabot-search huggingface dataset:
From correlation to causality: the case of <i>Subdoligranulum</i>
Authors: Matthias Van Hul, Tiphaine Le Roy, Edi Prifti, Maria Carlota Dao, Adrien Paquot, Jean-Daniel Zucker, Nathalie M. Delzenne, Giulio G. Muccioli, Karine Clément, Patrice D. Cani
Journal: Gut Microbes (2020)

Gut microbes are considered as major factors contributing to human health. Nowadays, the vast majority of the data available in the literature are mostly exhibiting negative or positive correlations between specific bacteria and metabolic parameters. From these observations, putative detrimental or beneficial effects are then inferred. Akkermansia muciniphila is one of the unique examples for which the correlations with health benefits have been causally validated in vivo in rodents and humans.In this study, based on available metagenomic data in overweight/obese population and clinical variables that we obtained from two cohorts of individuals (n = 108) we identified several metagenomic species (MGS) strongly associated with A. muciniphila with one standing out: Subdoligranulum. By analyzing both qPCR and shotgun metagenomic data, we discovered that the abundance of Subdoligranulum was correlated positively with microbial richness and HDL-cholesterol levels and negatively correlated with fat mass, adipocyte diameter, insulin resistance, levels of leptin, insulin, CRP, and IL6 in humans.Therefore, to further explore whether these strong correlations could be translated into causation, we investigated the effects of the unique cultivated strain of Subdoligranulum (Subdoligranulum variabile DSM 15176 T) in obese and diabetic mice as a proof-of-concept. Strikingly, there were no significant difference in any of the hallmarks of obesity and diabetes measured (e.g., body weight gain, fat mass gain, glucose tolerance, liver weight, plasma lipids) at the end of the 8 weeks of treatment. Therefore, the absence of effect following the supplementation with S. variabile indicates that increasing the intestinal abundance of this bacterium is not translated into beneficial effects in mice.In conclusion, we demonstrated that despite the fact that numerous strong correlations exist between a given bacteria and health, proof-of-concept experiments are required to be further validated or not in vivo. Hence, an urgent need for causality studies is warranted to move from human observations to preclinical validations.
Remodeling cancer stemness by collagen/fibronectin <i>via</i> the AKT and CDC42 signaling pathway crosstalk in glioma
Authors: Chuanhong Zhong, Bei Tao, Fangli Tang, Xiaobo Yang, Tangming Peng, Jian You, Kaiguo Xia, Xiangguo Xia, Ligang Chen, Lilei Peng
Journal: Theranostics (2020)

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix.However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression.Methods: The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining.The correlations between collagen/fibronectin and glioma progression were then analyzed.A 3D collagen/fibronectin cultured system was established for tumor cells culture in vitro.Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma.We used in vitro Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins.A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor in vivo.Results: Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth.In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics.More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways via integrin αvβ3, eliciting sustained tumor growth and cancer relapse.Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability. Conclusion:We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways.Blockade of the upstream molecular integrin αvβ3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse.
Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function
Authors: Ning Kon, Michael Churchill, Huan Li, Siddhartha Mukherjee, James J. Manfredi, Wei Gu
Journal: Cancer Research (2020)

Abstract p53 is a short-lived protein with low basal levels under normal homeostasis conditions. However, upon DNA damage, levels of p53 dramatically increase for its activation. Although robust stabilization of p53 serves as a “trademark” for DNA damage responses, the requirement for such dramatic protein stabilization in tumor suppression has not been well addressed. Here we generated a mutant p53KQ mouse where all the C-terminal domain lysine residues were mutated to glutamines (K to Q mutations at K367, K369, K370, K378, K379, K383, and K384) to mimic constitutive acetylation of the p53 C-terminus. Because of p53 activation, p53KQ/KQ mice were perinatal lethal, yet this lethality was averted in p53KQ/− mice, which displayed normal postnatal development. Nevertheless, p53KQ/− mice died prematurely due to anemia and hematopoiesis failure. Further analyses indicated that expression of the acetylation-mimicking p53 mutant in vivo induces activation of p53 targets in various tissues without obviously increasing p53 levels. In the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model, expression of the acetylation-mimicking p53-mutant protein effectively suppressed K-Ras–induced PDAC development in the absence of robust p53 stabilization. Together, our results provide proof-of-principle evidence that p53-mediated transcriptional function and tumor suppression can be achieved independently of its robust stabilization and reveal an alternative approach to activate p53 function for therapeutic purposes. Significance: Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.
Abstract 399: End-stage Heart Failure Causes Severe Lung Fibrosis and Dysfunction
Authors: Xiaohong Liu, Huan Wang, Ruru Shang, Jin Zhang, Yingjie Chen
Journal: Circulation Research (2016)

Chronic heart failure (CHF) causes trouble breathing in patients. We recently demonstrated that systolic pressure overload by transverse aortic constriction (TAC) causes severe left ventricular (LV) failure that is associated with massive lung fibrosis and lung vascular remodeling, and right ventricular (RV) dysfunction in mice. Here, we further studied the effect of CHF on lung structure and function in mice, and the effect of CHF on lung fibrosis in patients. We demonstrated that chronic TAC resulted in decrease of LV ejection fraction, and increases LV weight, lung weight, and RV weight, as well as their ratios to bodyweight. Interestingly, the development of LV failure is associated with a significant lung dysfunction as evidenced by a ~2-fold increase of lung resistance and a ~50% dramatic decrease of lung compliance in vivo . Lung compliance was also significantly reduced ~50% in lung isolated from CHF mice, indicating the decrease of lung compliance is due to the structure change of lung. The reduced lung compliance in CHF mice is significantly correlated with the decrease of LV ejection fraction, the increase of lung weight, and RV hypertrophy, suggesting the reduced lung compliance might contribute to the development of RV hypertrophy and failure. Histochemical analyses further demonstrated that CHF causes massive lung vascular, perivascular and interstitial fibrosis, as well as increase of lung myofibroblast proliferation. By using the chimeric mice created by transplantation of Bone Marrow Derived Cells (BMDCs) from GFP mice into wild type mice, we demonstrated that BMDCs contribute to the increased lung myofibroblasts and lung fibrosis. However, BMDCs don’t differentiate into lung smooth muscles cells in CHF mice. Moreover, we demonstrated that inhibition of lung inflammation by a cytokine therapy protocol is effective in attenuating TAC-induced lung fibrosis. Finally, we demonstrated that end-stage CHF causes increase of lung fibrosis in patients, and the increased lung fibrosis is associated with RV hypertrophy and dysfunction in patients. Together, our study demonstrated that end-stage CHF causes lung fibrosis and lung dysfunction, and inhibition of inflammation is effective in attenuating heart failure induced lung fibrosis.
ETMR-21. META-ANALYSIS OF PINEAL REGION TUMOURS DEMONSTRATES MOLECULAR SUBGROUPS WITH DISTINCT CLINICO-PATHOLOGICAL FEATURES: A CONSENSUS STUDY
Authors: Bryan K Li, Anthony P Y Liu, Elke Pfaff, Brian Gudenas, Sivan Gershanov, Christelle Dufour, Christian Aichmüller, Martin Sill, Tong Lin, Arzu Onar-Thomas, Brent A Orr, Cynthia Hawkins, David W Ellison, Matija Snuderl, Annie Laquierre, Eugene Hwang, Sri Gururangan, Matthias A Karajannis, Giles W Robinson, Eric Bouffet, Alexandre Vasiljevic, Amar Gajjar, Stefan M Pfister, Paul A Northcott, David T W Jones, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract Pineoblastomas (PB) are rare, aggressive pineal gland tumours with poor global OS of 50–70% and only 15–49% OS for patients &amp;lt;4 years, despite intensive treatments. Recently, three independent groups (German Cancer Research Centre, Rare Brain Tumour Consortium/SickKids, St. Jude Children’s Research Hospital) collectively analyzed large tumour cohorts and revealed molecular sub-groups of PB. To harmonize and better characterize clinico-pathologic associations of these sub-groups, we undertook a meta-analysis of molecular and clinical data of the combined cohorts. Unsupervised consensus cluster analyses of global methylation data from 227 unique cases identified five robust molecular sub-groups of pineal region tumours: PB_miRNA_1, PB_miRNA_2, PB_MYC/FOXR2, and PB_RB, mainly comprised of pediatric WHO grade 4 PBs and PNETs; and a fifth group: named PPTID, comprised of mainly pineal parenchymal tumours of intermediate differentiation, a WHO grade 2–3 tumour common in adults. PB_miRNA_1 and PB_miRNA_2 tumours, primarily arising in children (median ages 7.7, 11.4y, respectively), were characterized by alterations of miRNA biogenesis genes DICER1, DROSHA, and DGCR8. PB_MYC/FOXR2 and PB_RB groups, arising in infants/toddlers (median ages 1.4, 2.0y, respectively), were distinguished by recurrent MYC gain/amplification and RB1 loss, respectively. The PPTID group affected mainly adults (median age 33y) and exhibited limited CNAs. Higher rates of metastasis were observed with PB_miRNA_1 (42%), PB_MYC/FOXR2 (38%), and PB_RB (75%) tumours, compared to PB_miRNA_2 (20%) and PPTID (25%). Results from ongoing integrative survival analyses of this large cohort will provide critical data for design of future clinical trials.
SWK-06. ANSWERING 900 VOICES: A NATIONAL NONPROFIT ORGANIZATION RESPONDS TO A NATIONWIDE COMMUNITY HEALTH NEEDS ASSESSMENT THAT ELUCIDATED KEY CHALLENGES FACED BY PEDIATRIC BRAIN TUMOR FAMILIES
Authors: Kathy Riley
Journal: Neuro-Oncology (2020)

Abstract The five-year relative survival rate for childhood primary brain and other central nervous system tumors is nearly 75 percent (Central Brain Tumor Registry of the United States, 2017). Nevertheless, childhood brain tumor survivors often suffer from lifelong side effects caused by their illness or treatments such as surgery, radiation and chemotherapy. To define the nature and extent of problems survivors and their families face, the Pediatric Brain Tumor Foundation (PBTF), the world’s largest nonprofit solely dedicated to children and teens with brain tumors, conducted a 2017 national community health needs assessment in collaboration with the Sol Price Center for Social Innovation at the University of Southern California. The assessment found that pediatric brain tumor patients and their families face key challenges in four general areas: 1) interpersonal and emotional support, 2) logistical and financial support, 3) information and medical education gathering, and 4) educational and vocational anxieties. In 2020, the PBTF’s response to the 900 assessment participants who represent the thousands living with the effects of this disease includes the launch of a national Peer to Peer Mentoring program to meet the ongoing challenges families face; the disbursement of emergency financial assistance to hundreds of families in the throes of treatment; and the distribution of a resource notebook for newly diagnosed families and a comprehensive guidebook for survivors and their families. The results of the needs assessment suggest additional clear, actionable areas for impact not only by the PBTF but by medical professionals, other nonprofit organizations and governmental agencies.
[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease
Authors: Carlos Juri, Vasko Kramer, Patrick J. Riss, Cristian Soza-Ried, Arlette Haeger, Rossana Pruzzo, Frank Rösch, Horacio Amaral, Pedro Chana-Cuevas
Journal: Clinical Nuclear Medicine (2020)

Introduction Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [ 18 F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [ 18 F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. Methods Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I–II), and 13 moderate-advanced PD patients (Hoehn-Yahr III–IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [ 18 F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings. Results [ 18 F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% ( P &lt; 0.001). The observed pattern of reduction was posterior putamen &gt; anterior putamen &gt; substantia nigra pars compacta &gt; caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations. Conclusions [ 18 F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.
RADT-09. TYPE AND TIMING OF SYSTEMIC THERAPY USE PREDICT SURVIVAL IN PATIENTS WITH BRAIN METASTASES TREATED WITH RADIATION THERAPY
Authors: Kevin Fan, Nafisha Lalani, Nathalie Levasseur, Andra Krauze, Lovedeep Gondara, Kaylie Willemsma, Alan Nichol
Journal: Neuro-Oncology (2020)

Abstract PURPOSE We aimed to investigate whether systemic therapy (ST) use around the time of brain radiotherapy (RT) predicts overall survival for patients with brain metastases (BM). We also aimed to validate the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) in a population-based cohort. METHODS We used provincial RT and pharmacy databases to retrospectively review all adult patients in British Columbia, Canada, who received a first course of RT for BMs between 2012 and 2016. We used a randomly selected subset with complete baseline data to develop a multivariate analysis (MVA)-based nomogram including ST use to predict survival after RT and to validate the DS-GPA. RESULTS In our 3095-patient cohort, the median overall survival (OS) of the 999 recipients of ST after RT was 5.0 months (CI 4.1-6.0) longer than the OS of the 2096 non-recipients of ST after RT (p&amp;lt; 0.0001): targeted therapy (HR 0.42, CI 0.37-0.48), hormone therapy (HR 0.45, CI 0.36-0.55) and cytotoxic chemotherapy (HR 0.71, CI 0.64-0.79). The OS of patients who discontinued ST after RT was 0.9 months (CI 0.3-1.4) shorter than the OS of those who did not receive ST before nor after RT (p&amp;lt; 0.0001). A MVA in the 200-patient subset demonstrated that the traditional baseline variables: cancer diagnosis, age, performance status, presence of extracranial disease, and number of BMs predicted survival, as did the novel variables: ST use before RT and ST use after RT. The MVA-based nomogram had a bootstrap-corrected Harrell’s Concordance Index of 0.70. In the 179 patients within this subset with DS-GPA-compatible diagnoses, the DS-GPA overestimated OS by 6.3 months (CI 5.3- 9.8) (p= 0.0006). CONCLUSIONS The type and timing of ST use around RT predict survival for patients with BMs. A novel baseline variable “ST planned after RT” should be prospectively collected to validate these findings in other cohorts.
Long-term Outcomes Following Multiply Recurrent Clostridioides difficile Infection and Fecal Microbiota Transplantation
Authors: Ghadeer K. Dawwas, Colleen M. Brensinger, Ravy K. Vajravelu, Qufei Wu, Colleen R. Kelly, Loren Laine, Gary D. Wu, James D. Lewis
Journal: Clinical Gastroenterology and Hepatology (2020)
EPCO-36. GENOMIC INSTABILITY AND TRANSCRIPTOMIC SIGNATURES UNDERLYING EPIGENETIC MENINGIOMA SUBGROUPS REVEALS MECHANISMS OF IMMUNE INFILTRATION AND THERAPEUTIC VULNERABILITIES
Authors: Abrar Choudhury, Stephen Magill, Briana Prager, Charlotte Eaton, Tai-Chung Lam, Jenny Kan-Suen Pu, Lai Fung Li, Gerald Leung, Harish N Vasudevan, Calixto-Hope G Lucas, Jason W Chan, Jake Wendt, Geno Guerra, Matthew S Susko, Steve Braunstein, Javier Villanueva-Meyer, Nancy Ann Oberheim Bush, Penny K Sneed, Mitchel Berger, Arie Perry, David Solomon, Michael W McDermott, Joseph Costello, Stephen Francis, Jeremy Rich, David Raleigh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningioma treatments are limited due to incomplete understanding of meningioma biology. To address this, we performed multiplatform molecular profiling on 565 meningiomas with comprehensive clinical data to define genomic drivers and identify therapeutic vulnerabilities. METHODS DNA methylation profiling was performed on meningiomas from UCSF (n=200, discovery) and Hong Kong University (n=365, validation). Median follow-up was 5.6 years, and there were 388/142/35 WHO grade I/II/III meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on UCSF meningiomas. Cell type deconvolution, metagenomics, CRISPR, and pharmacology were used for mechanistic and functional validation. RESULTS Unsupervised hierarchical clustering of differentially methylated DNA probes revealed that meningiomas were comprised of 3 epigenetic subgroups associated with good, intermediate, and poor outcomes, with representation from all WHO grades in each subgroup. Meningiomas from the subgroup with the best outcomes (52% WHO grade I) were distinguished by recurrent gain of Chr5. Meningiomas from the subgroup with intermediate outcomes (31% WHO grade II) were distinguished by genomic stability, enrichment of innate immune genes, and immune infiltration in the setting of endogenous retroviral gene re-expression, a mechanism of immune recruitment. The most aggressive subgroup of meningiomas (57% WHO grade III) was distinguished by genomic instability, including recurrent loss of Chr22q harboring NF2, and decreased immune infiltration. Consistently, NF2 suppression in primary meningioma cells derived from immunogenic meningiomas decreased expression of innate immune genes critical for immune recruitment, suggesting a novel immunostimulatory function of NF2. The most aggressive subgroup of meningiomas were further distinguished by activation of the mitogenic FOXM1 transcriptional program, and recurrent loss of Chr9p harboring CDKN2A/B, which rendered primary meningioma cells from this subgroup susceptible to CDK4/6 inhibitors. CONCLUSIONS Meningiomas are comprised of 3 epigenetic subgroups defined by genetic mechanisms driving immune infiltration in the tumor microenvironment and meningioma cell proliferation.
NCOG-46. A PILOT STUDY OF GERMLINE CODING MUTATIONS ASSOCIATED WITH IMPAIRED DEVELOPMENT AND ADAPTIVE BEHAVIOR IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED ON HEAD START 4
Authors: Blake Sells, Erica Bell, Jessica Fleming, Joseph McElroy, Amy Webb, Yue Zhao, Richard Graham, Yingshi Guo, Tom Liu, Cynthia Timmers, Girish Dhall, Stephen Sands, Jonathan Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2020)

Abstract Children with brain tumors often carry germline mutations that have long been known to contribute to tumorigenesis and treatment response. However, less is known about how germline mutations may impact developmental and behavioral outcomes for children with tumors of the central nervous system (CNS). As the molecular mechanisms governing cancerous and normal tissue expand, we hypothesize that particular germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this preliminary study, 10 children on the Head Start 4 trial diagnosed with medulloblastoma were assessed for baseline adaptive functioning using the Adaptive Behavior Assessment System Third Edition (ABAS-III) and germline whole-exome sequencing was performed. After filtering for high impact variants, Welch’s T-tests were used to identify mutations associated with lower ABAS-III General Adaptive Composite (GAC) scores, reflecting developmental and adaptive behavior delays compared with peers their age. We found 20 genes with alterations associated with lower scores with P-values less than 0.05, although none met FDR significance cutoffs. Genes found to be significant included LAMC1 (P=0.04) and KRTAP1-1 (P=0.045), which encode members of the laminin and keratin family and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (P=0.007). We suspect that follow-up studies with more patients will reveal alterations in cell-to-cell communication and signal transduction pathways, as these are common molecular perturbations in tumors that would likely impact regular CNS function. Future research with larger cohorts is essential to validate these findings and to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for a more comprehensive view of the spectrum of neurodevelopmental impairment and novel strategies to circumvent these impairments. Funding: Thrasher Research Fund (JF, AC). R01CA108633, RC2CA148190, U10CA180850(NCI), and OSUCCC (AC).