tbuckley/cabot-search huggingface dataset:
Detection and elimination of a novel non-toxigenic <i>Clostridioides difficile</i> strain from the microbiota of a mouse colony
Authors: Jeffrey R. Maslanka, Christopher H. Gu, Isma Zarin, Joshua E. Denny, Susan Broadaway, Bryton Fett, Lisa M. Mattei, Seth T. Walk, Michael C. Abt
Journal: Gut Microbes (2020)

Clostridioides difficile is an enteric bacterial pathogen that can a cause nosocomial infection leading to debilitating colitis. The development of a murine model of C. difficile infection has led to fundamental discoveries in disease pathogenesis and the host immune response to infection. Recently, C. difficile endogenously present in the microbiota of mice has been reported and was found to complicate interpretation of mouse studies. Here, we report a novel C. difficile strain, named NTCD-035, isolated from the microbiota of our mouse colony. The presence of NTCD-035 in mice prior to challenge with a highly pathogenic C. difficile strain (VPI10463) led to significantly reduced disease severity. Phylogenetic characterization derived from whole genome sequencing and PCR ribotyping identified the isolate as a novel clade 1, ribotype 035 strain that lacks the pathogenicity locus required to produce toxins. Deficiency in toxin production along with sporulation capacity and secondary bile acid sensitivity was confirmed using in vitro assays. Inoculation of germ-free mice with NTCD-035 did not cause morbidity despite the strain readily colonizing the large intestine. Implementation of a culture-based screening procedure enabled the identification of mice harboring C. difficile in their microbiota, the establishment of a C. difficile-free mouse colony, and a monitoring system to prevent future contamination. Taken together, these data provide a framework for screening mice for endogenously harbored C. difficile and support clinical findings that demonstrate the therapeutic potential of non-toxigenic strains in preventing C. difficile associated disease. Abbreviations: PaLoc - Pathogenicity locus, CFUs - Colony forming units, TcdA - toxin-A, TcdB - toxin-B, CdtA - binary toxin A, CdtB - binary toxin B, CdtR - binary toxin R, NTCD - non-toxigenic C. difficile.
TAMI-49. THE ALTERNATIVE SPLICING FACTOR MBNL1 INHIBITS GLIOBLASTOMA TUMOR INITIATION AND PROGRESSION BY REDUCING HYPOXIA-INDUCED STEMNESS
Authors: Dillon Voss, Anthony Sloan, Eli Bar, Eli Bar
Journal: Neuro-Oncology (2020)

Abstract Muscleblind-like-proteins (MBNL) belong to a family of tissue-specific RNA metabolism-regulators that control pre-messenger RNA-splicing (AS). Inactivation of MBNL causes an adult-to-fetal AS transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer, glioblastoma (GBM), maintains stem-like features (GSC) through hypoxia-induced responses. Accordingly, we hypothesized that the hypoxia-induced responses in GBM might also include MBNL-based AS to promote tumor progression. When cultured in hypoxia, GSCs rapidly export MBNL1 out of the nucleus resulting in significant inhibition of MBNL1 activity. Notably, the hypoxia-regulated inhibition of MBNL1 also resulted in evidence of adult-to-fetal alternative splicing transitions. Forced expression of a constitutively active isoform of MBNL1 inhibited GSC self-renewal and tumor initiation in orthotopic transplantation models. Using a tetracycline-inducible system, induced expression of MBNL1 in established orthotopic tumors dramatically inhibited tumor progression resulting in a significant prolongation of survival. This study reveals that MBNL1 plays an essential role in GBM stemness and tumor progression, whereby hypoxic responses within the tumor inhibit MBNL1 activity, promoting stem-like phenotypes and tumor growth. Reversing these effects on MBNL1 may, therefore, yield potent tumor-suppressor activities, uncovering new therapeutic opportunities to counter this devastating disease.
EPCO-38. PRIMARY CNS DIFFUSE LARGE B-CELL LYMPHOMA WITH CIC-REARRANGEMENT IDENTIFYING FROM PAN-CANCER PATIENTS EXCLUDING SARCOMAS
Authors: Linbo Cai, Changguo Shan, Weiping Hong, Hui Wang, Ruyu Ai, Chao Song, Huijuan Qin, Xing Zhang, Jiaxing Sun, Yuhang Ji, Xueyu Yang, Yong Ren
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND CIC-rearrangements most commonly occur in patients with Ewing-like sarcomas, an emerging class of round cell sarcomas. CIC sarcoma has considered being a new entity in CNS tumors by cIMPACT-NOW conform classification of tumors of soft tissue and bone. However, not all patients harbor CIC fusion are sarcoma cases. Herein, we firstly report a case of primary CNS diffuse large B-cell lymphoma (DLBCL) harboring CIC-rearrangement with a novel partner. METHODS CIC fusions were screened in the tumor tissue or peripheral blood from 3,961 cases with different types of cancer excluded patients with sarcomas. Comprehensive genomic profiling with a 539 cancer-related genes panel was administrated based on next generation sequencing (NGS) which is adept in finding novel fusion mutations. The pathology diagnosis of every case was confirmed via hematoxylin and eosin (H&amp;E) stained. RESULTS Among the whole 3,961 cases, 3 CIC-rearrangements were observed. One case has been reported yet, one was a patient with lung adenocarcinoma, the last one was a patient harboring POU2F2 (Exon5) -CIC (Exon 11) with CNS arisen tumor, primary DLBCL. Literature review revealed only CIC-LEUTX was reported not only in sarcomas, but also in anaplastic ganglioglioma and CNS embryonal tumors. The partners of CIC sarcomas included DUX4, NUTM1, NUTM2A, FOXO4 and LEUTX, and whether specific partner affected biology of CIC-rearrangement tumors. CONCLUSIONS CIC-rearrangement arises in another type of brain cancer besides glioma and embryonal tumor, primary CNS DLBCL. Observation of novel partner provides new basis for further study of biology function of them in CIC fusions. Our study also indicates the presence of a specific tumor type with distinct histopathology driven by CIC fusions can be classified via CIC molecular pathology.
THER-06. THERAPEUTIC EFFICACY OF RRV-MEDIATED PRODRUG ACTIVATOR GENE THERAPY IN CLINICAL TRIALS OF RECURRENT HIGH-GRADE GLIOMA AND IN MURINE ORTHOTOPIC MODELS OF INTRACEREBRAL GLIOMA AND INTRACEREBELLAR MEDULLOBLASTOMA
Authors: Angela Richardson, Sara Collins, Akihito Inagaki, Valerie Armstrong, David Robbins, Nagi Ayad, Harry Gruber, Douglas Jolly, Timothy Cloughesy, Noriyuki Kasahara
Journal: Neuro-Oncology (2020)

Abstract Toca 511, a clinical-stage tumor-selective retroviral replicating vector (RRV), encodes optimized yeast cytosine deaminase (CD), which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU) within infected cancer cells. In preclinical models of intracerebral glioblastoma, 5-FU generated locally by Toca 511 (RRV-CD) prodrug activator gene therapy has also been shown to kill immunosuppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long-term survival. Early-phase clinical trials of Toca 511 in recurrent high-grade glioma showed highly promising evidence of therapeutic benefit, leading to a Phase III trial completed in late 2019 (n=400 patients, randomized 1:1 vs. standard chemotherapy), which appeared to show negative results overall. However, additional analysis showed possible efficacy in prespecified subgroups, and further clinical investigation is being pursued. In preclinical studies, we have also evaluated RRV for use in medulloblastoma, the most common malignant tumor of the pediatric nervous system. Both established and primary human medulloblastoma cell lines supported efficient RRV replication in vitro, with spread to &amp;gt;90% of cells by day 10 post-inoculation, and RRV-CD-transduced medulloblastoma cells showed significant dose-dependent reduction of viability upon exposure to 5-FC, compared to controls. In an intracerebellar HDMB03 medulloblastoma model, RRV-CD-treated mice exhibited long-term survival while on sequential cycles of 5-FC prodrug, until prodrug treatment was stopped, after which 25% long-term survival was observed (median survival 110 days) as compared to controls (median survival 28 days, 100% lethality) (p=0.00007). These results support further evaluation of RRV-mediated prodrug activator gene therapy for pediatric brain tumors.
Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p
Authors: Jianxing Yin, Xin Ge, Zhumei Shi, Chen Yu, Chenfei Lu, Yutian Wei, Ailiang Zeng, Xiefeng Wang, Wei Yan, Junxia Zhang, Yongping You
Journal: Theranostics (2020)

Rationale: Glioma stem-like cells (GSCs) contribute to temozolomide (TMZ) resistance in gliomas, although the mechanisms have not been delineated. Methods:In vitro functional experiments (colony formation assay, flow cytometric analysis, TUNEL assay) were used to assess the ability of extracellular vesicles (EVs) from hypoxic GSCs to promote TMZ resistance in glioblastoma (GBM) cells. RNA sequencing and quantitative Reverse Transcription-PCR were employed to identify the functional miRNA in hypoxic EVs. Chromatin immunoprecipitation assays were performed to analyze the transcriptional regulation of miRNAs by HIF1α and STAT3. RIP and RNA pull-down assays were used to validate the hnRNPA2B1-mediated packaging of miRNA into EVs. The function of EV miR-30b-3p from hypoxic GSCs was verified by in vivo experiments and analysis of clinical samples. Results: Hypoxic GSC-derived EVs exerted a greater effect on GBM chemoresistance than those from normoxic GSCs. The miRNA profiling revealed that miR-30b-3p was significantly upregulated in the EVs from hypoxic GSCs. Further, HIF1α and STAT3 transcriptionally induced miR-30b-3p expression. RNA immunoprecipitation and RNA-pull down assays revealed that binding of miR-30b-3p with hnRNPA2B1 facilitated its transfer into EVs. EV-packaged miR-30b-3p (EV-miR-30b-3p) directly targeted RHOB, resulting in decreased apoptosis and increased proliferation in vitro and in vivo. Our results provided evidence that miR-30b-3p in CSF could be a potential biomarker predicting resistance to TMZ. Conclusion: Our findings indicated that targeting EV-miR-30b-3p could provide a potential treatment strategy for GBM.
42P Pleural effusion is a negative prognostic factor for immunotherapy in non small cell lung cancer (NSCLC): The PLUIE study
Authors: N. Epaillard, J.C. Benitez, T. Gorria, E. Fabre-Guillevin, M. Ruidavets, R. Reyes, D. Planchard, N. Reguart Aransay, B. Besse, L. Mezquita, E. Auclin
Journal: Annals of Oncology (2020)
DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Jovana Pavisic, Chankrit Sethi, Chris Jones, Stergios Zacharoulis, Andrea Califano
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of &amp;gt;100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.
RONC-08. SURVIVAL IMPACT OF POSTOPERATIVE RADIOTHERAPY TIMING IN PEDIATRIC AND YOUNG ADULT EPENDYMOMA
Authors: Sunny Shah, Chase Mallory, Kevin Gates, Muni Rubens, Ossama Maher, Toba Niazi, Ziad Khatib, Haley Appel, Rupesh Kotecha, Minesh Mehta, Matthew Hall
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Postoperative radiotherapy is commonly given for WHO Grade 2–3 intracranial ependymoma. Clinicians generally aim to begin radiotherapy ≤5 weeks following surgery, but the optimal timing remains uncertain. METHODS The National Cancer Database was queried for patients (age ≤39 years) with localized WHO Grade 2–3 intracranial ependymoma treated with surgery and postoperative radiotherapy. Multivariable logistic regression was used to identify factors associated with delayed postoperative radiotherapy, defined as starting &amp;gt;8 weeks after surgery. Overall survival (OS) curves were plotted based on radiotherapy timing (≤5 weeks, 5–8 weeks, and &amp;gt;8 weeks after surgery) and compared by log-rank test. Multivariate analysis (MVA) was used to identify factors associated with OS. RESULTS In the final analytic set of 1,043 patients, age ≥21 years (OR 2.07, 95% CI 1.56–2.74) and WHO Grade 2 tumors (OR 1.41, 95% CI 1.08–1.85) were significantly associated with delayed time to adjuvant radiotherapy. No difference in 3-year OS was observed in patients who initiated radiotherapy ≤5 weeks, 5–8 weeks, and &amp;gt;8 weeks after surgery (89.8% vs. 89.1% vs. 88.4%; p= 0.796). On MVA, anaplastic histology (HR 2.414, 95% CI 1.784–3.268, p&amp;lt;0.001) and subtotal resection (HR 2.398, 95% CI 1.519–3.788, p&amp;lt;0.001) were significantly associated with reduced OS. Timing of radiotherapy, total radiotherapy dose, age, insurance status, and other factors were not significant. CONCLUSION Delayed postoperative radiotherapy was not associated with inferior survival in patients with intracranial ependymoma, suggesting delayed radiotherapy initiation may be considered in patients requiring longer postoperative recovery or referral to an appropriate radiotherapy center.
RADT-02. CLINICAL OUTCOMES OF BREAST BRAIN METASTASES BY SUBTYPE FOLLOWING LINAC BASED STEREOTACTIC RADIATION
Authors: Chetna Thawani, Matthew Mills, Nicholas Figura, Siriporn Sarangkasiri, Iman Washington, Timothy Robinson, Roberto Diaz, Arnold Etame, Michael Vogelbaum, Hsiang-Hsuan Yu, Kamran Ahmed
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Management of breast cancer brain metastases has become an increasing concern due to improved systemic control. Failure patterns in the brain may vary by breast cancer subtype. OBJECTIVE In this study, we sought to distinguish our institutional clinical outcomes following stereotactic radiation by breast cancer subtype. METHODS A total of 180 breast cancer patients treated over 279 stereotactic sessions to 646 brain metastases were identified from our LINAC based stereotactic radiation institutional registry. Patients were treated between August 2004 and May 2019. Outcomes including distant brain metastases control (DC) as well as overall survival (OS) following stereotactic radiation were assessed from review of the clinical chart and radiologic examinations. RESULTS The median age of patients was 55 (range: 28-86 years). Subtypes in order of decreasing frequency were hormone receptor (HR)+ (n=64; 36%), HR+/HER2+ (n=47; 26%), triple negative (TN) (n=43; 24%), and HR-/HER2+ (n=26; 14%). TN patients had the shortest interval from systemic metastases to brain metastases diagnosis; HR-/HER2 + 16 months, HR+ 13.3 months, HR+/HER2 + 11 months, and TN 1.4 months (p=0.02). Median follow-up from brain metastases diagnosis was 21.2 months (range: 0.9-135.4 months). Twenty-four month Kaplan-Meier (KM) DC rates varied by subtype and were 49% (HR+/HER2+), 38% (HR+), 33% (HR-/HER2+) and 21% (TN) (p=0.0004), respectively. Similar differences were noted in OS with 24 month KM rates of 58% (HR+/HER2+), 51% (HR-/HER2+), 27% (HR+), and 14% (TN), p&amp;lt; 0.0001. A total of 26 patients (14%) were noted to undergo leptomeningeal disease (LMD) progression. No differences were noted by subtype and LMD progression (p=0.88). CONCLUSIONS In our institutional series of breast cancer brain metastases treated with stereotactic radiation, significant differences were noted in clinical outcomes by breast cancer subtype. HR+/HER2+ patients had the best DC and OS rates while outcomes were poorest for TN patients.
TAMI-51. IDENTIFYING NEW TUMOR MICROENVIRONMENT (TME) CONTEXTS OF VULNERABILITY IN GLIOBLASTOMA
Authors: Kieron White, Maxime Meylan, Antoine Bougoüin, Kate Connor, Manuela Salvucci, Franck Bielle, Jochen H M Prehn, Maite Verreault, Ahmed Idbaih, Catherine Sautès-Fridman, Wolf H Fridman, Annette Byrne
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor with 85% of patients dying within two years. New effective precision medicine therapies are urgently required, especially for isocitrate dehydrogenase wild-type (IDHwt) disease. Despite efforts to subtype patients based on molecular profiles, this approach has yet failed to direct treatment strategies. Further interrogation of the tumor microenvironment (TME) across molecular subtypes and identification of new TME specific subtypes may guide new directions for future therapies. Here, we analysed transcriptomic data from selected GLIOTRAIN(www.gliotrain.eu)(n=120) and TCGA(n=69) IDHwt patients. Firstly, the microenvironment cell population (MCP)-counter method (a gene-expression-based TME deconvolution tool) was validated for use in the brain tumor setting using quantitative multiplex immunohistochemistry. In this context, immune markers (CD20/CD3/CD68/CD8) were significantly correlated with MCP-counter scores. We are currently optimizing and validating a vessel-density and microglial RNA-signature to provide a more robust representation of brain TME. Next, using MCP-counter, the TME composition of IDHwt tumors was assessed within proneural (24%), classical (38%) and mesenchymal (38%) subtypes. We initially classified the GLIOTRAIN cohort into 3 novel clusters characterised by differences in TME composition and validated our findings in the TCGA cohort. A TME-high group (37%) is characterized by elevated presence of lymphocytes and myeloid cells, and presents a high level of immune checkpoint genes: PDCD1(PD1) and CTLA4. In addition, the presence of tertiary lymphoid structures (TLS) is a feature of TMEhigh/mesenchymal+ patients. This finding has been validated by IHC and RNA-signature. TME-med (38%) displayed heterogenous immune populations and the TME-low (25%) represented an ‘immune-desert’ group. There was no significant difference in OS based on these TME subtypes(p=0.50). We hypothesise that PD1/CTLA4 blockade might be an effective treatment strategy in TME-high patients. These hypotheses will be tested (in the adjuvant setting) using appropriate syngeneic disease models which incorporate surgical resection.
Is Myocardial Perfusion Imaging an Important Predictor of Mortality in Women: And if So, Is This Likely Cost Effective?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: William E. Boden
Journal: JACC. Cardiovascular imaging (2011)
Off-clamp Retroperitoneoscopic Tumour Evacuation for Sporadic Renal Angiomyolipomas with High RENAL Nephrometry Scores: A Novel Surgical Technique and Its Outcomes
Authors: Kai Dong, Mengjun Shen, Guanqun Ju, Sha Han, Zhijun Wang, Kaining Lu, Dongliang Xu
Journal: European Urology (2020)
NCOG-23. PATTERNS OF DISTRESS IN OLDER PATIENTS WITH GLIOBLASTOMA: A FOLLOW-UP TO A SINGLE INSTITUTION CROSS-SECTIONAL STUDY OF DISTRESS IN PRIMARY BRAIN TUMOR PATIENTS
Authors: Margaret Johnson, James Herndon, Eric Lipp, Mary Affronti, Annick Desjardins, Manisha Bhattacharya, Henry Friedman, David Ashley, Katherine Peters, Dina Randazzo
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We previously reported to SNO, high levels of psychosocial distress in adult patients with primary brain tumors (PBTs), particularly during the first 6 months following diagnosis. The purpose of this follow-up study was to identify patterns of distress among older (≥ 65 years) patients with glioblastoma (GBM) compared to their younger (ages 18-64) counterparts. METHODS In our initial cross-sectional study, we collected the National Comprehensive Cancer Network’s Distress Thermometer (NCCN-DT) and problem list from adult patients with PBTs (WHO grades I-IV) seen at our institution between December 2013 and February 2016. We performed subsequent analyses on a subset of patients with GBM. RESULTS We identified 343 patients with GBM from the original dataset, of which 23.0% (n= 78) were ≥ 65 years old. The proportion of patients ≥ 65 years old with elevated distress (i.e. DT ≥ 4) was greater than the proportion of younger patients reporting elevated distress (47.4% vs 30.6%; p= 0.0068). Elevated distress was significantly greater during the first 6 months post diagnosis for all ages (p= 0.008). In subgroup analyses, a decrease in distress beyond 6 months was seen in younger patients (45.7% vs 27.4%; p= 0.021), but not in older patients. In older patients, a greater number of problems were selected on the NCCN DT and problem list tool: emotional and physical concerns were reported more frequently compared to their younger counterparts. Older patients were more likely to report difficulty with “bathing” and “getting around” (p= 0.009, p&amp;lt; 0.001, respectively). There were no differences in older versus younger GBM patients with regard to housing, transportation, treatment decisions, depression, fatigue, or memory. CONCLUSIONS In contrast to their younger counterparts, older patients with GBM experienced elevated levels of distress and a greater absolute number of specific psychosocial problems, mostly related to emotional and physical concerns.