tbuckley/cabot-search huggingface dataset:
TRTH-16. DUAL INHIBITION OF HISTONE DEACETYLATION AND PI3K PATHWAY RADIOSENSITIZES PEDIATRIC HIGH-GRADE GLIOMAS BY BLOCKING RADIATION INDUCED DNA DAMAGE RESPONSES
Authors: Sharmistha Pal, Xiaodong Yang, Whitney Fitts, Jing Ni, John Alberta, Jean Zhao, David Kozono, Sabine Mueller, Steven DuBois, Daphne Haas-Kogan
Journal: Neuro-Oncology (2017)

INTRODUCTION: We sought rational targeted agents that exhibit single agent activity and sensitize pediatric high-grade gliomas (pHGG) to radiation (RT). We investigated a novel dual inhibitor of class I and II histone deacetylases and class I PI3Ks in combination with RT. METHODS: pHGG cells including DIPGs were treated with CUDC-907 alone or in combination with radiation and effects on cell viability, cell cycle, apoptosis, DNA damage, DNA damage repair pathways were determined. Homologous recombination (HR) and non-homologous end joining (NHEJ) were assessed by functional repair assays and loss of formation/resolution of RAD51 (HR) and phospho-DNA-PKCs (NHEJ) foci, respectively. In vivo evaluation of CUDC-907 efficacy was performed using SF8628 (DIPG xenograft) cells implanted in mice brainstems and randomized to: (1) control, (2) RT (0.5 Gy x 6, M-W-F), (3) CUDC-907 (100 mg/kg, oral gavage, daily x 2 weeks), (4) CUDC907+concurrent RT. RESULTS: G1 cell cycle arrest, induction of apoptosis, and accumulation of double strand DNA breaks (DSB) as measured by g-H2AX contribute to CUDC-907-induced radiosensitization. CUDC-907 attenuates radiation-induced DNA damage responses and repressed DSB repair. Specifically, CUDC-907 impairs the key DSB repair pathways of HR and NHEJ through reduced expression of RAD51 and Ku proteins, respectively. CUDC-907-mediated down-regulation of DNA damage responses is partly transcriptional and is driven by RelB-p50-based NFkB complex and FOXM1, activators critical for expression of key DSB repair genes. Following irradiation, RelB-p50-FOXM1 recruitment on the promoters of RAD51 and KU70/80 is enhanced to induce DSB repair, and CUDC-907 reduces RelB-p50-FOXM1 binding at the promoters thus interfering with DSB repair. Radiosensitization by CUDC-907 is also observed in vivo in mice-bearing DIPG xenografts where CUDC907+RT combination treatment significantly prolongs survival compared to monotherapy (p<0.05 for combination vs CUDC-907, RT, or control). CONCLUSION: CUDC-907 impairs key DNA damage repair pathways, augments radiation-induced DNA damage, enhances apoptosis, and radiosensitizes pHGG.
Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling
Authors: Mattias K. Andersson, Maryam K. Afshari, Ywonne Andrén, Michael J. Wick, Göran Stenman
Journal: JNCI Journal of the National Cancer Institute (2017)

Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target.Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided.The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04).MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.
Association of a Surgical Task During Training With Team Skill Acquisition Among Surgical Residents
Authors: Jessica L. Sparks, Dustin L. Crouch, Kathryn Sobba, Douglas Evans, Jing Zhang, James E. Johnson, Ian Saunders, John Thomas, Sarah Bodin, Ashley Tonidandel, Jeff Carter, Carl Westcott, R. Shayn Martin, Amy Hildreth
Journal: JAMA Surgery (2017)

The human patient simulators that are currently used in multidisciplinary operating room team training scenarios cannot simulate surgical tasks because they lack a realistic surgical anatomy. Thus, they eliminate the surgeon's primary task in the operating room. The surgical trainee is presented with a significant barrier when he or she attempts to suspend disbelief and engage in the scenario.To develop and test a simulation-based operating room team training strategy that challenges the communication abilities and teamwork competencies of surgeons while they are engaged in realistic operative maneuvers.This pre-post educational intervention pilot study compared the gains in teamwork skills for midlevel surgical residents at Wake Forest Baptist Medical Center after they participated in a standardized multidisciplinary team training scenario with 3 possible levels of surgical realism: (1) SimMan (Laerdal) (control group, no surgical anatomy); (2) "synthetic anatomy for surgical tasks" mannequin (medium-fidelity anatomy), and (3) a patient simulated by a deceased donor (high-fidelity anatomy).Participation in the simulation scenario and the subsequent debriefing.Teamwork competency was assessed using several instruments with extensive validity evidence, including the Nontechnical Skills assessment, the Trauma Management Skills scoring system, the Crisis Resource Management checklist, and a self-efficacy survey instrument. Participant satisfaction was assessed with a Likert-scale questionnaire.Scenario participants included midlevel surgical residents, anesthesia providers, scrub nurses, and circulating nurses. Statistical models showed that surgical residents exposed to medium-fidelity simulation (synthetic anatomy for surgical tasks) team training scenarios demonstrated greater gains in teamwork skills compared with control groups (SimMan) (Nontechnical Skills video score: 95% CI, 1.06-16.41; Trauma Management Skills video score: 95% CI, 0.61-2.90) and equivalent gains in teamwork skills compared with high-fidelity simulations (deceased donor) (Nontechnical Skills video score: 95% CI, -8.51 to 6.71; Trauma Management Skills video score: 95% CI, -1.70 to 0.49).Including a surgical task in operating room team training significantly enhanced the acquisition of teamwork skills among midlevel surgical residents. Incorporating relatively inexpensive, medium-fidelity synthetic anatomy in human patient simulators was as effective as using high-fidelity anatomies from deceased donors for promoting teamwork skills in this learning group.
Oncolytic Reovirus Immune Priming: A Phase 1b Study of Reolysin with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Kevin R. Kelly, Kaijin Wu, Denice Tsao-Wei, Susan Groshen, Timothy Junius Triche, Ann Mohrbacher, Grace Chang, Donna Fernando, Imran N Siddiqi, Matt Coffey, George Gill, Amy Lee, Jennifer S. Carew, Steffan T. Nawrocki
Journal: Blood (2016)
Діагностична цінність допплерографічного дослідження при гепаторенальному синдромі
Authors: N.G. Virstyuk, N.O. Slyvka
Journal: GASTROENTEROLOGY (2017)

Актуальність. Цироз печінки алкогольної етіології часто ускладнюється гепаторенальним синдромом, при якому патофізіологічні зміни у нирках розглядаються у взаємозалежності з іншими органами, в тому числі з печінкою, проте існує досить обмежена кількість досліджень із одночасною оцінкою ниркового та печінкового кровотоку допплерівським методом залежно від стадії тяжкості у таких хворих. Мета дослідження. Визначити, порівняти зміни ультразвукових допплерівських параметрів печінкового та ниркового кровотоку у пацієнтів із алкогольним цирозом печінки залежно від стадії захворювання й оцінити взаємозв’язок цих показників із сурогатними маркерами функції нирок. Матеріали та методи. Всього обстежено 152 пацієнтів, які були розподілені на 3 групи відповідно до стадії захворювання: група 1 (n = 42), група 2 (n = 58), група 3 (n = 52). При допплерографії вивчали показники печінкового та ниркового кровотоку. Результати. Серед усіх допплерографічних показників суттєві відмінності за стадіями захворювання спостерігалися переважно для портального кровотоку, артеріальна ланка суттєвих відмінностей не зазнала. У пацієнтів групи 3 відзначалось суттєве зростання максимальної швидкості кровотоку у ворітній вені, збільшення конгестивного індексу та зменшення ворітно-селезінкового індексу, що може бути пояснено формуванням гіпокінетичного типу печінкової гемодинаміки. Показники ниркового кровотоку, за винятком максимальної швидкості у ниркових артеріях, показали суттєву різницю між стадіями захворювання. Ми спостерігали кореляцію між показниками портального кровотоку та показниками ниркового кровотоку залежно від стадії захворювання та віку пацієнтів. Висновки. Встановлено, що при прогресуванні алкогольного цирозу печінковий і нирковий кровотік зазнає паралельних змін, тому допплерографія ниркових артерій може бути рекомендована як складова частина комплексного спостереження таких пацієнтів, особливо при прогнозуванні короткострокової смертності та стратифікації тяжкості стану.
MICROBIC VIRULENCE AND HOST SUSCEPTIBILITY IN PARATYPHOID-ENTERITIDIS INFECTION OF WHITE MICE
Authors: Ida W. Pritchett
Journal: The Journal of Experimental Medicine (1927)

When 5 per cent of butter fat or cod liver oil is added to a bread and milk diet, in itself adequate to promote the breeding and rearing of a healthy stock of mice through a period of years, the resistance of these mice to per os infection with the paratyphoid mouse typhoid bacillus (B. pestis caviae), as compared to that of mice on the unmodified diet, is definitely increased. A similar effect may be obtained with a McCollum "complete" diet, even when the butter fat is omitted, and with a bread and milk diet in which the milk used has been rayed with a mercury vapor lamp. When an inactive fat like Crisco is added to the bread and milk diet, the results obtained are not very clear-cut. While seasonal fluctuations in resistance to mouse typhoid were not completely eliminated by the various modified diets, they were nevertheless reduced, the modified diets tending to stabilize the death rate at a point lower than that usually reached by the mice on the control diet.
Targeting <scp>PP</scp>2A and proteasome activity ameliorates features of allergic airway disease in mice
Authors: P. M. Nair, M. R. Starkey, T. J. Haw, G. Liu, J. C. Horvat, J. C. Morris, N. M. Verrills, A. R. Clark, A. J. Ammit, P. M. Hansbro
Journal: Allergy (2017)

Abstract Background Asthma is an allergic airway disease ( AAD ) caused by aberrant immune responses to allergens. Protein phosphatase‐2A ( PP 2A) is an abundant serine/threonine phosphatase with anti‐inflammatory activity. The ubiquitin proteasome system ( UPS ) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP 2A activity with fingolimod ( FTY 720) or 2‐amino‐4‐(4‐(heptyloxy) phenyl)‐2‐methylbutan‐1‐ol ( AAL (S) ), or inhibiting proteasome activity with bortezomib ( BORT ), could suppress experimental AAD . Methods Acute AAD was induced in C57 BL /6 mice by intraperitoneal sensitization with ovalbumin ( OVA ) in combination with intranasal (i.n) exposure to OVA . Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite ( HDM ) extract. Mice were treated with vehicle, FTY 720, AAL (S) , BORT or AAL (S) + BORT and hallmark features of AAD assessed. Results AAL (S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus‐secreting cell ( MSC ) numbers, type 2‐associated cytokines (interleukin ( IL )‐33, thymic stromal lymphopoietin, IL ‐5 and IL ‐13), serum immunoglobulin (Ig)E and airway hyper‐responsiveness ( AHR ). FTY 720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid ( BALF ) and tissue eosinophils and inflammation, IL ‐5, IL ‐13 and AHR . Combined treatment with AAL (S) + BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type 2 cytokines and AHR . AAL (S) , BORT and AAL (S) + BORT also reduced airway remodelling in chronic AAD . Conclusion These findings highlight the potential of combination therapies that enhance PP 2A and inhibit proteasome activity as novel therapeutic strategies for asthma.
TMOD-11. A NOVEL ANIMAL MODEL OF MEDULLOBLASTOMA METASTASIS
Authors: Chaomei Xiang, Valérie Baubet, Yingtao Bi, Logan Zhang, Sharmistha Pal, Donald O’Rourke, Maria Martinez-Lage, Ramana Davuluri, Nadia Dahmane
Journal: Neuro-Oncology (2017)
Cost-effectiveness Analysis Comparing Conventional, Hypofractionated, and Intraoperative Radiotherapy for Early-Stage Breast Cancer
Authors: Ashish A Deshmukh, Shervin M Shirvani, Lincy Lal, J Michael Swint, Scott B Cantor, Benjamin D Smith, Anna Likhacheva
Journal: JNCI Journal of the National Cancer Institute (2017)

Early-stage breast cancer is among the most prevalent and costly malignancies treated in the American health care system. Adjuvant radiotherapy after lumpectomy represents a substantial portion of breast cancer expenditures. The relative value of novel radiotherapeutic approaches such as intraoperative radiotherapy (IORT) and hypofractionated whole breast irradiation (HF-WBI) compared with conventionally fractionated whole breast irradiation (CF-WBI) is unknown. Therefore, we used prospectively collected outcomes from randomized clinical trials (RCTs) to compare the cost-effectiveness of these approaches.We constructed a decision-analytic model that followed women who were treated with lumpectomy for early-stage breast cancer. Recurrence, mortality, complication rates, and utilities (five-year radiation-associated quality of life scores), were extracted from RCTs. Costs were based on Medicare reimbursement rates. Cost-effectiveness from societal and health care sector perspectives was estimated considering two scenarios-the first assumes that radiation-associated disutility persists five years after treatment, and the second assumes that disutility discontinues. Lifetime outcomes were summarized using incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses evaluated the robustness of the results.HF-WBI dominated CF-WBI (ie, resulted in higher quality-adjusted life-years [QALYs] and lower cost) in all scenarios. HF-WBI also had a greater likelihood of cost-effectiveness compared with IORT; under a societal perspective that assumes that radiation-associated disutility persists, HF-WBI results in an ICER of $17 024 per QALY compared with IORT with a probability of cost-effectiveness of 80% at the $100 000 per QALY willingness-to-pay threshold. If radiation-associated disutility is assumed to discontinue, the ICER is lower ($11 461/QALY), resulting in an even higher (83%) probability of relative cost-effectiveness. The ICER was most sensitive to the probability of metastasis and treatment cost.For women with early-stage breast cancer requiring adjuvant radiotherapy, HF-WBI is cost-effective compared with CF-WBI and IORT.
DIPG-24. EPIGENETIC ANALYSIS OF FORMALIN-FIXED PARAFFIN-EMBEDDED PEDIATRIC GLIOMA TISSUE
Authors: Tina Huang, Andrea Piunti, Rintaro Hashizume, Elizabeth Bartom, Jin Qi, Tadanori Tomita, C. David James, Ali Shilatifard, Amanda Saratsis
Journal: Neuro-Oncology (2017)

BACKGROUND: Diffuse midline gliomas are uniquely characterized by missense mutations in Histone H3 isoforms H3.3 and H3.1, associated with distinct gene, protein and methylation profiles and poorer clinical outcomes. As a result, mutant H3 protein is of great interest as a potential driver of pediatric gliomagenesis. Importantly, mutant tumors harbor distinct patterns of post-translational modification (PTM) at key regulatory H3 amino acid residues affecting chromatin structure and function, and control of gene transcription. Chromatin immunoprecipitation sequencing (ChIP-Seq) is a powerful tool to evaluate genomic effects of histone PTMs. However, ChIP-Seq of diffuse midline glioma is limited due to the scarcity of fresh tumor tissue available for analysis, while primary tumor cell lines may not accurately reflect the tumor epigenome. METHODS: Our group recently developed a protocol that overcomes heavy DNA crosslinking and fragmentation characteristic of formalin-fixed, paraffin-embedded (FFPE) tissue to achieve successful chromatin extraction and sequencing. Using this approach, we performed the first successful extraction of chromatins from FFPE pediatric brain tumor tissue, observing genomic enrichment of H3K4me3 and H3K27ac via ChIP-Seq in a Juvenille Pilocytic Astrocytoma (JPA). We then applied this novel approach to rare diffuse midline glioma specimens. RESULTS: We applied our novel ChIP-Seq protocol to FFPE cell pellets from pediatric brainstem glioma (H3K27M) and supratentorial GBM (H3K27 wild-type) primary cell lines. Genomic enrichment of H3, H3K27ac and H3K27me3 is compared to corresponding fresh cells, FFPE mouse xenograft and subcutaneous tumor tissue derived from the same primary cell lines. ChIP-Seq of rare FFPE brainstem glioma specimens is now underway. CONCLUSIONS: Consistency of ChIP-Seq results from fresh and archival samples demonstrates the technical feasibility and biological relevance of FFPE tissue ChIP-Seq analysis. Our results suggest FFPE ChIP-Seq may serve as an alternative to fresh tumor analysis for elucidating genomic H3 deposition and tumor-specific patterns of H3 PTMs.
Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus
Authors: Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Magnus Ståhle, Justyna Leja-Jarblad, Gustav Ullenhag, Anna Dimberg, Raphael Moreno, Ramon Alemany, Angelica Loskog
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma. Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses. Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells. Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 23(19); 5846–57. ©2017 AACR.
TMOD-06. PRIMARY CELL LINES OF PEDIATRIC HIGH GRADE GLIOMAS (PHGGS) WITH HISTONE H3.3 MUTATIONS ARE MIMICKING INTER AND INTRA-TUMOR HETEROGENEITY
Authors: Anne-Florence Blandin, Aurélie Durand, Marie Litzler, Eric Guerin, Aurelien Tripp, Isabelle Lelong-Rebel, Monique Dontenwill, Izzie Jacques Namer, Dominique Guenot, Natacha Entz-Werle
Journal: Neuro-Oncology (2017)

Children diagnosed for pHGGs, comprising mostly tumors of the brain midline (brainstem and thalamic locations), are facing with a very dismal prognosis. Those brain cancers are bearing usually and in more than 80% of the cases the histone H3.3 mutations. Up to now, the only therapy improving transiently the outcome of those children is irradiation. Therefore, to develop new therapies’ approaches, we need preclinical models, which recapitulate at the best the extreme heterogeneity of these tumor subgroups even they are harboring the same driver mutations. Therefore, primary derived cell lines of pHGG bearing the H3.3 K27M mutation were developed and cultured in conditions, which are mimicking the different tumor environments and cell phenotypes of the original tumors. We cultured them in 2D (adherent on laminin) or 3D (neurospheres) conditions and in normoxic and hypoxic environments. The characterization was done by protein, genomic, metabolomic and clonogenic techniques, as well as drug and radiotherapy sensitivity. The paired in vivo models were also developed (PDX models). We focused on 4 tumors with concomitant ATRX and H3.3 K27M mutations, where the 4 conditions of culture were recapitulating the different parts of the original paired patient’s tumors and recreated the intra-tumor heterogeneity, as well as the intra-tumor heterogeneity. The 3D neurospheres were clearly bearing markers of stemness in normoxia and hypoxia, whereas 2D cultures are displaying an heterogeneous protein profile of differentiated cells. This genotypic and phenotypic heterogeneity was clearly impacting on each tumor response to new targeted therapies and to the standard radiotherapy. Such models are pivotal in the understanding of which combinations could be the most effective in all intra-tumor conditions to avoid treatment primary and secondary resistances and improve personalized therapy for those children.