tbuckley/cabot-search huggingface dataset:
EXTH-31. INCREASING TUMOR TREATING FIELDS (TTFIELDS) EFFICACY BY TARGETING THE G2 CELL CYCLE CHECKPOINT WITH WEE1 OR CHK1 INHIBITORS IN GLIOBLASTOMA CELL LINES
Authors: Paul L G Slangen, Mark C de Gooijer, Mariska van Geldorp, Olaf van Tellingen, Gerben R Borst
Journal: Neuro-Oncology (2020)

Abstract Tumor Treating Fields (TTFields) are a novel, noninvasive FDA-approved treatment modality for glioblastoma (GBM) that utilizes alternating electric fields. While the mechanism of action was at first exclusively attributed to the effects of TTFields on cells during mitosis, additional effects during interphase have recently come to light. The aim of our research is to elucidate the effect of TTFields on the cell cycle to advance the understanding of TTFields and to find novel targets for increasing its efficacy. We studied the effect of TTFields on cell cycle distribution by (propidium iodide and phospho-Histone H3 labeling) flow cytometry using double-thymidine block (DTB) synchronized cell populations. Following the release of the DTB, TTFields treatment caused GBM cells to accumulate in G2, which was prevented by concomitant exposure to a Wee1 inhibitor. Next, we compared the efficacy of TTFields with or without Wee1 or Chk1 inhibitors in multiple GBM cell lines (A172, SNB-19, and U251) by colony formation assays and observed a strong and synergistic decrease in colony formation potential in all cell lines. To investigate the underlying mechanism of G2 arrest, we quantified the amount of DNA damage, but found no difference in either γH2AX foci or comet tail moments between control and TTFields treated cells. To follow up on this surprising observation, we are using live cell imaging (inovitro Live™) of PIP-FUCCI-transduced cells. This tool will allow us to track individual cells, to evaluate the time spent in each phase of the cell cycle and to determine the ultimate cell fate in control and treatment conditions. Our finding that Wee1 or Chk1 inhibition dramatically boosts the efficacy of TTFields may have great implications for treatment of patients with TTFields. The in vivo validation of our in vitro findings will be performed in tumor-bearing mice by using the inovivo™ system.
RTID-04. A RANDOMIZED PHASE II TRIAL TO COMPARE THE EFFICACY OF STANDARD VERSUS COMBINATION THERAPY (PERAMPANEL, MEMANTINE PLUS STANDARD) IN THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM-A STUDY DESIGN
Authors: Xiao-Tang Kong, Bruce Albala, Senxi Du, Xiao-Tang Kong, Daniela Bota
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated neurogliomal synaptic communication through AMPA and NMDA receptors promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential enhancing strategy to prevent and to treat GBM progression given the two blockers act through different anti-glioma mechanisms. OBJECTIVE/HYPOTHESIS We hypothesize that adding AMPA blocker Perampanel (An anti-seizure medication) and NMDA blocker Memantine (An anti-dementia medication) to standard temozolomide plus radiation therapy (Stupp’s regimen) for the treatment of newly diagnosed GBM may prevent tumor progression. It may also reduce the frequency of onset/recurrence of seizure episodes and possibly improve radiation related cognition impairment. STUDY DESIGN This is a randomized, active controlled, open label, two arm phase II study of efficacy of treatment of GBM with combination therapy (dual AMPA and NMDA receptor blockers plus standard therapy) versus standard therapy. In the combination therapy arm, patients take Perampanel 2 mg daily and Memantine 5 mg bid, starting from -14 days to +14 days from initiation of concurrent chemo-radiation therapy. Titrating up at a 2 mg increment for Perampanel and 5 mg bid increment for Memantine until reaching MTD. If the patient has AE &amp;gt;= grade 2, then reduce doses at a decrement of 2 mg for Perampanel and decrement of 5 mg bid for Memantine. In the standard therapy arm, the patients are treated with Stupp’s regimen. PRIMARY AND SECONDARY ENDPOINTS PFS, 12, 24 month survival rates and response duration. Safety will be assessed by CTCAE V5. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.
Современные возможности колонопротекции у пациентов с синдромом раздраженного кишечника
Authors: D.T. Janelidze
Journal: GASTROENTEROLOGY (2020)

Поиск литературы проводился по базам данных Scopus и MedLine. Функциональные заболевания кишечника рассматривают как спектр кишечных симптомов, которые образуют 6 вариантов: синдром раздраженного кишечника (СРК), функциональный запор, функциональная диарея, функциональное вздутие/растяжение, неспецифическое функциональное кишечное расстройство и опиоидиндуцированный запор. На сегодняшний день причины возникновения симптомов СРК полностью не установлены. Отсутствие четкого понимания патогенетических механизмов развития того или иного функционального заболевания кишечника, в том числе СРК, с учетом наличия разнообразных структурно-морфологических нарушений в стенке кишки диктует необходимость поиска новых препаратов, действие которых будет направлено на разные звенья патогенеза кишечных заболеваний. В состав нового оригинального колонопротектора Колонзак входят следующие ингредиенты: кальция бутират — эквивалентно 250 мг масляной кислоты, фруктоолигосахариды (инулин) — 100 мг и 2,7 млрд штаммов бифидобактерий (B.bifidum &amp; B.lactis). Благодаря эффектам инулина, масляной кислоты и бифидобактерий Колонзак является колонопротектором, который восстанавливает энергетический потенциал колоноцитов, нормализует слизеобразование и функцию бокаловидных клеток, снижает проницаемость слизистой оболочки, оказывает канцеропревентивное действие в отношении нормальных колоноцитов и тормозит рост и репликацию опухолевых клеток кишечника. Также, будучи пре- и пробиотиком, препарат создает условия для роста и нормализации кишечной микро­флоры, изменения которой разной степени выраженности встречаются как при воспалительных, так и при функциональных заболеваниях кишечника. Применение препаратов, содержащих масляную кислоту и неферментируемые пищевые волокна, — перспективное направление в профилактике рака толстой кишки. Необходимо провести дальнейшие исследования в упомянутом направлении, которые позволят оптимизировать дозу и продолжительность лечения препаратом Колонзак, а также определить группы пациентов, наиболее чувствительных к лечению мультикомпонентными колонопротекторами.
COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience
Authors: Adrian M. Shields, Siobhan O. Burns, Sinisa Savic, Alex G. Richter, Ariharan Anantharachagan, Gururaj Arumugakani, Kenneth Baker, Sameer Bahal, William Bermingham, Malini Bhole, Evon Boules, Philip Bright, Siobhan Burns, Betsy Cleave, John Dempster, Lisa Devlin, Fatima Dhalla, Elizabeth Drewe, Christopher Duncan, Magdalena Dziadzio, Shuayb Elkhalifa, Andrew Gennery, Sarah Goddard, Sofia Grigoriadou, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Rashmi Jain, Stephen Jolles, Sarah Johnston, Lucy Leeman, Shanti Mahabir, Dylan MacLochlainn, Elizabeth McDermott, Siraj Misbah, Hadeil Morsi, Sai Murng, Sadia Noorani, Rachael O’Brien, Smita Patel, Arthur Price, Alex Richter, Sinisa Savic, Suranjith Seneviratne, Adrian Shields, Anna Shrimpton, Catherine Stroud, Prashantha Vaitla, Nisha Verma
Journal: Journal of Allergy and Clinical Immunology (2020)
IgA dominates the early neutralizing antibody response to SARS-CoV-2
Authors: Delphine Sterlin, Alexis Mathian, Makoto Miyara, Audrey Mohr, François Anna, Laetitia Claër, Paul Quentric, Jehane Fadlallah, Hervé Devilliers, Pascale Ghillani, Cary Gunn, Rick Hockett, Sasi Mudumba, Amélie Guihot, Charles-Edouard Luyt, Julien Mayaux, Alexandra Beurton, Salma Fourati, Timothée Bruel, Olivier Schwartz, Jean-Marc Lacorte, Hans Yssel, Christophe Parizot, Karim Dorgham, Pierre Charneau, Zahir Amoura, Guy Gorochov
Journal: Science Translational Medicine (2020)

Early specific antibody responses against SARS-CoV-2 include IgG, IgM, and IgA, but IgA may neutralize virus and control infection to a larger extent.
Ring Sclerosis in Prostate Cancer
Authors: Charles Marcus, Yoram Baum, Olayinka A. Abiodun-Ojo, Ashesh B. Jani, David M. Schuster
Journal: Clinical Nuclear Medicine (2020)

Abstract Prostate cancer osteoblastic metastases may have different morphologies, and some of these may overlap with certain benign bone lesions. In this series of 5 prostate cancer patients, we describe bone lesions with central lucency and surrounding peripheral sclerosis and their varying appearances on different imaging modalities. Although prostate cancer metastases are commonly associated with sclerotic lesions, they can also present as osteolytic or lucent lesions, and these lesions should be carefully evaluated. The findings emphasize the importance of correlation with prior imaging, comparing findings on different imaging techniques and follow-up to differentiate benign disease from metastatic disease in these situations.
MBRS-43. ELUCIDATING HOW NOVEL EXTRACELLULAR MATRIX SUBTYPES DIFFERENTIALLY IMPACT THE SURVIVAL OF MEDULLOBLASTOMA SUBGROUPS
Authors: James Johnson, Franziska Linke, Catherine L R Merry, Beth Coyle
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common malignant paediatric brain tumour and frequently exhibits metastasis and chemoresistance. MBs are categorised into four molecular subgroups (WNT, Sonic hedgehog, Group 3 and Group 4), each associated with different demographics and clinical features. We have shown that the expression of specific extracellular matrix proteins in the brain tumour microenvironment differ between subgroups. A prime example is laminin (an ECM glycoprotein) the expression of which correlates with good overall survival in the SHH subgroup and poor overall survival in Group 4. Our aim is to determine the cause of this difference in survival. Candidate laminin-responsive-genes (LRGs) were identified using the Cavalli data set and RNA-Seq analysis of MB cells grown on 3D hydrogels with and without laminin. The role of laminin in the regulation of MMPs and the other LRG candidates was investigated by qRT-PCR, western blotting and zymography in 2D and long-term 3D-hydrogel assays. Thus far we have shown that in CHLA-01-R (metastatic Group 4 cell line) three of our LRGs are upregulated in response to laminin in 2D, as well as in preliminary 3D studies. Additionally, we have observed a unique MMP9 secretion profile of SHH cells grown in 3D compared to 2D, suggesting that our 3D assay allows us to observe relevant phenotypes absent in 2D culture. We are now in the process of identifying which of these LRG candidates are involved in metastasis and chemoresistance. This will enable the elucidation of novel therapeutic targets and crucially increase our understanding of MB-microenvironment interactions.
DDRE-26. TARGETING THE UNFOLDED PROTEIN RESPONSE POTENTIATES MARIZOMIB ANTITUMOR ACTIVITY IN GLIOBLASTOMA
Authors: Christophe Severin, Jorge Benitez-Hernandez, C Dan Dumitru, Nishdallyh Beltran-Raygoza, Pierre Flandin-Blety, Laure Escoubet, Mark Rolfe
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most prevalent and aggressive malignant tumor of the central nervous system in adults. Patients with GBM have a poor prognosis, with a median survival of 15 months with current standard-of-care treatment, consisting of surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Marizomib is an irreversible, pan-proteasome inhibitor that crosses the blood–brain barrier, currently under investigation in a phase 3 trial for newly diagnosed GBM. This preclinical study investigated the mechanism of action of marizomib in patient-derived GBM spheres and explored a series of combination treatments to further enhance its antitumor potency. Marizomib inhibited the 3 proteolytic subunits of the 20S proteasome in a dose-dependent manner, and this correlated with reduced cell proliferation compared with vehicle control (dimethyl sulfoxide). Marizomib induced transient expression of unfolded protein response (UPR) pathway genes, with a sustained upregulation of the SQSTMI gene. Combining marizomib with the histone deacetylase (HDAC) inhibitors panobinostat and vorinostat demonstrated cooperative upregulation of UPR genes and enhanced inhibition of cell proliferation. Furthermore, marizomib treatment upregulated survivin, an inhibitor of apoptosis protein (IAP). Compared with marizomib alone, addition of the IAP inhibitors AZD5582 and LCL161 increased marizomib antiproliferative activity in GBM spheres. In conclusion, these findings indicate that combining marizomib with HDAC or IAP inhibitors can enhance the overall antitumor activity of marizomib in patient-derived GBM spheres. Additional studies in preclinical models of GBM are needed to corroborate these findings.
Tobacco Product Use Among Middle and High School Students — United States, 2020
Authors: Andrea S. Gentzke, Teresa W. Wang, Ahmed Jamal, Eunice Park-Lee, Chunfeng Ren, Karen A. Cullen, Linda Neff
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Tobacco use is the leading cause of preventable disease and death in the United States; nearly all tobacco product use begins during youth and young adulthood (1,2).CDC and the Food and Drug Administration (FDA) analyzed data from the 2019 and 2020 National Youth Tobacco Surveys (NYTS) to determine changes in the current (past 30-day) use of seven tobacco products among U.S. middle (grades 6-8) and high (grades 9-12) school students.In 2020, current use of any tobacco product was reported by 16.2% (4.47 million) of all students, including 23.6% (3.65 million) of high school and 6.7% (800,000) of middle school students.Electronic cigarettes (e-cigarettes) were the most commonly used tobacco product among high school (19.6%; 3.02 million) and middle school (4.7%; 550,000) students.From 2019 to 2020, decreases in current use of any tobacco product, any combustible tobacco product, multiple tobacco products, e-cigarettes, cigars, and smokeless tobacco occurred among high school and middle school students; these declines resulted in an estimated 1.73 million fewer current youth tobacco product users in 2020 than in 2019 (6.20 million) (3).From 2019 to 2020, no significant change occurred in the use of cigarettes, hookahs, pipe tobacco, or heated tobacco products.The comprehensive and sustained implementation of evidence-based tobacco control strategies at the national, state, and local levels, combined with tobacco product regulation by FDA, is warranted to help sustain this progress and to prevent and reduce all forms of tobacco product use among U.S. youths (1,2).NYTS is a cross-sectional, voluntary, school-based, selfadministered electronic survey of U.S. middle and high school students.A stratified three-stage cluster sampling procedure generated a nationally representative sample of U.S. students attending public and private schools in grades 6-12.Participants complete the survey in classrooms using a tablet computer.*In * The survey was programmed using an application that did not require Internet access for use.Eligible students who were absent on the day of survey administration could participate in the NYTS using a web-based make-up survey.
MODL-26. CHILDREN’S BRAIN TUMOR NETWORK: ACCELERATING RESEARCH THROUGH COLLABORATION AND OPEN-SCIENCE
Authors: Jena Lilly, Jennifer Mason, Elizabeth Appert, Allison Heath, Yuankun Zhu, Bo Zhang, Mateusz Koptyra, Mariarita Santi, Ian Pollack, Stewart Goldman, Sarah Leary, Anna Buccoliero, Mirko Scagnet, David Haussler, Derek Hanson, Jiangguo Zhang, Weiqing Wan, Chunde Li, Ron Firestein, Jason Cain, Joanna Phillips, Nalin Gupta, Sabine Mueller, Gerald Grant, Michelle Monje-Deisseroth, Sonia Partap, Jeffrey Greenfield, Brian Rood, Javad Nazarian, Eric Raabe, Eric Jackson, Stacie Stapleton, Robert Lober, David Kram, Phillip Storm, Rishi Lulla, Michael Prados, Adam Resnick, Angela Waanders
Journal: Neuro-Oncology (2020)

Abstract The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.
Pathway‐extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors
Authors: Ashis J. Bagchee‐Clark, Eliseos J. Mucaki, Tyson Whitehead, Peter K. Rogan
Journal: MedComm (2020)

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi-gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology-based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway-extended SVMs predicted responses in patients at accuracies of 70% (imatinib), 71% (lapatinib), 83% (sunitinib), 83% (erlotinib), 88% (sorafenib) and 91% (gefitinib). These best performing pathway-extended models demonstrated improved balance predicting both sensitive and resistant patient categories, with many of these genes having a known role in cancer aetiology. Ensemble machine learning-based averaging of multiple pathway-extended models derived for an individual drug increased accuracy to >70% for erlotinib, gefitinib, lapatinib and sorafenib. Through incorporation of novel cancer biomarkers, machine learning-based pathway-extended signatures display strong efficacy predicting both sensitive and resistant patient responses to chemotherapy.
TAMI-03. IDENTIFICATION OF NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS THROUGH IN VIVO FUNCTIONAL GENOMICS
Authors: Nikoo Aghaei, Fred Lam, Chitra Venugopal, Sheila Singh
Journal: Neuro-Oncology (2020)

Abstract Brain metastasis, the most common tumor of the central nervous system, occurs in 20-36% of primary cancers. In particular, 40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases, with a dismal survival of approximately 4-11 weeks without treatment, and 16 months with treatment. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). Genomic interrogation of LBM using CRISPR technology can inform preventative therapies targeting genetic vulnerabilities in both primary and metastatic tumors. Loss-of-function studies present limitations in metastasis research, as knocking out genes essential for survival in the primary tumor cells can thwart the metastatic cascade prematurely. However, gene overexpression using CRISPR activation (CRISPRa) has the potential for overcoming dependencies of gene essentiality. We theorize that an in vivo genome-wide CRISPRa screen will identify novel genes that, when overexpressed, drive LBM. We have developed a patient-derived orthotopic murine xenograft model of LBM using primary patient-derived NSCLC cell lines (termed LTX cells) from the Swanton Lab TRACERx study. We are now poised to transduce LTX cells with a human genome-wide CRISPRa single guide RNA (sgRNA) library, and to subsequently inject the cells into the lungs of immunocompromised mice. We will then track the process of LBM using bioluminescent and MRI imaging until mice reach endpoint. Sequencing of primary lung tumors and subsequent brain metastases promises to uncover enriched sgRNAs, which may represent novel drivers of primary lung tumor formation and LBM. To the best of our knowledge, this study is the first in vivo genome-wide CRISPRa screen focused on identifying novel drivers of LBM, and can inform future preventative therapies to improve survival outcomes for NSCLC patients.
IMMU-28. INDUCTION OF TERTIARY LYMPHOID STRUCTURE-LIKE T-CELL CLUSTERS BY DELIVERY OF A NOVEL GENE COMBINATION INTO AN IMMUNOCOMPETENT MOUSE MODEL OF GLIOBLASTOMA
Authors: Kira Downey, Bindu Hegde, Zinal Chheda, Jason Zhang, Hideho Okada
Journal: Neuro-Oncology (2020)

Abstract The lack of conventional lymphatic drainage to and from the brain parenchyma restricts the capacity of the peripheral immune system to recognize and respond to glioma antigens. In some peripheral solid tumor types and central nervous system autoimmunity, the spontaneous development of tertiary lymphoid structures (TLS) with varying degrees of organization have been observed in human patients and mice following chronic inflammation. In the cancer setting, presence of TLS are generally associated with improved prognosis, especially when they are characterized by intratumoral infiltration of CD8+ T-cells. We aimed to induce the development of TLS in vivo, utilizing our SB28 glioblastoma model which is sparsely infiltrated by lymphocytes. As a proof-of-concept study, we stably transduced SB28 with a combination of several TLS-stimulating factors that we’ve identified and injected these cells into the brain parenchyma of syngeneic C57BL/6J mice. A combination of the chemoattractant and lymphoid follicle-stimulating cytokines LIGHT, CCL21, IL-7, and IL-17 produced substantial infiltration of CD8+CD3+ T-cells into the tumor and nearby parenchyma. However, this combination was also associated with accelerated tumor growth. A modified gene combination including LIGHT, CCL21, and IL-7 promoted CD8+CD3+ T-cell infiltration by flow cytometry, T-cell clustering by immunofluorescence analysis, and inhibited tumor burden compared with the control as measured by bioluminescent imaging. There was also evidence of increased lymphatic vasculature around the margins of T-cell clustering as demonstrated by LYVE-1 staining. Together, these analyses highlight a role for these factors in stimulating the recruitment and clustering of T-cell to the glioblastoma microenvironment in a TLS-like phenomenon. Future studies will evaluate whether the recruitment of other lymphocytes and stromal cells to these TLS-like clusters can promote T-cell memory and persistence. Ultimately, we aim to provide these factors utilizing a gene delivery method that will prove translatable to the clinic and complementary to existing T-cell therapies.