tbuckley/cabot-search huggingface dataset:
GENE-37. VESTIBULAR SCHWANNOMA IS COMPRISED OF NEURAL CREST AND IMMUNE SUBGROUPS
Authors: S John Liu, Harish Vasudevan, Melike Pekmezci, Abrar Choudhury, Brian Lien, Jonathan Breshears, Danielle Swaney, Stephen Magill, Ursula Lang, William Chen, Chetna Gopinath, Maria Castro, Javier Villanueva-Meyer, Steve Braunstein, Patricia Sneed, Daniel Lim, Arie Perry, Nevan Krogran, Mike McDermott, Mitchel Berger, Philip Theodosopoulos, David Raleigh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Vestibular schwannomas (VS) are tumors arising from cranial nerve Schwann cells and show variable outcomes after treatment, including oscillation in size for many years after radiosurgery. To understand the unique biology of VS, we performed multiplatform molecular profiling to develop a single cell atlas of VS and reveal that VS exists on a molecular axis defined by neural crest and immune genes. METHODS Sixty-six sporadic VS with available tissue for molecular profiling from 59 consecutive patients at a single institution were included. 850K DNA methylation arrays and RNA sequencing were used to profile both primary (76%) and recurrent (24%) tumors. Single nuclei RNA sequencing of 7 tumors and single cell RNA sequencing of 3 tumors and cell lines were used to define the cellular composition of VS and heterogeneous changes in molecular programs following irradiation. Molecular subtyping was performed by hierarchical clustering of differentially-methylated DNA probes and validated using transcriptomic data. Mechanistic experiments were performed using cultured human schwann cells and human vestibular schwannoma cells, confocal microscopy, CRISPR interference, proteomic mass spectrometry and lymphocyte migration assays. RESULTS Multiplatform genomic profiling and machine learning revealed that VS is comprised of two distinct molecular subtypes characterized by heterogeneous cell populations. Neural crest enriched VS express primary cilia and are associated with misactivation of the Hedgehog pathway. Consistently, we find that the Hedgehog pathway antagonist vismodegib blocks the growth of human Schwann cells. Irradiation epigenetically reprograms tumors and cell lines to reduce ciliary length, attenuate Hedgehog signaling, activate senescence pathways, and express cytokines and apolipoproteins that recruit lymphocytes and macrophages to immune enriched VS. CONCLUSIONS Our data reveal novel molecular subtypes of VS and establish a framework for understanding how irradiation modifies the epigenome and tumor microenvironment.
Frequent Impaired Overall Neurocognitive and Executive Function in Children Ages 1-12 Years of Age with Sickle Cell Anemia in Uganda
Authors: Amelia Boehme, Paul Bangirana, Annet Birabwa, Deogratias Munube, Ezekiel Mupere, Robert Opoka, Philip Kasirye, Philip LaRussa, Nancy S. Green, Richard Idro
Journal: Blood (2019)
The Impact of Identifying the Syndromic and Genetic Diagnoses on Hematopoietic Stem Cell Transplantation Outcome in Patients with Inherited Bone Marrow Failure Syndromes
Authors: Yeon Jung Lim, Omri Avraham Arbiv, Melanie Evelyn Kalbfleisch, Robert J Klaassen, Conrad Fernandez, Meera Rayar, MacGregor Steele, Jeffrey H. Lipton, Geoffrey Cuvelier, Yves D. Pastore, Mariana Silva, Josee Brossard, Bruno Michon, Sharon Abish, Roona Sinha, Mark J. Belletrutti, Vicky R. Breakey, Lawrence Jardine, Lisa Goodyear, Lillian Sung, Tal Schechter-Finkelstein, Bozana Zlateska, Michaela Cada, Yigal Dror
Journal: Blood (2019)
Alterations in Oral Microbiota in HIV Are Related to Decreased Pulmonary Function
Authors: Libing Yang, Daniel G. Dunlap, Shulin Qin, Adam Fitch, Kelvin Li, Carl D. Koch, Mehdi Nouraie, Rebecca DeSensi, Ken S. Ho, Jeremy J. Martinson, Barbara Methé, Alison Morris
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Mechanisms of HIV-associated chronic obstructive pulmonary disease (COPD) are poorly understood. The oral microbiome shapes the lung microbiome, and gut dysbiosis can affect lung diseases; however, relationships of the oral and gut microbiome to COPD in HIV have not been explored.Objectives: To examine alterations in the oral and gut microbiome associated with pulmonary disease in persons with HIV (PWH).Methods: Seventy-five PWH and 93 HIV-uninfected men from the MACS (Multicenter AIDS Cohort Study) performed pulmonary function testing. Sequencing of bacterial 16S ribosomal RNA in saliva and stool was performed. We used nonmetric multidimensional scaling, permutational multivariate ANOVA, and linear discriminant analysis to analyze communities by HIV and lung function.Measurements and Main Results: Oral microbiome composition differed by HIV and smoking status. Alterations of oral microbial communities were observed in PWH with abnormal lung function with increases in relative abundance of Veillonella, Streptococcus, and Lactobacillus. There were no significant associations between the oral microbiome and lung function in HIV-uninfected individuals. No associations with HIV status or lung function were seen with the gut microbiome.Conclusions: Alterations of oral microbiota in PWH were related to impaired pulmonary function and to systemic inflammation. These results suggest that the oral microbiome may serve as a biomarker of lung function in HIV and that its disruption may contribute to COPD pathogenesis.
First-in-Human Imaging of Multiple Myeloma Using Copper-64-Labeled Daratumumab: Preliminary Results
Authors: Amrita Y. Krishnan, Vikram Adhikarla, Ammar Chaudhry, Joycelynne Palmer, Erasmus K Poku, Van Eric Biglang-awa, Nicole Bowles, Nitya Nathwani, Michael Rosenzweig, Firoozeh Sahebi, Chatchada Karanes, Jennifer Simpson, James F Sanchez, David Yamauchi, Maria Parayno, Arnab Chowdhury, Enrico Caserta, Anna Wu, Stephen J Forman, David Colcher, Paul Yazaki, John E. Shively, Flavia Pichiorri
Journal: Blood (2019)
SCIDOT-38. DEVELOPMENT OF AN IMAGE-INFORMED MATHEMATICAL MODEL OF CONVECTION-ENHANCED DELIVERY OF NANOLIPOSOMES FOR INDIVIDUAL PATIENTS
Authors: Ryan Woodall, David Hormuth, Michael Abdelmalik, Chengyue Wu, Xinzeng Feng, William Phillips, Ande Bao, Thomas Hughes, Andrew Brenner, Thomas Yankeelov
Journal: Neuro-Oncology (2019)

Abstract 186-Rhenium nanoliposomes (RNL) are an experimental theranostic being investigated for the treatment of recurrent Glioblastoma. While traditional external beam therapy exposures healthy tissue to radiation, RNL has the potential to deliver extremely large doses (&gt; 2000 Gy) of localized radiation, minimally exposing surrounding tissue. RNL is delivered directly to the malignancy by convection-enhanced delivery (CED) via intracranial catheter. For this reason, accurate and precise delivery of RNL to the target region is an imperative. While models of CED for molecular agents exist, we know of no such models for CED of liposomal nanoparticles. To that end, we are developing a patient-specific advection-diffusion model of RNL delivery and distribution, informed by pre-delivery quantitative magnetic resonance imaging (MRI) parameters, and validated by intra-delivery single-photon emission computed tomography (SPECT). Apparent liposome diffusivity and interstitial hydraulic conductivity are spatially informed by diffusion weighted MRI, while the clearance of interstitial fluid is spatially informed by the T1 enhancement ratio after contrast agent delivery. The model output is compared to SPECT images at two time points, acquired mid-way through and immediately following the RNL infusion. At the time of submission, the model has been calibrated by patient-specific data to match the spatiotemporal distribution of RNL in four patients. After calibration, the concordance correlation coefficient between the model and SPECT measurements was 0.80 +/- 0.23 mid-way through the infusion volume, and 0.86 +/- 0.14 immediately post-infusion. The DICE coefficient between the modeled delivery volume and measured delivery volume was 0.86 +/- 0.10 mid-way through the infusion volume, and 0.81 +/- 0.14 immediately post-infusion (reported as mean +/- 95% confidence intervals). These results provide preliminary evidence that the model can capture the spatiotemporal distribution of RNL during and after delivery, and may enable physicians to better plan CED procedures for liposomal nanotherapeutics in the future.
Naevus count and <i>MC1R R</i> alleles contribute to melanoma risk
Authors: D.L. Duffy, K.J. Lee, K. Jagirdar, A. Pflugfelder, M.S. Stark, E.K. McMeniman, H.P. Soyer, R.A. Sturm
Journal: British Journal of Dermatology (2019)

Melanoma is the most dangerous form of skin cancer: around 15% of cases worldwide are fatal, but with early detection, survival rates are better than 95%. Having many large moles or having red hair increases a person's risk of developing melanoma; having certain versions of the MC1R gene, called R alleles, the main cause of red hair, also increases melanoma risk. This study, from Australia, aimed to find out if having both those risk factors increased melanoma risk more than the two risk levels simply added together. 611 people with melanoma and 656 who had never had melanoma donated a DNA sample, and researchers recorded the number of large moles, their skin and eye colour, and hair colour at age 21. The authors found that people with red hair and 20+ large moles were 10 times more likely to have melanoma than people with 0‐4 moles and dark brown hair. Looking specifically at the types of the MC1R gene that people carried, people with 20+ moles and MC1R R/R genotype were 25 times more likely to have melanoma than people with 0‐4 moles and MC1R wildtype/wildtype (consensus) genotype. While the R/R genotype, with or without the red hair phenotype, and a high mole count are both strong melanoma risk factors on their own, when combined they result in an extremely high‐risk profile for melanoma. The absolute lifetime risk to age 75 of getting melanoma in Australia is 23.3% for men and 19.3% for women who have 20+ moles and MC1R R/R genotype, compared to just 0.8% for men and 0.7% for women with 0‐4 moles and MC1R wildtype/wildtype genotype. This is higher than the risk threshold for screening in other cancers, so the authors suggest that people with many moles and red hair should be regularly checked for melanoma by a doctor, and that people with many moles but non‐red hair should also be checked to determine if they have an MC1R R/R genotype.
Somatic Mutations Improve Risk Classification By Cytogenetic Abnormalities in Patients with Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation
Authors: Fevzi F. Yalniz, Rima M. Saliba, Orhan K. Yucel, Guillermo Garcia-Manero, Jeremy Ramdial, Uday Popat, Stefan O. Ciurea, Partow Kebriaei, Amin M. Alousi, Gheath Alatrash, Qaiser Bashir, Chitra Hosing, David Marin, Rohtesh Mehta, Amanda L. Olson, Katayoun Rezvani, Elizabeth J. Shpall, Gabriela Rondon, Richard E. Champlin, Betul Oran
Journal: Blood (2019)
Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Authors: Molly Gale, Yao Li, Jian Cao, Zongzhi Z. Liu, Marissa A. Holmbeck, Meiling Zhang, Sabine M. Lang, Lizhen Wu, Mariana Do Carmo, Swati Gupta, Keisuke Aoshima, Michael P. DiGiovanna, David F. Stern, David L. Rimm, Gerald S. Shadel, Xiang Chen, Qin Yan
Journal: Cancer Research (2019)

Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors in vivo. In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance. SIGNIFICANCE: These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.
A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma
Authors: Tae Min Kim, Nehal Lakhani, Justin Gainor, Manali Kamdar, Philip Fanning, Pierre Squifflet, Feng Jin, Hong Wan, Jaume Pons, Sophia S Randolph, Won Seog Kim
Journal: Blood (2019)
The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome
Authors: Namrata S Chandhok, Wei Wei, Ranjit Bindra, Stephanie Halene, Yu Shyr, Jing Li, Michael Berens, Chris Karlovich, S. Percy Ivy, Thomas Prebet
Journal: Blood (2019)
β-Catenin–TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
Authors: Petr Danek, Miroslava Kardosova, Lucie Janeckova, Elena Karkoulia, Karolina Vanickova, Matej Fabisik, Carlos Lozano-Asencio, Touati Benoukraf, Roberto Tirado-Magallanes, Qiling Zhou, Monika Burocziova, Sarka Rahmatova, Robert Pytlik, Tomas Brdicka, Daniel G. Tenen, Vladimir Korinek, Meritxell Alberich-Jorda
Journal: Blood (2020)
PATH-05. RAPID SIMULTANEOUS IDH MUTATION AND MGMT METHYLATION STATUS ASSESSMENT IN GLIOMA PATIENTS USING CRISPR-Cas9-TARGETED NANOPORE SEQUENCING
Authors: Thidathip Wongsurawat, Piroon Jejaroenpun, Annick DeLoose, David Ussery, Duah Alkam, J D Day, Intawat Nookaew, Analiz Rodriguez
Journal: Neuro-Oncology (2019)

Abstract Molecular classification of diffuse glioma enables more-precise diagnosis, prognosis, and treatment decisions. Currently, combination of two molecular markers, isocitrate dehydrogenase 1 and 2 (IDH1/ IDH2) gene mutation information and O6-Methylguanine-DNA-methyltranferase (MGMT) methylation status, are the main prognostic biomarkers of newly diagnosed diffuse gliomas. Furthermore, an accurate interpretation of MGMT-promoter methylation status is essential to determining which patients benefit from temozolomide (TMZ) therapy. The presence of an IDH mutation can be easily tested by PCR or next generation sequencing. However, there remains controversy with the identification of MGMT-promoter methylation status since there exists variable degrees of methylation and no clear consensus on cutoff values for “methylated” or “unmethylated” have been defined. To be best suited for routine clinical setting and research use, the optimal test should be reproducible, readily available, and timely. Therefore, we explored the feasibility of single-molecule nanopore third generation sequencing technology to comprehensively assess both mutation and methylation status simultaneously. This technology allows methylation detection directly from the native DNA sequence without requiring bisulfite treatment which reduces processing time. To specifically study IDH1, IDH2, and MGMT-promoter loci, we combined the CRISPR-Cas9 system to cut desired DNA fragments in a non–amplification dependent fashion. In addition, a data analysis pipeline was developed to quantitatively detect methylation. We applied our approach on human DNA controls, glioma cell lines and 4 patient brain tumor samples and were enabled to assess mutation and methylation status of targeted loci within 1.5 days. The promise of CRISPR-Cas9-targeted nanopore sequencing in accelerating and improving the molecular diagnostics of diffuse glioma will be illustrated in this meeting. These efforts are in line with improving precision medicine and can be applied to all cancer types.
RDNA-05. RADIOTHERAPY PROMOTES ONCOPROGRESSIVE CROSSTALK BETWEEN GLIOBLASTOMA TUMOR CELLS AND M2 MACROPHAGES VIA THE NLRP3 INFLAMMASOME PATHWAY
Authors: Shejuan An, Michael K Rooney, Jason Miska, Catalina Lee Chang, Peng Zhang, Yu Han, Aurora Lopez-Rosas, Maciej S Lesniak, Sean Sachdev
Journal: Neuro-Oncology (2019)

Abstract PURPOSE Radiotherapy (RT) is an essential component in the adjuvant treatment of glioblastoma (GBM); however, despite an initial benefit in tumor control, recurrence is nearly universal. The inflammasome is a multimeric cytosolic complex that has been shown to be activated in immune cells following RT. We investigated the relationship of inflammasome activation and disease progression after RT in GBM. METHODS We performed survival analysis for patients with recurrent GBM using the TCGA dataset, stratifying according to expression of inflammasome pathway molecules Caspase 1 (CASP1), IL-1β, and NLRP3. IL-1β expression and colocalization with CD11b+ myeloid cells were analyzed at different time points following RT in a murine glioma GL261 model. We detected the secreted IL-1β, CASP1 activity, and NLRP3 expression in both tumor and infiltrating immune cells, and the downstream effects of their interplay, including cellular apoptosis, proliferation, and viability. RESULTS High expression of CASP1, IL-1β, and NLRP3 are associated with poor survival in recurrent GBM. In a mouse model, recurrent tumors after treatment with RT display higher levels of the inflammasome effector molecule IL-1β, which colocalizes with infiltrating CD11b+ myeloid cells. Using a co-culture system of tumor cell and M2 macrophages, we found that RT enhances inflammasome activation in both cell types, and this interaction restores the proliferative capacity of surviving tumor cells following treatment. RT induces the inflammasome pathway activation in the setting of an associated immune microenvironment rich in tumor-associated macrophages and myeloid-derived suppressor cells (TAM/MDSCs) and not in tumor cells alone. CONCLUSIONS Inhibition of the oncoprogressive crosstalk between GBM tumor cells and M2 macrophages, possibly through disruption of the inflammasome pathway, might be a potential therapeutic strategy with RT.
ACTR-64. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/mTOR INHIBITOR GDC-0084 IN GBM PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE (MGMT) PROMOTER STATUS
Authors: Patrick Wen, John DeGroot, James Battiste, Samuel Goldlust, James Garner, Jeremy Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). GDC-0084 crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. GDC-0084 was given as once daily dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established PI3K/mTOR inhibitor class-effects. The MTD identified was 45mg once daily. METHODS The current study is conducted in the newly diagnosed GBM patient with unmethylated MGMT promotor status upon completion of standard adjuvant XRT/TMZ. It has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability, MTD (Part 1, followed by an expansion cohort (Part 2) commencing once MTD is established. Dose-escalation started at 60mg, and progressed in 15mg increments, per standard 3 + 3 rules. Part 2 recruits 20 patients, who are randomized to take GDC-0084 at the identified MTD, in fed and fasted states. RESULTS Part 1 of the study is complete. There were no DLTs among 3 pts treated at the 60mg. Among 6 pts treated at 75mg, DLTs were identified as hyperglycaemia (symptomatic) and oral mucositis. Adverse effects seen were generally modest, manageable and consistent with the PI3K-class. PK parameters are in line with phase 1 data. Part 2 recruitment is ongoing. CONCLUSION GDC-0084 displays a safety profile consistent with previous data in recurrent high-grade glioma but appears better tolerated in the newly diagnosed GBM setting. An MTD of 60mg is identified.
The U.S. Insulin Crisis — Rationing a Lifesaving Medication Discovered in the 1920s
Authors: Michael Fralick, Aaron S. Kesselheim
Journal: New England Journal of Medicine (2019)

Interview with Dr. Michael Fralick on contributors — and proposed solutions — to high insulin prices in the United States. (07:41)Download The members of the team that discovered insulin sold the patent to the University of Toronto for $1 each because they felt that the drug belonged to the public. Nearly 100 years later, insulin is inaccessible to thousands of Americans because of its high cost.
Financial Incentives to Increase Stool Collection Rates for Microbiome Studies in Adult Bone Marrow Transplant Patients
Authors: Jillian C. Thompson, Yi Ren, Kristi M. Romero, Meagan V. Lew, Amy T. Bush, Julia A. Messina, Sin-Ho Jung, Julie M. Miller, Zachary Zenko, Robert R. Jenq, Jonathan U. Peled, Marcel R.M. van den Brink, Nelson J. Chao, Anthony D. Sung
Journal: Blood (2019)
Feature-Tracking Global Longitudinal Strain Predicts Mortality in Patients With Preserved Ejection Fraction
Authors: Simone Romano, Robert M. Judd, Raymond J. Kim, John F. Heitner, Dipan J. Shah, Chetan Shenoy, Kaleigh Evans, Benjamin Romer, Pablo Salazar, Afshin Farzaneh-Far
Journal: JACC. Cardiovascular imaging (2019)
Should Psychiatrists Tell?
Authors: S. J. G. Spencer
Journal: BMJ (1964)

SIR,-Mr. A. Staveley Gough (Supple- ment, 25 July, p. 50) states that "the vast majority of consultants accepted it " (i.e., the present position).What is his evidence for this, I wonder ?It may well have been true 16 years ago, but I doubt whether this is the true consensus to-day.The fact that the C.C. and S. Committee accepts the position is not relevant ; its members are there by reason of their many other abilities and dedication, but not because they do or do not support the present system (under which we are not allowed to know how many of them-if any-are themselves holders of such awards).I would like to see the B.M.A. undertake a ballot of the 6,900 consultants