tbuckley/cabot-search huggingface dataset:
DRES-02. PARYLATION OF MGMT BY PARP IS REQUIRED FOR MGMT MEDIATED TEMOZOLOMIDE-INDUCED O6-METHYLGUANINE REPAIR: A NOVEL MECHANISM OF MGMT ACTION
Authors: Shaofang Wu, Feng Gao, Dimpy Koul, Alfred Yung
Journal: Neuro-Oncology (2019)

Abstract Temozolomide (TMZ) is the standard chemotherapy for malignant gliomas (MG), and resistance to this drug is mediated by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in about 40% patients is associated with loss of MGMT expression that compromises DNA repair leading to favorable response to TMZ therapy. Understanding the mechanism of MGMT mediated repair and modulating MGMT activity will enhance TMZ activity in MGMT unmethylated MG. Here we report a novel mode of regulation of MGMT protein activity by Poly-ADP-ribose polymerase (PARP). We found that PAPR physically interacts with MGMT and PARylates MGMT in response to TMZ treatment. We further showed PARylation of MGMT by PAPR is required for MGMT binding to DNA and to remove O6-methylguanine adducts in damaged DNA induced by TMZ. All 4 PARP inhibitors (trapping and non-trapping) tested (Talazoparib, Pamiparib, Veliparib, Olaparib) can inhibit PARP-MGMT binding, PARylation of MGMT, binding to DNA and subsequent removal of O6 - lesions in damaged DNA. We showed combination of PARP inhibitor with TMZ potentiated TMZ cytotoxicity in both MGMT methylated and unmethylated Glioma stem cell lines, but more profoundly in unmethylated group in vitro and in vivo. PARP inhibition acted as a double-edged sword in MGMT unmethylated MG: blocking BER/SSBR pathway to repair TMZ induced N7-MetG and O3-MetA, and more importantly, suppressing PARP-mediated PARylation of MGMT and thus silencing MGMT activity to repair O6-MetG, resulting in augmented cytotoxicity. This is the first study to show that PARylation of MGMT by PARP is required for repairing TMZ-induced O6-methylguanine adducts, and inhibition of MGMT PARylation abolishes MGMT function and renders sensitization to TMZ treatment. This finding provides a rationale for combining TMZ/CCNU and PARP inhibitors in MGMT unmethylated MG patients to enhance the benefit of adjuvant chemotherapy.
IMMU-30. UTILIZING A NOVEL MASS CYTOMETRY-BASED IMMUNOMONITORING PLATFORM FOR THE CHARACTERIZATION OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T-CELLS IN HLA-A*0201+ PATIENTS WITH K27M+ DIFFUSE MIDLINE GLIOMAS
Authors: Jared Taitt, Payal Watchmaker, Takahide Nejo, Neil Almeida, Kaori Okada, Maryam Shahin, Ryan Gilbert, Sabine Mueller, Hideho Okada
Journal: Neuro-Oncology (2019)

Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.
Curious case of gut dysmotility
Authors: Phey Shen Lee, Laura Jopson, Stephanie J Needham, Christopher G Mountford, Nick P Thompson
Journal: Gut (2019)

A previously fit 78-year-old man presented with a 2-month history of dysphagia, epigastric pain, bloating, intermittent vomiting and 1½ stone weight loss. There was no history of new medications or recent travel abroad. Oesophagogastroduodenoscopy (OGD) showed a ‘cup and spill’ stomach with mild gastritis. Oesophageal biopsies were normal. CT scan of abdomen/pelvis showed extensive small bowel dilatation to the caecum but no transition point (figure 1A). Exploratory laparotomy revealed dilated small bowel loops without mechanical obstruction. Initial duodenal biopsies showed non-specific flattened villi with thickening and eosinophilia of submucosal vessels. Autoimmune screen including tissue transglutaminase and anti-neuronal antibodies were negative. The patient had normal renal and cardiac function.



Figure 1 
(A) CT showing dilated, fluid-filled loops of small …
Isabella Mary Shirley
Authors: David Farman, Rowan Wallace
Journal: BMJ (2019)

Brought up in Troon, Ayrshire, Isabella Mary Shirley (“Diz”) had her first encounter with sarcoidosis (at that time unrecognised) during her clinical training in Glasgow, which led to her delayed graduation. Recurrence (and formal diagnosis) during postgraduate training at University College Hospital, London, dashed her hopes of a career in obstetrics. However, after a period as a local authority medical officer, Diz returned to …
RBTT-11. NRG ONCOLOGY NRG-BN006: A PHASE II/III RANDOMIZED, OPEN-LABEL STUDY OF TOCA 511 AND TOCA FC WITH STANDARD OF CARE COMPARED TO STANDARD OF CARE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Manmeet Ahluwalia, Stephanie Pugh, Benjamin Ellingson, Rupesh Kotecha, Timothy Cloughesy, Michael Vogelbaum, Kenneth Aldape, Yunfeng Cui, Terri Armstrong, Minesh Mehta
Journal: Neuro-Oncology (2019)

Abstract The standard of care (SOC) in newly diagnosed glioblastoma (nGBM) includes resection and chemoradiotherapy. With a median overall survival (OS) of only 16–18 months for well-selected patients in clinical trials, better therapeutic options are needed. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5- fluorocytosine,5-FC) into 5-fluorouracil. Preclinical evidence demonstrates that Toca 511 &amp; 5-FC kill cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to durable antitumor immune responses. Three phase (P) 1 studies in patients with recurrent high grade glioma have demonstrated tolerable safety profile and encouraging efficacy. NRG-BN006 is a randomized P2/3 trial of Toca 511 &amp; Toca FC with SOC versus SOC for patients with nGBM. Optune use is allowed on the SOC arm, but not on the experimental arm. Patients will be stratified by age and KPS score for 1:1 randomization. The primary endpoint is progression-free survival for P2 and OS for P3. The secondary endpoints include objective response rate in patients with measurable disease and safety. Key inclusion criteria include presumptive diagnosis of glioblastoma with anticipated 80% resection, unifocal tumor, and KPS≥70. Immune monitoring and molecular profiling will be performed. P2 has 90% power to detect a hazard ratio (HR)=0.67 in 250 nGBM patients. P3 has 85% power to detect a HR=0.75 in 720 nGBM patients. Since patients are enrolled prior to surgery and confirmatory diagnosis of GBM, approximately 900 patients will be enrolled, and two interim analyses are planned for OS. In addition, two interim safety analyses will be conducted for the experimental treatment, with the first 15 and 30 eligible and analyzable patients randomized to the experimental arm. NRG-BN006 is anticipated to start enrollment in Q4 2019. Supported by grants U10CA180868, U10CA180822 from NCI and Tocagen.
SP 和 NK1R: 治疗慢性瘙痒的新靶点
Authors: S. Ständer, G. Yosipovitch
Journal: British Journal of Dermatology (2019)

慢性瘙痒症(瘙痒)会严重影响生活质量;它可能与几种不同的皮肤病或全身性疾病(不仅影响皮肤,而且影响整个身体)有关。当前治疗方法并不总是能取得成功,对瘙痒机理的更全面理解应该可以得出更好的治疗方法。 神经纤维分泌的 P 物质在瘙痒中起重要作用。它与中枢神经系统和周围神经系统的几种细胞类型的受体神经激肽 1 结合。 来自德国的作者回顾了有关这些物质在慢性瘙痒中作用的已知信息。 他们发现,P 物质和神经激肽 1 受体在与瘙痒相关的几种疾病中过表达(产生过多)。 他们还回顾了拮抗神经激肽 1 受体结合的药物的临床研究。这些药物包括阿瑞匹坦,这是一种口服药物(经口服用),已用于治疗化疗引起的恶心和呕吐。 但是,专门为减轻瘙痒而开发的 serlopitant 和 tradipant 在某些疾病,如结节性瘙痒和特应性湿疹的安慰剂对照试验(意味着某些人服用药物,而另一些人服用一种模拟药或安慰剂,并比较其结果)中显示出更大的前景。 作者指出,需要进一步试验来评估这些药物在慢性瘙痒中的安全性和有效性。
Nonsteroidal Antiinflammatory Drugs as Potential Disease‐Modifying Medications in Axial Spondyloarthritis
Authors: Runsheng Wang, Joan M. Bathon, Michael M. Ward
Journal: Arthritis & Rheumatology (2019)

Nonsteroidal antiinflammatory drugs ( NSAID s) are the first‐line pharmacotherapy for patients with axial spondyloarthritis (SpA). In recent years, treatment options have expanded with the availability of biologic agents, including tumor necrosis factor inhibitors and interleukin‐17 inhibitors. However, a treatment strategy that clearly prevents syndesmophyte formation has not been established. Observational studies of patients with ankylosing spondylitis indicated potential disease‐modifying effects of NSAID s, but two randomized trials came to different conclusions. More broadly, whether any of the currently available medications for axial SpA have an effect on spine radiographic progression, beyond symptom control, remains inconclusive. In this article, we will review clinical studies of the disease modification effects of NSAID s and biologics in axial SpA; examine genetic, animal, and clinical evidence of the effects of NSAID s on bone formation; and discuss how future studies may investigate the question of disease modification in axial SpA.
PATH-11. THE PROGNOSTIC ROLE OF IDH MUTATIONS IN HOMOGENEOUSLY TREATED PATIENTS WITH MALIGNANT DIFFUSE ASTROCYTOMAS
Authors: Arne Christians, Rouzbeh Banan, Florian Stockhammer, Christian Hartmann
Journal: Neuro-Oncology (2019)

Abstract Detection of IDH mutations in patients with diffuse malignant astrocytomas resulted in substantial modifications in the WHO classification. An important observation was that patients with anaplastic astrocytomas (AA) IDH-wt had a clinical course similar to that glioblastoma (GBM) patients. The observations of the GGN and NOA-04, were based on mixed cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually only had radiotherapy or chemotherapy. This shortcoming raises the question whether AA IDH-wt patients did not behave prognostically better than GBM patients when receiving combined radiochemotherapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of IDH mutations are important if vascular proliferation or necrosis are undetectable. All patients investigated here with diagnosis of a malignant astrocytoma received combined standard radiochemotherapy independently of the histopathological diagnosis. Thus, the analysis allows to clarify whether patients with AA of IDH-wt have a prognosis similar to that of GBM patients under equivalent therapeutic conditions. We determined the IDH1/2 status by sequencing, the MGMT status by pyrosequencing. Patients with the histopathological diagnosis of an AA IDH-wt showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a glioblastoma (mOS 13 months). Instead, patients with an AA IDH-mut receiving same therapy had a mOS of 54 months. Thus, it can be concluded that in absence of IDH mutations, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and IDH mutations are examined, there is a difference between patients showing necrosis and/or vascular proliferation and those whose tumors do not. Accordingly, for patients with malignant astrocytomas with IDH mutations it can be concluded that differentiation between AA IDH-mut and GBM IDH-mut remains beneficial from a prognostic perspective.
The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin
Authors: Madlen Jentzsch, Marius Bill, Juliane Grimm, Dominic Brauer, Julia Schulz, Karoline Goldmann, Dietger Niederwieser, Uwe Platzbecker, Sebastian Schwind
Journal: Blood (2019)
Dendritic cells license regulatory B cells to produce IL-10 and mediate suppression of antigen-specific CD8 T cells
Authors: Joanne Boldison, Larissa Camargo Da Rosa, Joanne Davies, Li Wen, F. Susan Wong
Journal: Cellular and Molecular Immunology (2019)

Abstract Regulatory B cells (Bregs) suppress and reduce autoimmune pathology. However, given the variety of Breg subsets, the role of Bregs in the pathogenesis of type 1 diabetes is still unclear. Here, we dissect this fundamental mechanism. We show that natural protection from type 1 diabetes in nonobese diabetic (NOD) mice is associated with increased numbers of IL-10-producing B cells, while development of type 1 diabetes in NOD mice occurs in animals with compromised IL-10 production by B cells. However, B cells from diabetic mice regain IL-10 function if activated by the innate immune receptor TLR4 and can suppress insulin-specific CD8 T cells in a dendritic cell (DC)-dependent, IL-10-mediated fashion. Suppression of CD8 T cells is reliant on B-cell contact with DCs. This cell contact results in deactivation of DCs, inducing a tolerogenic state, which in turn can regulate pathogenic CD8 T cells. Our findings emphasize the importance of DC–Breg interactions during the development of type 1 diabetes.
An Autosomal Dominant SCID Form Due to a Gain of Function Mutation in the RAC2 Gene
Authors: Chantal Lagresle-Peyrou, Aurélien Olichon, Hanem Sadek, Philippe Roche, Claudine Tardy, Cindy Da Silva, Alexandrine Garrigue, Alain Fischer, Despina Moshous, Yves Collette, Capucine Picard, Jean-Laurent Casanova, Isabelle André, Marina Cavazzana
Journal: Blood (2019)
Impact of Renal Dysfunction Measured By Estimated Glomerular Filtration Rate (eGFR) on Outcomes after Allogeneic Hematopoietic Cell Transplantation (HCT)
Authors: Nosha Farhadfar, Ajoy L. Dias, Tao Wang, Caitrin Fretham, Hemant S. Murthy, Brent R. Logan, Shin Mineishi, Bipin N. Savani, Edward A. Stadtmauer, Saurabh Chhabra, John R. Wingard, Siddhartha Ganguly, Marcelo C. Pasquini
Journal: Blood (2019)
Leukaemia and Phenylbutazone
Authors: G. J. Thorpe
Journal: BMJ (1964)

BRiTisH 1707 suffering from a carbuncle on her back.She was afebrile.On Wednesday, 13 May, she developed a temperature of 100' F. (37.8'C.).She had no symptoms except that she " felt hot."The carbuncle was clearing.On Thursday, her temperature rose to 103' F. (39.5'C.).On this same day (14 May) her companion, who shared lodgings with her, developed a temperature, and on Friday, 15 May, was admitted to the Crombie Hall Sick Bay with a temperature of 104' F. (40' C.).On Friday night, 15 May, the second student developed mild diarrhoea.On Saturday the first patient had a mild epistaxis.Both students were admitted to the Nurses' Ward at the Royal Infirmary on the evening of Saturday, 16 May, and barrier-nursed.The first student developed diarrhoea after admis- sion to the Royal Infirmary.Blood and stool cultures were reported as "suspicious " on Tuesday, 18 May, and the patients were immediately transferred to the City Hospital and the M.O.H. notified.On Wednesday, 19 May, the blood and stool cultures were confirmed as positive Salnonella typhi H.
TMIC-55. CHARACTERIZATION OF TUMOR-MICROENVIRONMENT INTERACTIONS IN GLIOBLASTOMAS AT THE SINGLE-CELL LEVEL
Authors: Rohit Rao, Feng Zhang, Ravinder Verma, Jincheng Wang, Dazhuan Xin, Richard Lu
Journal: Neuro-Oncology (2019)

Abstract Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma will have different microenvironmental composition and exhibit distinct responses to therapies. To understand whether gliomas induced by different oncogenic drivers affect microenvironment composition, we induced mouse gliomas using a PDGFB and dnp53 driver to model proneural glioma and HRasV12 and dnp53 to model mesenchymal glioma, respectively. We performed single cell transcriptomic profiling to characterize the tumor microenvironment in these glioma models. We found that in the PDGFB/dnp53 glioma model had a large microglia contribution with about 30% tumor-associated microglia. In contrast, the HRasV12/dnp53 glioma model had only sparse microenvironmental cells. In addition, microglia in each model displayed subtype-specific gene expression programs, with microglia in the HRasV12/dnp53 tumor model expressing increased antigen presenting genes while increased levels of osteopontin in the PDGFB/dnp53 tumor model. To determine the tumor-microenvironment interactions, we performed receptor-ligand analysis using CellPhoneDb to identify secretory ligands that support tumor cell growth in microenvironmental cells. We found that tumor-associated pericytes are an important source of growth factor ligands in both PDGFB/dnp53 and HRasV12/dnp53 glioma models. We are investigating the contribution of microglia and pericytes to tumor growth and survival through cell depletion and pharmacological inhibition and determining whether the differences in tumor microglia between the models affects sensitivity to therapies including immunotherapy. Understanding how tumor-intrinsic signaling modulates microenvironment niches and tumor-microenvironment communications aids rational design of combinations targeting the malignant brain tumors.
Response Rates and Quality of Life Outcomes in Australasian Leukaemia &amp; Lymphoma Group NHL29: A Phase II Study of Ibrutinib, Rituximab and Mini-CHOP in Very Elderly Patients with Newly Diagnosed Diffuse Large B Cell Lymphoma
Authors: Emma Verner, Amanda Johnston, Nalini Pati, Eliza A Hawkes, Hui-Peng Lee, Tara Cochrane, Chan Y. Cheah, Duncan Purtill, Anoop K Enjeti, Christina Brown, Nicholas E. Murphy, Jennifer Curnow, Julia Carlson, Belinda Butcher, Judith Trotman
Journal: Blood (2019)
Sociodemographic Disparities in the Receipt of Adjuvant Chemotherapy Among Patients With Resected Stage I–III Pancreatic Adenocarcinoma
Authors: Nina N. Sanford, Todd A. Aguilera, Michael R. Folkert, Chul Ahn, Brandon A. Mahal, Herbert Zeh, Muhammad S. Beg, John Mansour, David J. Sher
Journal: Journal of the National Comprehensive Cancer Network (2019)

Adjuvant therapy for resected pancreatic adenocarcinoma was given a category 1 NCCN recommendation in 2000, yet many patients do not receive chemotherapy after definitive surgery. Whether sociodemographic disparities exist for receipt of adjuvant chemotherapy is poorly understood.The National Cancer Database was used to identify patients diagnosed with nonmetastatic pancreatic adenocarcinoma who underwent definitive surgery from 2004 through 2015. Multivariable logistic regression defined the adjusted odds ratio (aOR) and associated 95% CI of receipt of adjuvant chemotherapy. Among patients receiving chemotherapy, multivariable logistic regression assessed the odds of treatment with multiagent chemotherapy.Among 18,463 patients, 11,288 (61.1%) received any adjuvant chemotherapy. Sociodemographic factors inversely associated with receipt of any adjuvant chemotherapy included uninsured status (aOR, 0.61; 95% CI, 0.50-0.74), Medicaid insurance (aOR, 0.66; 95% CI, 0.57-0.77), and lower income (P<.001 for all income levels compared with ≥$46,000). Black race (aOR, 0.72; 95% CI, 0.57-0.90) and female sex (aOR, 0.75; 95% CI, 0.65-0.86) were associated with lower odds of receiving multiagent chemotherapy. There was a statistically significant interaction term between black race and age/comorbidity status (P=.03), such that 26.4% of black versus 35.8% of nonblack young (aged ≤65 years) and healthy (Charlson-Deyo comorbidity score 0) patients received multiagent adjuvant chemotherapy (P=.006), whereas multiagent adjuvant chemotherapy rates were similar among patients who were not young and healthy (P=.15).In this nationally representative study, receipt of adjuvant chemotherapy appeared to be associated with sociodemographic characteristics, independent of clinical factors. Sociodemographic differences in receipt of adjuvant chemotherapy may represent a missed opportunity for improving outcomes and a driver of oncologic disparities.
Circulating Small Noncoding RNAs As Novel Semi-Invasive Markers of Patient Survival in Myelodysplastic Syndromes
Authors: Michaela Dostalova Merkerova, Andrea Hrustincova, Zdenek Krejcik, David Kundrat, Katarina Szikszai, Jaroslav Cermak, Jitka Vesela, Monika Hruba, Monika Belickova
Journal: Blood (2019)
Trends and Rapidity of Dose Tapering Among Patients Prescribed Long-term Opioid Therapy, 2008-2017
Authors: Joshua J. Fenton, Alicia L. Agnoli, Guibo Xing, Lillian Hang, Aylin E. Altan, Daniel J. Tancredi, Anthony Jerant, Elizabeth Magnan
Journal: JAMA Network Open (2019)

A 2016 Centers for Disease Control and Prevention prescribing guideline cautioned against higher-dose long-term opioid therapy and recommended tapering daily opioid doses by approximately 10% per week if the risks outweigh the benefits. Warnings have since appeared regarding potential hazards of rapid opioid tapering.
Single Cell RNA-Seq Reveals Deranged Developmental Hierarchy with Coexisting Oncogenic States and Immune Evasion Programs in ETP T-ALL
Authors: Amy Guillaumet-Adkins, Praveen Anand, Huiyoung Yun, Yotam Drier, Anna Rogers, Madhu M. Ouseph, Monica S. Nair, Sayalee Potdar, Randi Isenhart, Jake A. Kloeber, Tushara Vijaykumar, Guangwu Guo, Julia Frede, Marian H. Harris, Lewis B. Silverman, Andrew A. Lane, Daniel J. DeAngelo, Jon C. Aster, Bradley E. Bernstein, Jens G. Lohr, Birgit Knoechel
Journal: Blood (2019)