tbuckley/cabot-search huggingface dataset:
Circulating Progenitor Cells and Racial Differences
Authors: Ayman Samman Tahhan, Muhammad Hammadah, Heval Mohamed Kelli, Jeong Hwan Kim, Pratik B. Sandesara, Ayman Alkhoder, Belal Kaseer, Mohamad Mazen Gafeer, Matthew Topel, Salim S. Hayek, Wesley T. O’Neal, Malik Obideen, Yi-An Ko, Chang Liu, Iraj Hesaroieh, Ernestine Mahar, Viola Vaccarino, Edmund K. Waller, Arshed A. Quyyumi
Journal: Circulation Research (2018)

Rationale: Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. Objective: To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. Methods and Results: CPCs were enumerated by flow cytometry as CD45med + blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (−17.6%; [95% confidence interval (CI), −23.5% to −11.3%]; P &lt;0.001), CD34+/CD133+ cells (−15.5%; [95% CI, −22.4% to −8.1%]; P &lt;0.001), CD34+/CXCR4+ cells (−17.3%; [95% CI, −23.9% to −10.2%]; P &lt;0.001), and CD34+/VEGF2R+ cells (−27.9%; [95% CI, −46.9% to −2.0%]; P =0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P =0.02). Blacks had significantly lower plasma MMP-9 levels ( P &lt;0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%–33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12–7.20]; P =0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09–2.94]; P =0.02) without significant interaction. Conclusions: Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.
Government is accused of “dragging its feet” on air pollution
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The UK government must move more quickly to cut vehicle emissions to tackle air pollution and improve the nation’s health, a cross party group of MPs has said.

In March a critical joint committee report1 (Environment, Food and Rural Affairs; Environmental Audit; Health and Social Care; and Transport) said that the government had failed to protect the public from poisonous air, and it called for urgent action to tackle what has become “a national health emergency.”2

The MPs made a series of recommendations to the government, including bringing forward the date by …
HGG-16. MOLECULAR PATHOPHYSIOLOGY OF HISTONE 3.3 G34R MUTANT CHILDHOOD BRAIN TUMOURS; TOWARDS THE DEVELOPMENT OF NOVEL TARGETED THERAPIES.
Authors: Farhana Haque, Katie Foot, Anbarasu Lordusuamy, Ruman Rahman, Robert Layfield, Richard Grundy
Journal: Neuro-Oncology (2019)

There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very poor prognosis. These cancers harbour mutations affecting histone 3 proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We have generated and validated a Histone 3.3 (H3.3) G34R antibody, and investigated the downstream effects of H3.3 G34R mutations in pHGG. In order to identify the genes that may be deregulated by G34R mutant histone expression, we have performed chromatin immunoprecipitation (ChIP) assays with our H3.3 G34R and wild type H3 antibodies, using pHGG H3 G34R mutant and wild type cell lines. Initial analyses of ChIP data have implicated deregulation of various cell-signaling pathways including Notch1, Hedgehog, PPAR-1, PLC-beta and Androgen, in H3 G34R mutated pHGG. We are currently determining the effects of altered expression of Notch pathway components, HES1, HES5 and Notch intracellular domain (NICD) on tumorigenesis of H3 G34R mutated pHGG, through gene and protein expression and inhibition assays. In parallel, we are also determining the effect of Hedgehog signalling pathway components Gli2, PTHLH, TGFβ2 in H3 G34R mutated pHGG and if there is cross talks between these two pathways. These analyses would enable us to find potential novel therapeutic targets. Results of these analyses/experiments will be presented.
LGG-43. CLINICAL EXPERIENCE OF BRAF AND MEK INHIBITOR THERAPY IN PAEDIATRIC GLIOMA
Authors: Patricia O’Hare, Thalia Loka, Felice D’Arco, Sarita Depani, Anthony Michalski, Olga Slater, Mette Jorgensen, Thomas Jacques, Darren Hargrave
Journal: Neuro-Oncology (2018)

MAPK pathway activation is a druggable target and characteristic of paediatric low-grade(pLGG) and also found in high-grade glioma(pHGG), typically resulting from BRAFV600E/BRAF-fusion/NF1 mutations. A retrospective cohort study of 23 patients, who received BRAF inhibitor monotherapy (BRAFi)(11 BRAFV600E, one BRAFV600D mutation), MEKi monotherapy (MEKi) (6 BRAF fusion and 4 with NF1) or BRAFi and MEKi combination (Combi) therapy (2 BRAF V600 mutations). 12 patients were treated with BRAFi, with a median of 51.5 weeks treatment, (5 pHGG, 7 pLGG). 10 patients with pLGG were treated with MEKi (median of 30 weeks treatment). Toxicity of BRAFi included development of new melanocytic naevi (73%), erythema nodosum (60%), pyrexia (42%), xerosis (40%), hair changes (27%) and raised creatinine (17%). Toxicity of MEKi included acneform/papulopustular rash (65%), paronychia (59%), hair changes (57%), xerosis (47%) and mouth ulcers (20%). No patient stopped treatment due to toxicity. Response evaluations are available for 11 BRAFi patients, of whom 3 have PR (2 pLGG, 1pHGG), 2 have MR (pLGG), 3 have SD (pLGG) and 2 patients had PD (pHGG). 1 further patient with pHGG, had an initial prolonged SD (102 weeks on BRAFi), developed a new lesion, which subsequently responded to addition of MEKi therapy. Response evaluations are available for 9 MEKi patients (all with LGG) of whom 2 had PR, 4 had SD and 3 patients had PD. 1 patient with pLGG treated with Combi had MR. Both BRAFi and MEKi therapy were well tolerated and provided significant and durable responses in paediatric glioma.
NSRG-16. LESION LOCALIZATION IN POSTERIOR FOSSA SYNDROME
Authors: Fatimah Albazron, Joel Bruss, Robin Jones, Torunn Yock, Margaret Pulsifer, Annah Abrams, Mariko Sato, Aaron Boes
Journal: Neuro-Oncology (2018)

Posterior fossa syndrome (PFS) develops in about 25% of children undergoing cerebellar tumor resection. This syndrome is characterized by mutism, ataxia, emotional lability, and behavioral changes. The exact pathogenesis of this syndrome is not well understood. To evaluate lesion location relative to PFS development. 203 pediatric patients who underwent cerebellar tumor resection from University of Iowa Hospitals and Clinics and Massachusetts General Hospital were evaluated for PFS through chart review. We tested for variables associated with PFS using demographics, tumor type, and lesion location. Each post-surgical lesion was manually mapped onto a template brain. Using a case-control design we compared each patient with PFS to two subjects without PFS, matched by age, gender and lesion volume. We evaluated the hypothesis that lesions of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) are associated with PFS. PFS was present in 47 of 203 subjects (23.2%). Lesions of the cerebellar outflow pathway were significantly associated with PFS development (P = 0.002). Moreover, using a novel metric of cerebellar outflow tract “lesion load”, we show that the damaged proportion of cerebellar outflow is strongly associated with the rate of PFS. In addition, the rate of medulloblastoma was significantly higher in the PFS group (P = 0.035). In this large lesion mapping study we show that disruption of the cerebellar outflow pathway is significantly associated with the diagnosis of PFS. Moreover, the rates of PFS vary in accordance with the proportion of the cerebellar outflow pathway affected.
Global Diabetes Prevention Interventions: A Systematic Review and Network Meta-analysis of the Real-World Impact on Incidence, Weight, and Glucose
Authors: Karla Ivette Galaviz, Mary Beth Weber, Audrey Straus, Jeehea Sonya Haw, K.M. Venkat Narayan, Mohammed Kumail Ali
Journal: Diabetes Care (2018)

Understanding the real-world impacts of lifestyle modification (LSM) for diabetes prevention is imperative to inform resource allocation. The purpose of this study was to synthetize global evidence on the impact of LSM strategies on diabetes incidence and risk factors in one parsimonious model.PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for studies published between January 1990 and April 2015. Effectiveness/translation studies of any design testing LSM strategies, targeting high-risk populations (with prediabetes or diabetes risk factors), and reporting diabetes incidence, weight, or glucose outcomes were included. We extracted number of diabetes cases/incidence rates and mean changes in weight (kg), fasting blood glucose (FBG, mmol/L), 2-h postload glucose (mmol/L), and hemoglobin A1c (%). Pairwise random-effects and frequentist random-effects network meta-analyses were used to obtain pooled effects.Sixty-three studies were pooled in the meta-analysis (n = 17,272, mean age 49.7 years, 28.8% male, 60.8% white/European). In analyses restricted to controlled studies (n = 7), diabetes cumulative incidence was 9% among intervention participants and 12% among control participants (absolute risk reduction 3%; relative risk 0.71 [95% CI 0.58, 0.88]). In analyses combining controlled and uncontrolled studies (n = 14), participants receiving group education by health care professionals had 33% lower diabetes odds than control participants (odds ratio 0.67 [0.49, 0.92]). Intervention participants lost 1.5 kg more weight [-2.2, -0.8] and achieved a 0.09 mmol/L greater FBG decrease [-0.15, -0.03] than control participants. Every additional kilogram lost by participants was associated with 43% lower diabetes odds (β = 0.57 [0.41, 0.78]).Real-world LSM strategies can reduce diabetes risk, even with small weight reductions.
Somatostatin Receptor PET/CT Features of Carcinoid Heart Disease
Authors: Saurabh Arora, Averilicia Passah, Nishikant A. Damle, Rajiv Narang, Atul Sharma, Madhav P. Yadav, Sanjana Ballal, Dinkar Bhasin, Chandrasekhar Bal
Journal: Clinical Nuclear Medicine (2018)

We present the case of a 35-year-old woman with metastatic neuroendocrine tumor undergoing treatment with long-acting octreotide and Lu-DOTATATE therapy. We present features of carcinoid heart disease on Ga-DOTANOC PET/CT, which revealed dilated right atrium, pericardial effusion, ascites, and congestive hepatopathy apart from the metastatic lesions in the liver. The scan cardiac findings were confirmed by echocardiography. This highlights the significance of identifying such patients early because additional management is required for carcinoid heart disease per se and a cautious approach is needed in administering amino acid infusion during PRRT that can result in fluid overload.
LGG-14. PEDIATRIC DIFFUSE GLIOMA WHO-GRADE II: PROGNOSTIC IMPACT OF MOLECULAR GENETIC VARIANTS
Authors: Astrid K Gnekow, Daniela Kandels, Monika Warmuth-Metz, Brigitte Bison, René Schmidt, Rolf-Dieter Kortmann, Marco Gessi, Torsten Pietsch
Journal: Neuro-Oncology (2018)

We investigated the frequency of histological and molecularly defined variants of pediatric diffuse gliomas WHO grade II (DG2) and their prognostic impact within the German and Swiss SIOP-LGG-2004 cohort. Hundred DG2 were confirmed by central histological review among 1645 pediatric low-grade gliomas, registered between April 1st, 2004 and March 31st, 2012 (6.1%; median age at diagnosis 9.44 years (0.8-17.8); sex ratio (m:f) 1.2:1; neurofibromatosis NF1 4%). Localization: cerebral hemispheres 42, supratentorial midline 27, focal pontine-medullary 11, cerebellar 10, spinal cord 10 cases. In 64/100 cases, material for molecular genetic investigations was available. We identified 10 IDH-, 4 Histone3-K27M-, 12 BRAF-V600E-mutated DG2, 5 with KIAA1549-BRAF-fusion, and 33 DG2 wild-type for IDH/H3/BRAF. Further rare aberrations were revealed by additional Nanostring RNA analysis and methylation profiling. Treatment included 1-3 surgical resections without (n=68) or with subsequent non-surgical therapy (16 primary vincristine/carboplatin chemotherapy, 16 primary irradiation, 16/32 multiple salvage treatments). Within a median observation time of 7.1 years (0.04-23.1), progression to high-grade glioma was documented by follow-up surgery in 9 cases, and 13 patients with tumors of the thalamus (6), caudal brain-stem (4) or elsewhere (3) died (4/4 Histone-, 1/10 IDH-, 1/12 BRAF-V600E-mutated, 0/5 BRAF-fusion positive, 3/33 IDH/H3/BRAF wild-type tumors, and 4/36 without material). 5year-OS was 89.6% (±3.1%). Pediatric DG2 represents a genetically and clinically heterogeneous group. Histone3-K27M-mutation heralded progression and death, while other genetic features lacked prognostic impact. Larger homogeneously treated patient cohorts should be evaluated to validate the impact of molecular characteristics in the setting of multimodal treatment.
Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial
Authors: Anna Candoni, Cristina Papayannidis, Giovanni Martinelli, Erica Simeone, Michele Gottardi, Ilaria Iacobucci, Filippo Gherlinzoni, Giuseppe Visani, Michele Baccarani, Renato Fanin
Journal: American Journal of Hematology (2018)

Abstract The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab‐Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first‐line therapy in CD33 positive AML. We treated 130 patients, aged &lt;65, with a median age of 52 years. FLAI‐GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (2 g/sqm) on days 1–5; idarubicin (10 mg/sqm) on days 1, 3, and 5; and GO (3 mg/sqm) on day 6. SCT was planned for all high‐risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of MRD by WT1 expression, feasibility and outcome of consolidation with SCT, overall survival (OS) and disease‐free survival (DFS). After induction with FLAI‐GO, complete remission (CR) rate was 82%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI‐GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI‐GO, the mean of WT1 copies dropped from 8337±9936 copies/10 4 ABL (diagnosis) to 182 ± 436 copies after induction therapy ( p = 0.0001) showing a very good disease debulking. After a median follow‐up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5‐year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5‐year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI‐GO is an active and safe treatment strategy for CD33‐positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow‐up, support the reintroduction of GO in clinical practice.
MBRS-62. REPRESSIVE CHROMATIN REMODELERS IN SHH-DRIVEN MEDULLOBLASTOMA
Authors: Rong-Hua Tao, Tara Dobson, Shinji Maegawa, Jyothismathi Swaminathan, Shavali Shaik, Pete Taylor, Bridget Kennis, Lin Qi, Soumen Khatua, Stewart Goldman, Rishi Lulla, Jason Fangusaro, Tobey MacDonald, Xiao-Nan Li, Cynthia Hawkins, Veena Rajaram, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is a malignant pediatric brain tumor characterized by poor neuronal differentiation. The RE1 Silencing Transcription Factor (REST), which negatively regulates neurogenesis by promoting repressive chromatin remodeling via epigenetic modifications, is overexpressed in human MBs. Analyses of a publically available gene expression array data set revealed association of elevated REST expression in patients with Sonic Hedgehog (SHH) medulloblastoma with poor prognosis. Upon closer evaluation, we identified a subset of highly undifferentiated SHHα tumors with elevated REST expression and activity as determined by expression of REST target genes. These patients had an overall survival rate of 50% at 5 years. To understand the underlying mechanisms, we generated a novel mouse model expressing human REST transgene in a conditional manner in granule neural progenitors (GNPs), the cells of origin of SHH driven MB. Mice with constitutive activation of Shh signaling and REST elevation (Ptch+/-/RESTTG) in their GNPs developed tumors with a significant decrease in latency and increase in penetrance. We observed that 100% of Ptch+/-/RESTTG animals developed heterogeneously proliferative and undifferentiated tumors compared to tumor-bearing Ptch+/- animals. Mechanistic studies revealed deregulation of the Shh signaling pathway by REST-dependent G9a activity, accompanied by loss of Ptch1 heterozygosity in Ptch+/-/RESTTG tumors. Thus, our studies suggest that REST contributes to mis-regulation of SHH activity and drives an aggressive disease course by deregulating proliferation and differentiation. Ours is also the first study to implicate G9a, a repressive chromatin remodeler, in medulloblastoma pathogenesis and as a potential therapeutic target.
Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1
Authors: Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Sanae Teshigawara, Atsuhito Tone, Haruhito A. Uchida, Jun Eguchi, Atsuko Nakatsuka, Daisuke Ogawa, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada
Journal: Diabetes Care (2018)

OBJECTIVE Because quantifying glycans with complex structures is technically challenging, little is known about the association of glycosylation profiles with the renal prognosis in diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS In 675 patients with type 2 diabetes, we assessed the baseline urinary glycan signals binding to 45 lectins with different specificities. The end point was a decrease of estimated glomerular filtration rate (eGFR) by ≥30% from baseline or dialysis for end-stage renal disease. RESULTS During a median follow-up of 4.0 years, 63 patients reached the end point. Cox proportional hazards analysis revealed that urinary levels of glycans binding to six lectins were significantly associated with the outcome after adjustment for known indicators of DKD, although these urinary glycans, except that for DBA, were highly correlated with baseline albuminuria and eGFR. Hazard ratios for these lectins were (+1 SD for the glycan index) as follows: SNA (recognizing glycan Siaα2-6Gal/GalNAc), 1.42 (95% CI 1.14–1.76); RCA120 (Galβ4GlcNAc), 1.28 (1.01–1.64); DBA (GalNAcα3GalNAc), 0.80 (0.64–0.997); ABA (Galβ3GalNAc), 1.29 (1.02–1.64); Jacalin (Galβ3GalNAc), 1.30 (1.02–1.67); and ACA (Galβ3GalNAc), 1.32 (1.04–1.67). Adding these glycan indexes to a model containing known indicators of progression improved prediction of the outcome (net reclassification improvement increased by 0.51 [0.22–0.80], relative integrated discrimination improvement increased by 0.18 [0.01–0.35], and the Akaike information criterion decreased from 296 to 287). CONCLUSIONS The urinary glycan profile identified in this study may be useful for predicting renal prognosis in patients with type 2 diabetes. Additional investigation of glycosylation changes and urinary glycan excretion in DKD is needed.
MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)
Authors: Giles W Robinson, Vasilisa A Rudneva, Ivo Buchhalter, Catherine A Billups, Sebastian M Waszak, Kyle Smith, Daniel C Bowers, Anne Bendel, Paul Fisher, Sonia Partap, John Crawford, Tim Hassall, Daniel J Indelicato, Frederick Boop, Paul Klimo, Noah D Sabin, Zoltan Patay, Thomas E Merchant, Clinton F Stewart, Brent A Orr, Jan O Korbel, David T W Jones, Tanvi Sharma, Peter Lichter, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, Robert P Sanders, Arzu Onar-Thomas, David W Ellison, Amar Gajjar, Paul A Northcott
Journal: Neuro-Oncology (2018)

iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer, reduce, or delay radiation exposure. We assembled a molecular cohort of 190 iMBs and a SJYC07 trial cohort of 81 iMBs. Tumors were sub-classified into molecular subgroups based on DNA methylation profiles and overlaid with mutations and copy-number alterations. PFS and OS for the SJYC07 cohort was estimated across clinical risk groups, consensus molecular subgroups, and in the context of novel MB subtypes. Computational analysis of DNA methylation array data divided iMB into three of the four consensus subgroups: SHH, G3, and G4 (absent WNT). Clinical outcome of iMBSHH was superior to iMBGroup3/Group4 (5-year PFS: 51 ± 8% vs 11 ± 10%, P<0.001; 5-year OS: 72 ± 8% vs 51 ± 12%, P<0.05). t-distributed stochastic neighbor embedding (t-SNE) analysis recognized two subtypes of iMBSHH (iMBSHH-I and iMBSHH-II) and distributed iMBGroup3/Group4 into eight recently described subtypes (I-VIII). 5-year PFS of iMBSHH-II surpassed iMBSHH-I (75 ± 10% vs 28 ± 10%, P=0.003) and exceeded 90% in low-risk iMBSHH-II (<3y, M0, R0, DN/MBEN). Through integrative genomics, we described the molecular landscape of iMB. Application of these data to a trial cohort identifies: a low-risk SHH-subtype (iMBSHH-II) that exhibits excellent PFS in the absence of radiation, intra-ventricular chemotherapy, and high-dose chemotherapy; a high-risk SHH-subtype (iMBSHH-I); and very poor PFS for iMBGroup3/Group4. These findings will shape risk stratification on future iMB trials.