tbuckley/cabot-search huggingface dataset:
Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice
Authors: Jennifer Fraszczak, Charles Vadnais, Marissa Rashkovan, Julie Ross, Hugues Beauchemin, Riyan Chen, Damien Grapton, Cyrus Khandanpour, Tarik Möröy
Journal: Leukemia (2018)

Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating gene expression and limits the activation of p53 by facilitating its de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 in mice causes a fatal myeloproliferative disease (MPN) that could progress to leukemia after additional mutations. Both KO and KD mice accumulate myeloid cells that show signs of metabolic stress and high levels of reactive oxygen species. However, only KO cells have elevated levels of Lysine 372 methylated p53. This suggests that in contrast to absence of GFI1, KD of GFI1 leads to the accumulation of myeloid cells because sufficient amount of GFI1 is present to impede p53-mediated cell death, leading to a fatal MPN. The combination of myeloid accumulation and the ability to counteract p53 activity under metabolic stress could explain the role of reduced GF1 expression in human myeloid leukemia.
RADI-15. PERFUSION IMAGING IN PRESUMED PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA: A UK REGIONAL ANALYSIS
Authors: John-Paul Kilday, Catherine Pringle, Ian D Kamaly-Asl, Barry Pizer, Conor Mallucci, Dawn Hennigan, Shivaram Avula, Edmund Cheesman, Daniel du Plessis, Stavros Stivaros
Journal: Neuro-Oncology (2018)

The radiological diagnosis of childhood diffuse intrinsic pontine glioma (DIPG) has historically been founded upon characteristic magnetic resonance imaging metrics. Modern neuro-imaging now incorporates multi-parametric physiological assessments including perfusion and diffusion sequences. Concurrently, histological analysis of presumed DIPGs in the molecular era has resulted in a proportion being re-classified as pontine embryonal tumors; lesions with contrasting management and potential outcomes. We postulated whether integrating modern multi-parametric imaging could discriminate between the two tumors at presentation. A retrospective diagnostic MRI analysis of children that had undergone biopsy for presumed DIPG at Manchester and Liverpool Pediatric Neuro-oncology Centers over the last decade was performed. Perfusion was assessed by both arterial spin labeling and dynamic contrast susceptibility weighted techniques. Thirteen patients were identified (median age 4.2 (2.6 – 7.8) years). All lesions had characteristic, non-differentiating T1, T2 and FLAIR appearances, with varying contrast enhancement. Ten were confirmed DIPG (Grade II (3), Grade III (2), Grade IV (4), NOS (1)), while three were embryonal tumors. Reduced perfusion was identified in all embryonal lesions and Grade II DIPGs, whereas increased perfusion was observed in Grade III and IV DIPGs. Diffusion restriction was observed in embryonal lesions compared to Grade II DIPGs. Low perfusion within a presumed DIPG may reflect a lower grade of glioma or indeed an embryonal pontine tumor, particularly if accompanied by overt intra-lesional diffusion. While requiring validation in larger cohorts, we propose perfusion imaging is a vital adjunct in DIPG radiological phenotyping and should be employed at presentation.
RADI-17. EVALUATION OF A NOVEL 18F-LABELED TRYPTOPHAN TRACER FOR PET IMAGING OF BRAIN TUMORS IN A MEDULLOBLASTOMA MOUSE MODEL
Authors: Nagma Dalvi, Shaohui Zhang, Alisa Litan, Yangchun Xin, Xuyi Yue, Zhiqin Li, Hua Li, Hancheng Cai, Harry Chugani, Diane Chugani, Sigrid Langhans
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common malignant brain tumor of childhood. Despite major advances, long-term survival is hindered by relapse and leptomeningeal spread, necessitating the development of novel diagnostic and therapeutic approaches. Abnormal tryptophan metabolism, via the immunomodulatory indoleamine-2,3-dioxygenase (IDO)/ tryptophan-2,3 dioxygenase (TDO)-mediated kynurenine pathway (KP), has been demonstrated in tumors, and is emerging as a valid target for immunotherapy as well as non-invasive tumor imaging. Previously, a positron emission tomography (PET) tracer, α-[11C] methyl-L-tryptophan ([11C] AMT), has been successfully used to evaluate the increased tryptophan metabolism and uptake through KP in patients with glioma. Nevertheless, the short half-life of the carbon-11 isotope has limited the broad applications of [11C] AMT in clinical research and diagnostics. In this study, using a novel PET tracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-1-[18F]FETrp) with similar pathophysiological and metabolic properties as [11C] AMT, we assessed the tryptophan metabolism in a transgenic mouse model of the Sonic hedgehog (Shh) subgroup of medulloblastoma. In Smo-Smo mice, preliminary PET imaging data showed increased accumulation of L-1-[18F]FETrp in tumors as compared to normal brain tissue. Immunofluorescence and molecular analysis of tumor tissues obtained from Smo-Smo mice indicated increased expression of TDO2, but not IDO1. Both TDO2 and IDO1 are tissue-specific first step and rate-limiting enzymes of the KP of tryptophan metabolism. Thus, our preclinical studies in Smo-Smo mice indicate that L-1-[18F]FETrp may be a suitable tracer for PET imaging of medulloblastoma tumors and could provide valuable information for noninvasive assessment of immunotherapy response and move towards targeted therapy for medulloblastoma in the future.
Assessment of Neurocognitive Functions in 7-Year-Old Children at Familial High Risk for Schizophrenia or Bipolar Disorder
Authors: Nicoline Hemager, Kerstin J. Plessen, Anne Thorup, Camilla Christiani, Ditte Ellersgaard, Katrine Søborg Spang, Birgitte Klee Burton, Maja Gregersen, Anne Søndergaard, Aja Neergaard Greve, Ditte Lou Gantriis, Gry Poulsen, Larry J. Seidman, Ole Mors, Merete Nordentoft, Jens Richardt Møllegaard Jepsen
Journal: JAMA Psychiatry (2018)

Children at familial high risk of schizophrenia spectrum disorders (FHR-SZ) or bipolar disorder (FHR-BP) exhibit neurocognitive impairments. Large studies of neurocognition in young children at familial high risk at the same age are important to differentiate the pathophysiology and developmental trajectory of these 2 groups.To characterize neurocognitive functions in 7-year-old children with FHR-SZ or FHR-BP and a control population.This multisite population-based cohort study collected data from January 1, 2013, to January 31, 2016, in the first wave of the Danish High Risk and Resilience Study VIA 7 at 2 university hospital research sites in Copenhagen and Aarhus using Danish registries. Participants (n = 514) included 197 children with FHR-SZ, 118 with FHR-BP, and 199 controls matched with the FHR-SZ group for age, sex, and municipality. Assessors were blinded to risk status.Parents with schizophrenia, bipolar disorder, or neither diagnosis.Neurocognitive functions were measured across 23 tests. Four neurocognitive domains were derived by principal component analysis, including processing speed and working memory, verbal functions, executive and visuospatial functions, and declarative memory and attention.A total of 514 children aged 7 years were included in the analysis (46.3% girls), consisting of 197 children with FHR-SZ (46.2% girls), 118 with FHR-BP (46.6% girls), and 199 controls (46.2% girls). Children with FHR-SZ were significantly impaired compared with controls on processing speed and working memory (Cohen d = 0.50; P < .001), executive and visuospatial functions (Cohen d = 0.28; P = .03), and declarative memory and attention (Cohen d = 0.29; P = .02). Compared with children with FHR-BP, children with FHR-SZ performed significantly poorer in processing speed and working memory (Cohen d = 0.40; P = .002), executive and visuospatial functions (Cohen d = 0.35; P = .008), and declarative memory and attention (Cohen d = 0.31; P = .03). Children with FHR-BP and controls did not differ.Children with FHR-SZ had widespread neurocognitive impairments, supporting the hypothesis of neurocognitive functions as endophenotypes of schizophrenia. The absence of neurocognitive deficits in children with FHR-BP suggests distinct neurodevelopmental manifestations in these familial high-risk groups at this age. Early detection of children with FHR-SZ and cognitive impairments is warranted to investigate associations of neurocognition with transition to psychosis, add to the knowledge of their developmental pathophysiology, and inform early intervention programs.
Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors
Authors: Marat S. Pavlyukov, Hai Yu, Soniya Bastola, Mutsuko Minata, Victoria O. Shender, Yeri Lee, Suojun Zhang, Jia Wang, Svetlana Komarova, Jun Wang, Shinobu Yamaguchi, Heba Allah Alsheikh, Junfeng Shi, Dongquan Chen, Ahmed Mohyeldin, Sung-Hak Kim, Yong Jae Shin, Ksenia Anufrieva, Evgeniy G. Evtushenko, Nadezhda V. Antipova, Georgij P. Arapidi, Vadim Govorun, Nikolay B. Pestov, Mikhail I. Shakhparonov, L. James Lee, Do-Hyun Nam, Ichiro Nakano
Journal: Cancer Cell (2018)
MBCL-23. HIGH-DOSE THIOTEPA, CARBOPLATIN AND ETOPOSIDE WITH AUTOLOGOUS HEMATOPOIETIC STEM-CELL TRANSPLANTATION FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Asmik Gevorgian, Polina Tolkunova, Tatiana Iukhta, Ilya Kazantsev, Elena Morozova, Tatiana Andreeva, Andrew Kozlov, Svetlana Safonova, Yury Punanov, Ludmila Zubarovskaya, Olga Zheludkova, Boris Afanasyev
Journal: Neuro-Oncology (2018)

AIM: Most patients with recurrent medulloblastoma (rMB) have very poor prognosis with only few of them achieving prolonged response to second-line conventional treatment. This study evaluates the possible role of treatment intensification with thiotepa, carboplatin and etoposide-containing high-dose chemotherapy (HDCT) regimen and subsequent autologous hematopoietic stem-cell transplantation (auto-HSCT) in these patients. A consecutive cohort of 45 rMB patients receiving HDCT with auto-HSCT in 2010 to 2017 was evaluated. The median age at the time of recurrence was 12 (range 4-48), all patients received second-line induction chemotherapy including carboplatin and etoposide with liposomal intraventricular etoposide. The HDCT regimen consisted of thiotepa (150 mg/m2 on days -8, -7, -6, -5), carboplatin (500 mg/m2 or AUC7 on days -8, -7, -6, -5), etoposide (250 mg/m2 on days -8, -7, -6, -5), and intraventricular liposomal etoposide (1 mg on days -8, -7, -6, -5, -4 in patients with Ommaya reservoir). The median follow-up is 60 (range 24–202) months. The median time to engraftment after auto-HSCT was day +11 (range 8–39 days). Five-year overall (OS) and disease-free (DFS) survival were 70% and 66%, accordingly. Five-year DFS was significantly better among patients in CR or PR (76%) in compared to children only achieving SD (25%) after induction therapy (p=0.002). Transplant-related mortality was 13%, there were 6 patients dying due to toxic complications. HDCT with auto-HSCT in may be a feasible option for rMB patients achieving CR or PR after induction chemotherapy, but is probably not a good option for salvage treatment.
Chemotherapy efficacy in metastatic colorectal cancer (mCRC) patients treated with adjuvant or first-line FOLFOX-based chemotherapy.
Authors: Emmanuelle Samalin, Tien Tuan Nguyen, Simon Thezenas, Fabienne Portales, Thibault Mazard, Sophie Gourgou, Eric Assenat, Marc Ychou
Journal: Journal of Clinical Oncology (2017)

e15048 Background: Efficacy results of Folfox or Folfiri chemotherapies (CT) are not different as 1 st line in mCRC patients, alone or with targeted therapies. No data reported on progression-free survival (PFS) of 1 st line Folfiri after Folfox-based adjuvant CT and of 2 nd line Folfiri-based CT after a Folfox-based 1 st line. The objective was to evaluate the efficacy of a Folfiri-based CT after adjuvant or 1 st line Folfox-based treatment. Methods: 210 of 568 pts from a mCRC database were retrospectively selected and divided in 2 cohorts: pts who received adjuvant Folfox then Folfiri as 1 st line treatment (n = 76, AdjF) and those treated with Folfox as 1 st line treatment then Folfiri 2 nd line (n = 134, FFox). PFS1 was the time from beginning of Folfox to 1 st progression and PFS2 the time from the Irinotecan-based CT to 2 nd progression. Results: Median age was 62 (22-80). 49.3% pts had synchronous liver (72%) metastases. Primary tumour was right and left colon in 22% and 70% patients. Primary tumour was resected in 91% pts (98.7% and 86.6% in the AdjF and FFox groups, p= 0.003). KRASand BRAF-mutated status were found in 21.8% and 4.7% pts. In the AdjF group, pts received Folfiri as 1 st line combined with Bevacizumab (Beva) or anti-EGFR therapy (Cetuximab or Panitumumab) in 70% and 13% cases. In the FFox group, 1 st line Folfox-based CT was associated with Beva and anti-EGFRs in 7 and 6% pts, and 2 nd line Folfiri-based CT with Beva or Aflibercept in 51 and 4% pts, and with anti-EGFRs in 7.5%. Median duration of a therapeutic line was 5 months (0-29.8). Grade 3-4 toxicities were for the AdjF and FFox groups respectively, diarrhea 13/15%, neutropenia (febrile) 16(7)/37%(1%) and neuropathy 24/18%. Response rates were 55.3% and 68.7% in the AdjF and FFox groups. Median PFS1 were 14 (95%CI:10-16) and 10 (95%CI:8-11) months in the AdjF and FFox groups, and PFS2 10 (95%CI:8-11) and 7 (95%CI:6-9) months, respectively. Median overall survival was 43 (95%CI:39-50) and 33 months (95%CI:26-36) respectively. Conclusions: Results in terms of survival are in favor of the AdjFFox group. It would be interesting to identify a subgroup of pts rapidly progressing after adjuvant Folfox, who might show the same profile than pts in the FFox group.
Abstract 17655: Assessing Bleeding Risk in 4824 Asian Patients With Atrial Fibrillation: The Beijing PLA Hospital Atrial Fibrillation Project
Authors: Yutao Guo, Yundai Chen, Gregory Y H Lip
Journal: Circulation (2016)

Introduction: The risks of major bleeding and intracranial hemorrhage (ICH) are higher in Asian patients with atrial fibrillation (AF) compared to non-Asians. Hypothesis: We aimed to investigate th...
QOL-54. THE RELATIONSHIP BETWEEN MATHEMATICS AND WORKING MEMORY IN PAEDIATRIC BRAIN TUMOUR SURVIVORS TREATED WITH RADIATION
Authors: Carmelinda Longo, Lovetta Monteiro, Alanah Throop, Donald Mabbott
Journal: Neuro-Oncology (2018)

Brain tumours are the leading cause of death and disability among childhood diseases in developed countries. Cranial-spinal irradiation (CSI) is frequently required for effective tumour control but is associated with significant cognitive morbidity. Research has documented significant learning and cognitive difficulties, particularly in mathematics and working memory following CSI. Previous research has shown that in healthy controls, math skills and working memory are strongly linked. The relationship between working memory and math competences in pediatric brain tumour survivors (PBTS) has yet to be established. The goal of the study was to investigate the relationship between working memory and mathematic abilities in PBTS treated with CSI. We administered standardized measures of working memory, intelligence and math skills to 27 PBTS. Tumour and treatment related effects were combined into a single composite score and was included as a predictor variable. Multiple linear regression analyses were used to investigate the unique contribution of working memory on mathematics. The results revealed that both intelligence and verbal working memory were significant predictors of various mathematical competencies. However, verbal working memory emerged as the most significant predictor for both arithmetic and math fluency skills, uniquely accounting for 38% and 37% of the variance, respectively. While intellectual functioning had the greatest influence on math problem solving skills, verbal working memory uniquely accounted for 15% of the variance. Overall, mathematical difficulties in PBTS are, in part, related to deficits in verbal working memory. The findings suggest that interventions targeting working memory may improve math skills within this population.
Longitudinal assessment of neutrophil-to-lymphocyte ratio (NLR) from diagnosis until death reveals a biphasic trend in metastatic pancreatic adenocarcinoma patients
Authors: C. Morelli, V. Formica, S. Pellicori, A. Nardecchia, M. Roselli
Journal: Annals of Oncology (2018)

Introduction: Baseline NLR has been found to have a significant prognostic value in metastatic pancreatic adenocarcinoma (mPA) patients. However, NLR assessment during the entire course of mPA disease has never been reported. Methods: We analyzed 1025 cell blood counts (CBCs) saved to PTV-BIO.CA.RE. (Biospecimen Cancer Repository) in 44 mPA patients (23.3 CBCs/patient) who had reached the overall survival endpoint (death ascertained) and NLR was calculated as per standard. Trend of NLR over the remaining weeks to death was analyzed, and where a clear correlation was observed a standard regression analysis was performed. Potential association between NLR trends and short survival was analyzed. Results: NLR values over the time had a clear biphasic trend, remaining roughly constant (median NLR 2.5, 95% CI 2.2-2.7) up to 24 weeks prior to death (correlation coefficient R 0.03, p 0.603) and then displaying a marked rectilinear increase from week -24 to death (time 0) (R 0.48, p < 0.001). The equation that expressed the rectilinear increase of NLR during the last 24 weeks of life was NLR=9.663 – 0.325* (weeks-to-death), indicating an increase of about +0.3 in NLR for every week passing from -24 to 0 (death). A NLR above 3.0 with a confirmed increase of > +0.3 points/week in two subsequent CBCs was able to predict an imminent death (within 24 weeks) in 97.8% of cases (Relative Risk as compared with NLR < 3 and/or increase rate < 0.3points/week: 2.75, p < 0.0001). Conclusion: Longitudinal assessment of NLR in mPA patients is able to predict with great precision death occurring within 24 weeks. Treatments able to lessen the unfavourable NLR increase rate of + 0.3 points/week are likely to change the natural history of this disease.
Strategies for clinical development of monoclonal antibodies beyond first-in-man trials: Tested doses and rationale for dose selection.
Authors: Marie Vinches, Alice Cuenant, Marie Alexandre, Anna Durigova, Nadia Hayaoui, Caroline Mollevi, Luca Gianni, Diego Tosi
Journal: Journal of Clinical Oncology (2015)

3040 Background: We conducted a comprehensive survey (J. Clin. Oncol., in press) on the design, implementation and outcome of first-in-human trials (FIHT) of monoclonal antibodies (mAbs) over the last decade. We showed that, due to the limited observed toxicity, the maximum tolerated dose was infrequently reached and therefore the recommended phase II dose (RP2D) for subsequent clinical trials was only tentatively defined. Methods: In order to evaluate strategies of mAb development beyond FIHT, we performed a MEDLINE search to identify articles reporting single agent trials of mAbs whose FIHT was published between April 1, 2003 and April 1, 2013. For each mAb, we examined the doses tested in these non-FIH trials (NFIHT) with regard to the corresponding FIHT results, as well as the rationale for dose selection in NFIHT. Results: Sixty-nine NFIHT of 36 mAbs were selected for analysis, of which 30 were phase I, 37 phase II and 2 phase III trials. For each mAb, the number of trials ranged from 1 to 8. In phase I NFIHT, the maximum administered dose (MAD) coincided with the FIHT MAD for the tested mAb in 12 cases (40%), and the ratio between the NFIHT and FIHT MAD ranged from 0.28 to 2. An RP2D was indicated in only 14 phase I NFIHT (47%) and coincided with the FIHT RP2D or MAD for the tested mAb in 2 and 8 trials, respectively. The ratio between the phase I NFIHT RP2D and the FIHT RP2D or MAD ranged from 0.33 to 2 and from 0.28 to 2, respectively. While a FIHT RP2D was available for the tested mAb in 22 phase II-III NFIHT (56%), the dose actually administered was the FIHT RP2D in only 11 trials (28%) and the FIHT MAD in 12 other trials (31%). In the 16 phase II-III NFIHT (41%) in which the tested dose was different from FIHT RP2D or MAD, a rationale for dose selection was indicated in few cases, reporting former pharmacokinetics data (4 trials) or safety issues (1 trial). Conclusions: The RP2D and the MAD determined in FIHT is infrequently used in the subsequent clinical development of mAbs. The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published papers, a fact that represents a weakness in the development of this class of drugs, and may lead to wrong-dosing.
Interplay between ShcA Signaling and PGC-1α Triggers Targetable Metabolic Vulnerabilities in Breast Cancer
Authors: Young Kyuen Im, Ouafa Najyb, Simon-Pierre Gravel, Shawn McGuirk, Ryuhjin Ahn, Daina Z. Avizonis, Valérie Chénard, Valerie Sabourin, Jesse Hudson, Tony Pawson, Ivan Topisirovic, Michael Pollak, Julie St-Pierre, Josie Ursini-Siegel
Journal: Cancer Research (2018)

The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcriptional coactivator, a central regulator of mitochondrial metabolism. Breast tumors that engaged ShcA signaling were critically dependent on PGC-1α to support their increased metabolic rate. PGC-1α deletion drastically delayed breast tumor onset in an orthotopic mouse model, highlighting a key role for PGC-1α in tumor initiation. Conversely, reduced ShcA signaling impaired both the metabolic rate and flexibility of breast cancer cells, rendering them reliant on mitochondrial oxidative phosphorylation. This metabolic reprogramming exposed a targetable metabolic vulnerability, leading to a sensitization of breast tumors to inhibitors of mitochondrial complex I (biguanides). Genetic inhibition of ShcA signaling in the Polyoma virus middle T (MT) breast cancer mouse model sensitized mammary tumors to biguanides during the earliest stages of breast cancer progression. Tumor initiation and growth were selectively and severely impaired in MT/ShcA-deficient animals. These data demonstrate that metabolic reprogramming is a key component of ShcA signaling and serves an unappreciated yet vital role during breast cancer initiation and progression. These data further unravel a novel interplay between ShcA and PGC-1α in the coordination of metabolic reprogramming and demonstrate the sensitivity of breast tumors to drugs targeting oxidative phosphorylation.Significance: This study uncovers a previously unrecognized mechanism that links aberrant RTK signaling with metabolic perturbations in breast cancer and exposes metabolic vulnerabilities that can be targeted by inhibitors of oxidative phosphorylation. Cancer Res; 78(17); 4826-38. ©2018 AACR.