tbuckley/cabot-search huggingface dataset:
Epigenetic Activation of the pH Regulator MCT4 in Acute Myeloid Leukemia Exploits a Fundamental Metabolic Process of Enhancing Cell Growth through Proton Shifting
Authors: Cheuk-Him Man, David T. Scadden, Francois Mercier, Nian Liu, Wentao Dong, Gregory Stephanopoulos, Li Jiang, Yookyung Jung, Charles Lin, Anskar Y.-H. Leung
Journal: Blood (2019)
TMIC-02. JUNCTIONAL ADHESION MOLECULE-A (JAM-A) DEFICIENCY DRIVES SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA PROGRESSION VIA DIFFERENTIAL MICROGLIA RESPONSES IN THE TUMOR MICROENVIRONMENT
Authors: Soumya Turaga, Daniel Silver, Evi Paouri, Defne Bayik, Sen Peng, James Connor, Jill Barnholtz-Sloan, Joshua Rubin, Michael Berens, Dimitrios Davalos, Justin Lathia
Journal: Neuro-Oncology (2019)

Abstract Despite the male preponderance for developing glioblastoma (GBM) and better survival outcomes in females, current treatment paradigms do not account for biological sex as a biological or clinical variable. Sex-specific molecular alterations that drive tumor cell growth and therapy response have been documented, however, sex-specific extrinsic differences in the tumor microenvironment have yet to be identified. Based on well-established sex-specific gene signatures and functional differences in microglia, we interrogated influences of male and female microglia in driving GBM growth. Specifically, manipulation of JAM-A expression, a tight junction protein on microglia, was exploited as a paradigm for determining effects on in vivo syngeneic GBM mouse models. Male and female JAM-A KO mice that received orthotopic injection of syngeneic GBM cells presented differential overall survival distinct from their wildtype counterparts. Wild-type male mice phenocopied human males, presenting shorter overall survival than females, this trend was reversed in JAM-A KO mice. Compared to the other genotypes, female JAM-A KO mice presented the greatest number of phagocytic, tumor-promoting, activated microglia. RNA-sequencing of tumors from JAM-A KO and WT mice revealed that female JAM-A KO mice had increased expression of Ifi202b (interferon activated gene 202b), a member of the Activity-regulated Inhibitor of Death (AID) gene family that contributes to mitochondrial resistance to cellular stress. Ifi202b has a role in sex-specific inflammatory diseases, which is consistent with our observation. Female KO microglia had enhanced Ifi202b expression, along with the secretion of Ifi202b associated cytokines, including interleukin-6. Treatment of wild-type female microglia with a JAM-A function blocking antibody demonstrated an increase in Ifi202b levels, confirming direct regulation of Ifi202b expression by neutralizing JAM-A. While cell intrinsic, sex-specific differences have been reported in GBM, our findings demonstrate that differences in the GBM tumor microenvironment also drive sexually dimorphic tumor growth.
MNGI-10. ATYPICAL MENINGIOMA: EARLY OUTCOMES WITH OR WITHOUT POSTOPERATIVE RADIATION
Authors: Peter Pan, David Pisapia, Rohan Ramakrishna, Theodore Schwartz, Philip Stieg, Howard Fine, Susan Pannullo, Jonathan Knisely, Gloria Chiang, Jana Ivanidze, Benjamin Liechty, Andrew Brandmaier, Rajiv Magge
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Adjuvant radiotherapy (RT) in atypical meningioma, especially for gross-totally resected tumors, remains controversial. METHODS We retrospectively identified histologically-confirmed cases of WHO Grade II atypical meningioma at a large academic institution from 2004–2018. Clinicodemographic, surgical, radiation therapy (RT), and histopathologic data were collected, as well as imaging and clinical outcomes, with a median follow-up time of 26 months (IQR 32). Patients were stratified by resection status and whether or not upfront RT was administered. Additionally, subanalyses were performed to compare external beam RT (EBRT) and stereotactic radiosurgery (SRS). Progression was defined by radiology report. RESULTS Of 122 patients, 45 were excluded for lacking adequate records of previous treatment, less than 3 months follow-up, or lacking MR imaging. Of 77 patients analyzed, 57% (44/77) were female; median 59-years-old. 48% (24/50) of gross-total-resections (GTR) received upfront RT – only a single case progressed, at 39 months. Of 26 GTR patients without upfront RT, 8/26 (31%) progressed at median 19.5 months – of these, 2 were lost to follow-up, 5 received salvage RT, and 1 had surgery alone. Adjuvant RT was associated with superior progression free survival (PFS) in GTR (Cox proportional hazard ratio 0.15, likelihood-ratio p=0.025; median PFS not reached). Of 15 subtotal resections (STR) receiving upfront RT, 11 received EBRT and 4 received SRS – 6 progressed (median 37 months), all after EBRT. Upfront SRS demonstrated superior PFS over EBRT following STR (p=0.036). Across the cohort there was one confirmed death, a GTR patient (without RT) who suffered an ischemic stroke at 11 months. CONCLUSION This large single-center retrospective analysis indicates adjuvant RT improves PFS in GTR atypical meningiomas, in concordance with prior studies. It is limited by short median follow-up, possibly related to long-term stability in treated patients. In STR tumors, SRS may contribute to improved PFS compared to EBRT.
Next Generation Flow Cytometry Provides a Standardized, Highly Sensitive and Informative Method for the Analysis of Circulating Plasma Cells in Newly Diagnosed Multiple Myeloma: A Single Center Study in 182 Patients
Authors: Evangelos Terpos, Ioannis V. Kostopoulos, Aristea-Maria Papanota, Konstantinos Papadimitriou, Panagiotis Malandrakis, Paraskevi Micheli, Ioannis Ntanasis-Stathopoulos, Despina Fotiou, Andreas Metousis, Nikolaos Kanellias, Magdalini Migkou, Evangelos Eleutherakis-Papaiakovou, Maria Gavriatopoulou, Eftathios Kastritis, Ourania E. Tsitsilonis, Meletios A. Dimopoulos
Journal: Blood (2019)
Current Selection Patterns, Toxicities and Outcomes of Pre-Transplant Salvage Treatment Regimens in Patients with Relapsed/Refractory Hodgkin Lymphoma: Results of a Multicenter Retrospective Analysis
Authors: Jakub Svoboda, Hatcher J. Ballard, Steven M. Bair, Rahul Banerjee, Charalambos Andreadis, Tatyana A. Feldman, Elizabeth L. McCarthy, Niloufer Khan, Alison J. Moskowitz, Victor M. Orellana-Noia, Craig A. Portell, Sarah J. Nagle, Sunita Dwivedy Nasta, Daniel J. Landsburg, Stefan K. Barta, Elise A. Chong, Stephen J Schuster
Journal: Blood (2019)
Depletion of Pre-Transplant Skeletal Muscle Is a Significant Poor Prognostic Factor in Allogeneic Hematopoietic Cell Transplantation
Authors: Yasuhiko Shibasaki, Kenta Kobayashi, Tatsuya Suwabe, Kyoko Fuse, Miwako Narita, Hirohito Sone, Masayoshi Masuko
Journal: Blood (2019)
CMET-22. CAPMATINIB (INC280) IN METΔEX14-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC): EFFICACY DATA FROM THE PHASE 2 GEOMETRY MONO-1 STUDY
Authors: Rebecca S Heist, Takashi Seto, Ji-Youn Han, Noemi Reguart, Edward B Garon, Harry J M Groen, Daniel S W Tan, Toyoaki Hida, Maja de Jonge, Sergey V Orlov, Egbert F Smit, Pierre-Jean Souquet, Johan Vansteenkiste, Sylvie Le Mouhaer, Anna Robeva, Maeve Waldron-Lynch, Monica Giovannini, Juergen Wolf
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here. METHODS GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed. RESULTS As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2. CONCLUSION These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.
The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability
Authors: Yun Huang, Brice Mouttet, Hans-Jörg Warnatz, Thomas Risch, Fabian Rietmann, Fabian Frommelt, Quy A. Ngo, Maria Pamela Dobay, Blerim Marovca, Silvia Jenni, Yi-Chien Tsai, Sören Matzk, Vyacheslav Amstislavskiy, Martin Schrappe, Martin Stanulla, Matthias Gstaiger, Beat Bornhauser, Marie-Laure Yaspo, Jean-Pierre Bourquin
Journal: Cancer Cell (2019)
Early Biological Aging and Fetal Exposure to High and Low Ambient Temperature: A Birth Cohort Study
Authors: Dries S. Martens, Michelle Plusquin, Bianca Cox, Tim S. Nawrot
Journal: Environmental Health Perspectives (2019)

BACKGROUND: Although studies have provided estimates of premature mortality to either heat or cold in adult populations, and fetal exposure to ambient temperature may be associated with life expectancy, the effects of temperature on aging in early life have not yet been studied.Telomere length (TL) is a marker of biological aging, and a short TL at birth may predict lifespan and disease susceptibility later in life.OBJECTIVES: We studied to what extent prenatal ambient temperature exposure is associated with newborn TL.METHODS: In the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort in Flanders, Belgium, we measured cord blood and placental TL in 1,103 mother-newborn pairs (singletons with ≥36 wk of gestation) using a quantitative real-time polymerase chain reaction (qPCR) method.We associated newborn TL with average weekly exposure to ambient temperature using distributed lag nonlinear models (DLNMs) while controlling for potential confounders.Double-threshold DLNMs were used to estimate cold and heat thresholds and the linear associations between temperature and TL below the cold threshold and above the heat threshold.RESULTS: Prenatal temperature exposure above the heat threshold (19.5°C) was associated with shorter cord blood TL.The association with a 1°C increase in temperature was strongest at week 36 of gestation and resulted in a 3.29% [95% confidence interval (CI): -4:67, -1:88] shorter cord blood TL.Consistently, prenatal temperature exposure below the cold threshold (5.0°C) was associated with longer cord blood TL.The association with a 1°C decrease in temperature was strongest at week 10 of gestation with 0.72% (95% CI: 0.46, 0.97) longer cord blood TL.DISCUSSION: Our study supports potential effects of prenatal temperature exposure on longevity and disease susceptibility later in life.Future climate scenarios might jeopardize the potential molecular longevity of future generations from birth onward.
Long-term survival without graft-versus-host-disease following infusion of allogeneic myeloma-specific Vβ T cell families
Authors: S. Yado, G. Luboshits, O. Hazan, R. Or, M. A. Firer
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Despite chemo-induction therapy and autologous stem cell transplantation (ASCT), the vast majority of patients with Multiple Myeloma (MM) relapse within 7 years and the disease remains incurable. Adoptive Allogeneic T-cell therapy (ATCT) might be curative for MM, however current ATCT protocols often lead to graft versus host disease (GvHD). Transplanting only tumor reactive donor T cells that mediate a graft-versus-myeloma (GvM) but not GvHD may overcome this problem. <h3>Methods</h3> We used an MHC-matched/miHA-disparate B10.D2 → Balb/c bone marrow transplantation (BMT) murine model and MOPC315.BM MM cells to develop an ATCT protocol consisting of total body irradiation, autologous-BMT and infusion of selective, myeloma-reactive lymphocytes of T cell receptor (TCR) Vβ 2, 3 and 8.3 families (MM-auto BMT ATCT). <h3>Results</h3> Pre-stimulation ex vivo of allogeneic T cells by exposure to MOPC315.BM MM cells in the presence of IL-2, anti-CD3 and anti-CD28 resulted in expansion of the myeloma-reactive T cell TCRVβ 2, 3 and 8.3 subfamilies. Their isolation and infusion into MM-bearing mice resulted in a vigorous GvM response without induction GvHD and long-term survival. Repeated infusion of naïve myeloma-reactive T cell TCRVβ 2, 3 and 8.3 subfamilies was also effective. <h3>Conclusions</h3> These data demonstrate that a transplantation protocol involving only selective tumor-reactive donor T cell families is an effective immunotherapy and results in long-term survival in a mouse model of human MM. The results highlight the need to develop similar ATCT strategies for MM patients that result in enhanced survival without symptoms of GvHD.
Hematological Count Recovery in Patients Undergoing Treatment with Chimeric Antigen Receptor T Cells (CAR T)
Authors: Tania Jain, Andrea Knezevic, Martina Pennisi, Josel D Ruiz, Sean M. Devlin, Molly A. Maloy, Elizabeth Halton, Claudia Diamonte, Michael Scordo, Craig S. Sauter, Elena Mead, Bianca Santomasso, M. Lia Palomba, Gunjan L. Shah, Connie Lee Batlevi, Eric L Smith, Sergio A. Giralt, Renier J. Brentjens, Jae H. Park, Miguel-Angel Perales, Sham Mailankody
Journal: Blood (2019)
Parent and Guardian Knowledge of Hematopoietic Cell Transplantation As a Treatment Option for Sickle Cell Disease
Authors: Alicia M Stallings, Navneet S. Majhail, Amy S Nowacki, Grace I. Onimoe, Rabi Hanna, Jillian Wen, Charles T Quinn, Lewis L. Hsu, Connie M. Piccone
Journal: Blood (2016)
Impact of Elotuzumab Plus Pomalidomide and Dexamethasone on Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Enrolled in the ELOQUENT-3 Study
Authors: Katja Weisel, Agne Paner, Monika Engelhardt, Fiona Taylor, Kim Cocks, Mihaela Popa-McKiver, Clara Chen, Michele Cavo
Journal: Blood (2019)
First-in-Human Study of the EZH1/2 Dual Inhibitor Valemetostat in Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) - Updated Results Focusing on Adult T-Cell Leukemia-Lymphoma (ATL)
Authors: Satoko Morishima, Kenji Ishitsuka, Koji Izutsu, Shigeru Kusumoto, Junya Makiyama, Atae Utsunomiya, Kisato Nosaka, Takashi Ishida, Yoshitaka Imaizumi, Nobuhiko Yamauchi, Kazushi Araki, Nobuaki Adachi, Tomonari Yamashita, Ryo Atsumi, Kunihiro Tsukasaki, Kensei Tobinai
Journal: Blood (2019)
Enhanced Responses to Fostamatinib As Second-Line Therapy and in Persistent Immune Thrombocytopenia (ITP) Patients
Authors: Ralph Boccia, Michael A. Boxer, Waleed Ghanima, Quentin A. Hill, Michelle Sholzberg, Michael D. Tarantino, Yuliya Kreychman, Robert P. Numerof, Brian Olender, Leslie Todd, Sandy Tong, Anne-Marie Duliege, Nichola Cooper, James B. Bussel
Journal: Blood (2019)
Australian Familial Haematological Cancer Study - Findings from 15 Years of Aggregated Clinical, Genomic and Transcriptomic Data
Authors: Christopher N Hahn, Milena Babic, Peter J Brautigan, Parvathy Venugopal, Kerry Phillips, Julia Dobbins, Peer Arts, Amilia Wee, Deepak Singhal, Devendra K Hiwase, Jinghua Feng, Andreas W Schreiber, Richard J D'Andrea, Nicola Poplawski, Anna L Brown, Hamish S Scott
Journal: Blood (2019)
Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis
Authors: Chutima Kunacheewa, Lei Feng, Elisabet E. Manasanch, Qaiser Bashir, Krina K. Patel, Rohtesh S. Mehta, Gregory P. Kaufman, Swaminathan P. Iyer, Sheeba K. Thomas, Donna M. Weber, Robert Z. Orlowski, Muzaffar H. Qazilbash, Hans C. Lee
Journal: Blood (2019)
Temozolomide is cytotoxic to carmustine-resistant cancer cells due to mismatch repair that was increased during the acquisition of carumustine-resistance
Authors: Takahiro Yamauchi, Masami Ogawa, Akiko Morisada, Takanori Ueda
Journal: Cancer Research (2006)

541  Temozolomide (TMZ) is a relatively new mono-functional alkylating agent. The drug is effectively used for brain tumors that are resistant to a bi-functional alkylator, carmustine (BCNU). However, the efficacy of TMZ against BCNU-resistant tumors has not yet been mechanistically elucidated. As the cytotoxicity of bi-functional alkylators is associated with inter-strand cross-links, efficient repair of them by the combination of nucleotide excision repair and recombination leads to drug insensitivity. Increased mismatch repair (MMR) is also suggested to be involved in the resistance to bi-functional alkylators. For mono-functional agents, cytotoxicity is mediated by MMR, the loss of which is related to drug resistance. We hypothesized that TMZ would be cytotoxic to cancer cells resistant to BCNU because MMR may affect sensitivity to each in a converse way. Here, we investigated the cytotoxic activity of TMZ in BCNU-resistant cancer cells. Human leukemia CCRF-CEM cells (CEM-S) and one cell line developed to be resistant to BCNU (CEM-R), which had 2-fold greater nucleotide excision repair activity, were used. CEM cells originally have a low level of MMR activity. Real time RT-PCR revealed that the mRNA level of alkylguanine alkyltransferase was increased in CEM-R cells, suggesting its contribution to the resistance. The mRNA levels of hMLH1 and hMSH2, MMR-related repair proteins, were 2-fold greater in CEM-R cells than CEM-S cells, suggesting that the MMR function was increased during the development of BCNU-resistance. The mRNA level of glutathione S-transferase was identical in both cells, suggesting no contribution of detoxification to drug sensitivity. XTT assay revealed that CEM-R cells were 8-fold more resistant to BCNU than CEM-S cells. Nevertheless, CEM-R cells were 7-fold more sensitive to TMZ than CEM-S cells. Co-treatment with methoxyamine, an inhibitor of base excision repair, sensitized CEM-S cells to TMZ, but not CEM-R cells, suggesting that N7-guanine and N3-adenine adducts were not cytotoxic in CEM-R cells. Co-treatment with benzylguanine, an inhibitor of alkylguanine alkyltransferase, sensitized CEM-R cells to TMZ, but not CEM-S cells, which confirmed the cytotoxic impact of O6-alkylguanine on CEM-R cells that had increased MMR. Co-treatment with cadmium chloride, an inhibitor of MMR, lowered the sensitivity of CEM-R cells to TMZ, but did not alter the sensitivity of CEM-S cells. The growth inhibition effect was almost identical between CEM-S cells treated with TMZ alone and CEM-R cells treated with TMZ plus cadmium. These results suggested that MMR was responsible for the increased TMZ-sensitivity in CEM-R cells. In conclusion, TMZ was more cytotoxic to BCNU-resistant cells than to the BCNU-sensitive counterpart. This might be attributed to MMR that was 2-fold increased during the acquisition of BCNU-resistance.
NIMG-61. USING MACHINE LEARNING TO BUILD RADIOMICS MODELS THAT DISTINGUISH REGIONS OF GLIOBLASTOMA RECURRENCE VS TUMOR PROGRESSION ON MRI
Authors: Hyunsoo Yoon, Andrea Hawkins-Daarud, Akshay Save, Kyle Singleton, Kamala Clark-Swanson, Lujia Wang, Bernard Bendok, Maciej Mrugala, Teresa Wu, Jeffrey Bruce, Leland Hu, Jing Li, Peter D Canoll, Kristin Swanson
Journal: Neuro-Oncology (2019)

Abstract Recurrent glioblastoma is challenging to distinguish from so called “treatment effect” on routine clinical imaging. Further, within tumor heterogeneity reveals that some regions can be histologically dominated by tumor progression whilst others can be dominated by secondary effects of treatment response. Apparent tumor progression on MRI can be very difficult to manage clinically as it is unclear the degree to which the imaging changes are actually tumor progression vs response to treatment (including inflammatory response and necrosis). In this analysis, we study a unique cohort of patients for whom image localized-biopsies reveal heterogeneity in response vs progression. Our dataset included 70 biopsy samples from 32 patients with GBM each histolopatholgically characterized for tumor abundance vs immune infiltrate. Six multiparametric MRI contrasts were available, including T1, T1gd, T2, FLAIR, SWI, and ADC. Images were co-registered. Radiomic (statistical + texture) features were extracted from the region of six image contrasts locally matched with each biopsy sample. Machine learning models were built to predict each biomarker using radiomic features. Leave-one-out cross validation was used to evaluate the prediction accuracy. Radiomic features were found to be informative to the prediction of biomarkers. ANOVA tests show significant improvement of using radiomic features compared with the null model. The prediction accuracy was higher when considering the biomarkers on a binary scale using the median as the cutoff than on a numerical scale. Spatially-informed radiomics models for tumor progression vs treatment effect are possible and can play an instrumental role in navigating confounding imaging changed common during treatment progression.
Induction of Malignant Tumors in the Guinea Pig by Oral Administration of Diethylnitrosamine&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: M F ARGUS, C HOCH-LIGETI
Journal: JNCI Journal of the National Cancer Institute (1963)

Diethylnitrosamine given orally induced from the 16th week onward hepatic carcinomas in 14 of 15 guinea pigs. The majority of the tumors were of trabecular carcinomatous or adenocarcinomatous pattern, or both; 1 sarcomatous and several anaplastic tumors were seen. The tumors invaded lymphatic and blood vessels and metastasized to the lymph nodes, omentum, lung, kidney, and adrenal. Hyperplasia of the mucosa and 1 adenocarcinoma of the gallbladder occurred. In the large bronchi, squamous metaplasia and 2 squamous papillomas were observed. Multiple nodules of peripheral bronchiolar tumor were present in 7 animals. The significance of the high susceptibility of the guinea pig and the possible effect of metabolic dealkylation on the carcinogenic activity of diethylnitrosamine are discussed.