tbuckley/cabot-search huggingface dataset:
Turkish Acute Lymphoblastic Leukemia Registry, Retrospective Phase Data
Authors: Fatih Demirkan, Rafiye Ciftciler, Omur Gokmen Sevindik, Emre Tekgündüz, Mehmet Ali Erkurt, Filiz Vural, Burhan Turgut, Leylagul Kaynar, Kadriye Bahriye Payzin, Mehmet Hilmi Dogu, Volkan Karakus, Fevzi Altuntas, Yahya Buyukasik
Journal: Blood (2019)
NIMG-27. EVALUATING THE POTENTIAL OF 18F-FLUCICLOVINE POSITRON EMISSION TOMOGRAPHY TO DETECT WHOLE BRAIN TUMOR BURDEN: A PRECLINICAL STUDY
Authors: Matthew Scarpelli, Debbie Healey, Ernesto Luna Melendez, Shwetal Mehta, Chad Quarles
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Accurately identifying the boundary of invasive brain tumors is critical for planning effective treatment. Conventional imaging includes T1-weighted contrast-enhanced MRI to identify regions where tumor angiogenesis has broken down the blood-brain barrier. However, conventional MRI has limited sensitivity for identifying invading tumor cells. Amino acid PET with 18F-fluciclovine may offer improved sensitivity. We investigate whether 18F-fluciclovine PET provides a superior measure of tumor burden than MRI. METHODS Rats were implanted with patient-derived glioblastoma xenografts that had been transduced to enable fluorescent imaging of the TdTomato protein. When the tumors grew to a sufficient size, the rats were scanned with 18F-fluciclovine PET followed immediately by contrast-enhanced MRI. Rats were sacrificed and whole brains were removed. Western blots were performed to measure amino acid transporter levels. Fluorescent imaging of optically cleared brain slices enabled visualization of the labelled tumor and determination of whole tumor burden. A methodology for registering in vivo PET/MRI slices to ex vivo fluorescent images of optically cleared brain slices (1-mm thickness) has been developed. Tumor volumes are manually segmented on all images. RESULTS The ratio of tumor to normal brain uptake (TNB) of 18F-fluciclovine peaked ten minutes post-injection (mean value 7.1) and was followed by a continual decrease in the TNB ratio (mean value 4.6 at fifty minutes post-injection). The mean percentage of MRI segmented tumor volume that was inside the PET segmented tumor volume was 95%. The mean percentage of PET segmented tumor volume that was inside the MRI segmented tumor volume was 40%. Tumors with the highest level of amino acid transporters had the highest 18F-fluciclovine uptake. CONCLUSIONS The majority of 18F-fluciclovine PET identified tumor regions were not identified using conventional MRI, indicating the potential of this approach to detect invasive tumor cells and provide a more robust assessment of whole tumor burden.
Nitrous Oxide in Dentistry
Authors: A. Tom
Journal: BMJ (1961)

About half an hour later he was again anaesthetized, using a 50: 50 mixture of cyclopropane and oxygen (without premedication) and in the semi-prone position, without incident.In this patient fainting was easily recognized, but this is not always so, and it may pass unnoticed even by experienced practitioners who are specifically watching for this complication.Nevertheless, careful observation should detect, at the time, most cases of fainting in the dental chair.In this case there were three possible aetiological factors-namely, an excessive period of starvation, nervousness, and induction with pure nitrous oxide in the sitting position, each of which may have contributed its quota to the final result.-Iam, etc.,
Demonstration of the Safety of Post Induction Infusion of Ex-Vivo Expanded Cord Blood Progenitor Cells in Pediatric Patients with Relapsed/Refractory Acute Myelogenous Leukemia
Authors: Ann Dahlberg, Muna Qayed, Katherine Tarlock, Jessica A. Pollard, Filippo Milano, Soheil Meshinchi, Colleen Delaney
Journal: Blood (2019)
Genome-wide interaction target profiling reveals a novel <i>Peblr20</i>-eRNA activation pathway to control stem cell pluripotency
Authors: Cong Wang, Lin Jia, Yichen Wang, Zhonghua Du, Lei Zhou, Xue Wen, Hui Li, Shilin Zhang, Huiling Chen, Naifei Chen, Jingcheng Chen, Yanbo Zhu, Yuanyuan Nie, Ilkay Celic, Sujun Gao, Songling Zhang, Andrew R. Hoffman, Wei Li, Ji-Fan Hu, Jiuwei Cui
Journal: Theranostics (2019)

Background: Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. Methods: We utilized a RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile the mouse genome-wide interaction targets for lncRNAs that are screened by RNA-seq. Results: We identified Peblr20 (Pou5F1 enhancer binding lncRNA 20) as a novel lncRNA that is associated with stem cell reprogramming. Peblr20 was differentially transcribed in fibroblasts compared to induced pluripotent stem cells (iPSCs). Notably, we found that Peblr20 utilized a trans mechanism to interact with the regulatory elements of multiple stemness genes. Using gain- and loss-of-function experiments, we showed that knockdown of Peblr20 caused iPSCs to exit from pluripotency, while overexpression of Peblr20 activated endogenous Pou5F1 expression. We further showed that Peblr20 promoted pluripotent reprogramming. Mechanistically, we demonstrated that Peblr20 activated endogenous Pou5F1 by binding to the Pou5F1 enhancer in trans, recruiting TET2 demethylase and activating the enhancer-transcribed RNAs. Conclusions: Our data reveal a novel epigenetic mechanism by which a lncRNA controls the fate of stem cells by trans-regulating the Pou5F1 enhancer RNA pathway. We demonstrate the potential for leveraging lncRNA biology to enhance the generation of stem cells for regenerative medicine.
Macular Atrophy in Neovascular Age-Related Macular Degeneration
Authors: Mark C. Gillies, Alex P. Hunyor, Jennifer J. Arnold, Robyn H. Guymer, Sebastian Wolf, Francois L. Pecheur, Marion R. Munk, Ian L. McAllister
Journal: Ophthalmology (2019)

To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD).A phase 4 randomized, partially masked, multicenter study.Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more.Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections.The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24.Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups.No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.
CBMT-19. THE ALTERNATIVE LENGTHENING OF TELOMERE (ALT) MECHANISM PROVIDES COLLATERAL SENSITIVITY TO LETHAL TELOMERIC FUSION INDUCED BY TRAPPING PARP INHIBITORS
Authors: Joydeep Mukherjee, Cecelia Dalle-Ore, Tor-Christian Johanessen, Ajay Pandita, Shigeo Ohba, Daniel Cahill, Russell O Pieper
Journal: Neuro-Oncology (2019)

Abstract A subset of human tumors, including all IDH1-mutant astrocytomas, use a homologous recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Because ALT is not used by normal cells, targeting of the process may provide new therapeutic options for patients with ALT-dependent tumors. We here report that reliance on the ALT mechanism makes tumors collaterally hypersensitive to clinically-available trapping PARPi (t-PARPi). Specifically we noted that astrocytoma cells dependent on the ALT-mechanism (IDH1-mutant and ATRX-deficient genetically-modified human astrocytes and MGG119 PDX) were significantly more sensitive to trapping PARPi than matched ALT-independent isogenic ATRXWT astrocytes and MGG152 PDX cells, respectively) both in vitro and in vivo. Surprisingly this hypersensitivity was not associated with BRCA-ness, the extent of PARP inhibition, or with t-PARPi-created genomic DNA damage as is the case in most PARPi-sensitive populations. Rather the enhanced activity of t-PARPi in ALT-dependent cells was associated with a novel t-PARPi-induced, lethal telomere fusion. Furthermore, the extent of chromosomal fusion was proportional to the PARP-trapping ability of the five PARP inhibitors tested, and could be prevented by exogenous expression of TERT, which eliminated reliance on ALT but did not alter levels of PARPi-induced genomic DNA damage. The extent of tPARPi-induced telomeric fusion in ALT-dependent cells, which could be directly measured in small amounts of DNA using a q-PCR approach, was also directly proportional to tPARPi-induced cell death in vitro and to prolonged survival of tumor-bearing mice in vivo. These results therefore identify clinically available tPARPi as a new treatment modality for a select and easily genetically definable group of ALT tumors, and also define telomeric fusion as a biomarker of drug action in these tumors.
Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton's Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies
Authors: Chan Y. Cheah, Nicholas Wickham, Costas K. Yannakou, Katharine L Lewis, Chi-Hung Hui, Pek Sang Tang, Tejasvi Turpuseema, Hari P Miskin, Jian-Ping Tang, Emmanuel Normant, Alejandro D. Ricart, Constantine S. Tam
Journal: Blood (2019)
Case 35-2019: A 66-Year-Old Man with Pancytopenia and Rash
Authors: Marcela V. Maus, Mark B. Leick, Kristine M. Cornejo, Valentina Nardi
Journal: New England Journal of Medicine (2019)

A 66-year-old man presented to the hospital for evaluation of pancytopenia and rash. Examination was notable for a scaling, erythematous rash on the legs and the absence of lymphadenopathy. Positron-emission tomography revealed increased 18F-fluorodeoxyglucose uptake in the spleen. A diagnostic test was performed, and management decisions were made.
CSIG-05. TRPM7 INDUCES MECHANISTIC TARGET OF Rap1b THROUGH DOWNREGULATION OF miR-28-5p IN GLIOMA PROLIFERATION AND INVASION
Authors: Jingwei Wan, Alyssa Guo, Mingli Liu
Journal: Neuro-Oncology (2019)

Abstract Our previous findings demonstrate that TRPM7 is critical in regulating human glioma tumorigenesis. miRNA participate in complex regulatory networks that may affect almost every cellular and molecular processes in glioma formation and progression, because a specific miRNA may simultaneously regulate many targets; While, a single protein target can be regulated by different miRNAs. Here, we explored the role of miRNAs in the progression of human gliomas by comparing miRNA expression profiles due to differentially expressed TRPM7. We determined 1) miRNA targets of TRPM7 by miroRNA microarray analysis upon TRPM7 silencing in glioma cell lines. 2) whether TRPM7 regulates glioma cell proliferation (MTT) and migration/invasion (transwell invasion assay) through different functional domains by transfecting wild-type human TRPM7 (wtTRPM7) or constructs with the α-kinase domain deleted (Δkinase) or with a point mutation within the ATP binding site of the α-kinase domain (K1648R-KR) into glioma cells. 3) the roles of miR-28-5p in glioma tumorigenesis by over- or under-expressing miR-28-5p in vitro. 4) whether Rap1b is a target of miR28-5p and the role of Rap1b in glioma tumorigenesis. 5) whether Rap1b can counteract the miR28-5p function on glioma tumorigenesis. We found 1) a list of 16 downregulated and 10 upregulated miRNAs that are statistically significant with fold changes greater than 2 by TRPM7 knock-down by miRNA microarray, and miR-28-5p as a promising candidate for functional analyses. 2) cell invasion was significantly reduced in Δkinase or K1648R transfectants, indicating that TRPM7 kinase activity is required for glioma cell migration/invasion. 3) overexpression of miR-28-5p caused a significant decrease in cell proliferation and migration by targeting Rap1b. 4) Co-transfection with siRap1b with miR28-5p inhibitor reduced the glioma cell proliferation and invasion caused by the latter. In summary, TRPM7 induces mechanistic target of Rap1b through downregulation of miR-28-5p in glioma proliferation and invasion.
Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia
Authors: Adekemi Taylor, Martine Allard, Cecile Kresja, Dana Lee, Greg Slatter
Journal: Blood (2019)
Cloud-based data systems in drug regulation: an industry perspective
Authors: Andrew S. Robertson, Hilary Malone, Fabio Bisordi, Helen Fitton, Carlos Garner, Stacy Holdsworth, Peter Honig, Mathias Hukkelhoven, Robert Kowalski, Sandra Milligan, Liza O’Dowd, Khyati Roberts, Michelle Rohrer, Jerry Stewart, Mark Taisey, Roopal Thakkar, Karin Van Baelen, Max Wegner
Journal: Nature Reviews Drug Discovery (2019)
Ionizable lipid nanoparticles encapsulating barcoded mRNA for accelerated in vivo delivery screening
Authors: Pedro P.G. Guimaraes, Rui Zhang, Roman Spektor, Mingchee Tan, Amanda Chung, Margaret M. Billingsley, Rakan El-Mayta, Rachel S. Riley, Lili Wang, James M. Wilson, Michael J. Mitchell
Journal: Journal of Controlled Release (2019)
Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals
Authors: Dingwei Xue, Huan Wang, Yuanlei Chen, Danyang Shen, Jieyang Lu, Mingchao Wang, Abudureheman Zebibula, Liwei Xu, Haiyang Wu, Gonghui Li, Liqun Xia
Journal: Molecular Cancer (2019)

Circular RNA (circRNA) is a type of circular endogenous RNA produced by special selective splicing and participates in progression of diverse diseases. However, the role of circRNA in clear cell renal cell carcinoma (ccRCC) is still rarely reported.We detected lower circ-AKT3 expression in ccRCC using the circular RNA microarray. Then, qPCR array was applied to verify the expression of circ-AKT3 in between 60 ccRCC tissues and adjacent normal tissues, as well as ccRCC cell lines and human normal kidney cell (HK-2). We investigated the function of circ-AKT3 in ccRCC in vitro and in vivo and detected underlying mechanisms by Western blotting, bioinformatic analysis, RNA pull-down assay and luciferase reporter assay.Circ-AKT3 was verified significantly downregulated in ccRCC. Knockdown of circ-AKT3 promoted ccRCC migration and invasion, while overexpression of circ-AKT3 suppressed ccRCC metastasis. Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis.Circ-AKT3 suppresses ccRCC metastasis by enforcing E-cadherin expression through competitively binding miR-296-3p. Circ-AKT3 may therefore serve as a novel therapeutic to better suppress ccRCC metastasis.
Impact of Disease Burden in Myelofibrosis Patients: A Sub Analysis from Italian Romei Observational Study
Authors: Francesca Palandri, Massimo Breccia, Carmine Selleri, Francesco Mendicino, Giuseppe A. Palumbo, Elisabetta Abruzzese, Anna Marina Liberati, Nicola Di Renzo, Fabrizio Pane, Mario Tiribelli, Robin Foà, Elena Maria Elli, Giovanni Caocci, Mara Morelli, Paola Guglielmelli, Francesco Passamonti
Journal: Blood (2019)
NCMP-19. STROKE IN CANCER PATIENTS
Authors: Marilou Ching, Edina Komlodi-Pasztor
Journal: Neuro-Oncology (2019)

Abstract Patients with malignancy have an increased tendency for venous and arterial embolism, and for increased risk for bleeding. Clinical decisions regarding anticoagulation in this population has been challenging and complicated by the availability of various anticoagulants. Currently, there is no evidence-based guideline available for the prevention of arterial embolism and thrombosis, such as stroke, in cancer patients. The aim of the study is to assess the use of anticoagulant medications in cancer patients who suffer a stroke. ICD-9/-10 codes were used to identify patients with cancer who were admitted between September 1, 2017 and November 30, 2017 to the Buffalo General Hospital with the diagnosis of stroke. Chart review was used to verify the history of cancer and stroke and to collect additional information. The diagnosis of acute stroke and cancer were verified in 87 patients. Among them, 31 patients had active malignancy. Of the 31 patients, 9 were diagnosed with intracranial hemorrhage and 22 with ischemic strokes. Of the 9 patients with intracranial hemorrhage,3 were anticoagulated and 1 patient was off anticoagulation. Of the 22 patients with ischemic stroke, 4 patients were anticoagulated, although 1 patient was underdosed based on INR. Seven of the 22 patients were taken off of anticoagulation; 3 had side effects and 4 were awaiting a surgical procedure. Five of the 9 patients with intracranial hemorrhage and 10 of the 22 patients with ischemic stroke were made comfort care and passed away shortly after the diagnosis of stroke.
Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy
Authors: Bin Yang, Lin Wei, Yuequan Wang, Na Li, Bin Ji, Kaiyuan Wang, Xuanbo Zhang, Shenwu Zhang, Shuang Zhou, Xiaohui Yao, Hang Song, Yusheng Wu, Haotian Zhang, Qiming Kan, Tao Jin, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2019)

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC
Attributable Fractions of Nonalcoholic Fatty Liver Disease for Mortality in the United States: Results From the Third National Health and Nutrition Examination Survey With 27 Years of Follow‐up
Authors: Christian S. Alvarez, Barry I. Graubard, Jake E. Thistle, Jessica L. Petrick, Katherine A. McGlynn
Journal: Hepatology (2019)

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of conditions, from simple steatosis to nonalcoholic steatohepatitis. Studies in the United States have reported an increased mortality risk among individuals with NAFLD; therefore, the population attributable fractions (PAFs) for mortality were examined.A total of 12,253 adult individuals with ultrasound assessment of NAFLD from the Third National Health and Nutrition Examination Survey and mortality follow-up through 2015 were included in the analysis. Cox proportional hazard regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for NAFLD in association with all-cause and cause-specific mortality. Overall, sex- and race/ethnicity-specific PAFs and 95% CIs were estimated. In the current study, presence of NAFLD was associated with a 20% increased risk of all-cause mortality (HR, 1.20; 95% CI, 1.08, 1.34). The overall PAF for all-cause mortality associated with NAFLD was 7.5% (95% CI, 3.0, 12.0). The PAF for diabetes-specific mortality was 38.0% (95% CI, 13.1, 63.0) overall, 40.8% (95% CI, 2.1, 79.6) in men, and 36.8% (95% CI, 6.6, 67.0) in women. The PAF for liver disease (LD)-specific mortality was notably higher in men (68.3%; 95% CI, 36.3, 100.0) than women (3.5%; 95% CI, -39.7, 46.8). In the race-specific analysis, the PAFs of NAFLD for all-cause mortality (9.3%; 95% CI, 4.0, 14.6) and diabetes-specific mortality (44.4%; 95% CI, 10.8, 78.0) were significantly greater than zero only for whites.In the United States, approximately 8% of all-cause mortality and more than one-third of LD- and diabetes-specific deaths are associated with NAFLD. With these high percentages, efforts are needed to reduce the burden of NAFLD in the United States.
Optimum DTT Concentration and Treatment Time for CD38 Inactivation on RBCs Analyzed By a Newly-Devised Flow Cytometric Antibody Binding Assay
Authors: Hiroaki Furumaki, Akihiro Takeshita, Chiaki Yamada, Harumi Fujihara, Keiko Ishizuka, Hiroki Shibata, Takahito Sinba, Momoko Sunako, Naoki Nemoto, Kaede Ino, Akari Ozawa, Hiroko Watanabe, Yukako Obata
Journal: Blood (2019)
HOUT-03. CLINICAL OUTCOMES OF PATIENTS WITH VESTIBULAR SCHWANNOMAS: THE RELEVANCE OF TUMOR SIZE AND RECURRENCE
Authors: Amy Zhao, Elena Fomchenko, Evgeniya Tyrtova, Anita Huttner, Yawei Zhang, Robert Fulbright, E Zeynep Erson-Omay, Lan Jin, Jennifer Moliterno
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Vestibular schwannomas (VS) are known to be slow-growing lesions that can present significant issues for patients. Here, we sought to better understand their outcomes and risks for recurrence. METHODS We retrospectively reviewed clinical outcomes data for patients who had VS tumor that underwent whole-exome sequencing after surgical resection between 2015 and 2018. The association between any two categorical variables was investigated using Fisher’s exact test. The mean of a continuous variable was compared between groups using either a two-tailed t-test or ANOVA. RESULTS Forty patients met our inclusion criteria. Interestingly, men were more likely than women to experience recurrence (p = 0.05). In accordance with previous research demonstrating a significant association between NF2 and bilateral vestibular schwannomas, most VS were NF2-mutants, with only four being were non-NF2. Pre-operative tumor size significantly correlated with progression-free survival time from surgical resection to recurrence, such that larger tumors were more likely to recur slower post-operatively (p = 0.043). There appeared to be no significant association between the extent of surgical resection (EOR) and recurrence (p = 0.653). In addition, there was no significant difference in post-operative complications or clinical outcomes, including EOR and facial nerve function, between different surgical approaches (p &gt; 0.30). Patients with pre-operative intra-tumoral hemorrhage were more likely to have smaller tumors, suggesting they present more acutely (p = 0.119). Finally, patients with NF2-mutated VS had a longer time from original diagnosis to surgery than patients who had non-NF2 VS mutants (p = 0.041). CONCLUSIONS Surgery for VS offers good clinical outcomes overall with low recurrence rates, regardless of prior treatment. Though not related to Ki67, larger tumors appear to confer a slower growth potential and lower risk of recurrence over time.