tbuckley/cabot-search huggingface dataset:
My Own Blood
Authors: Benjamin D. Carson
Journal: Annals of Internal Medicine (2020)

Ad Libitum15 December 2020My Own BloodBenjamin D. Carson, PhDBenjamin D. Carson, PhDBridgewater State University, Bridgewater, Massachusetts (B.D.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-3181 Audio Reading - “My Own Blood” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “My Own Blood” by Benjamin D. Carson, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail “I am made by her, and undone.”—Thom GunnI told her I liked the lines on her face,the way her crow's-feet speak of longing.And she said, thank you. You are kind.I told her I liked her smile, the way itbrings out her eyes, how, in their depth,they speak of loss. And she said, thankyou. You are a gentleman.I held her hand and told her I liked herpale blue veins and her calluses, howthey speak of work and the lessons oftime. And smiling, she said, thank you,you are kind, a gentleman.I brushed her white hair and told her ... Author, Article, and Disclosure InformationAffiliations: Bridgewater State University, Bridgewater, Massachusetts (B.D.C.)Current Author Address: Benjamin D. Carson, PhD; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “My Own Blood” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “My Own Blood” by Benjamin D. Carson, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 15 December 2020Volume 173, Issue 12Page: 1040KeywordsBloodVeins ePublished: 15 December 2020 Issue Published: 15 December 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
MBCL-31. TREATMENT RESULTS AMONG 106 PATIENTS WITH MEDULLOBLASTOMA OF MOLECULAR SUBGROUP 3
Authors: Olga Zheludkova, Lyudmila Olkhova, Yuri Kushel’, Armen Melikyan, Marina Ryzhova, Lyudmila Shishkina, Andrey Golanov, Alexey Kislyakov, Evgeny Shultz, Irina Borodina, Svetlana Gorbatykh, Vladimir Popov, Marina Mushinskaya, Olga Polushkina, Еugenia Inyushkina, Natalia Yudina, Lyudmila Privalova, Lyudmila Minkina, Artem Zaichikov, Evgeny Matsekha, Ivan Fisyun, Daniil Sakun, Nadezhda Dunaeva, Svetlana Avanesyan, Vladislav Mitrofanov, Sergey Kovalenko, Ekaterina Grishina, Oleg Chulkov, Nadezhda Pishchaeva, Nikolay Vorob’ev, Alexey Nechesnyuk, Natalia Popova, Dmitriy Pogorelov, Alexander Matitsyn, Alexander Shapochnik, Valentina Timofeeva, Andrey Korchunov, Elena Slobina
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To evaluate the treatment results among 106 patients of molecular subgroup 3 and to determine the factors affecting the prognosis. PATIENTS AND METHODS In all the patients, initial removal of the tumor was performed. All the patients got chemoradiotherapy according to the HIT protocol. There were 34girls and 72boys. Most patients were over 3 years:74 compared to 32 younger than 3. The majority of the patients had stage M+: 65; in 38 stage M0 was determined; in 3patients, stage was not specified, Mx.MYC amplification was found in 20 patients; MYCN amplification, in 4 patients. Classic medulloblastoma was predominant: 65, and 41 patients had anaplastic/large cell medulloblastoma. RESULTS The five-year progression-free survival was 0.51±0.05, the five-year overall survival was 0.52±0.04.The median survival was 82months,and the median progression-free survival was 37 months. There were no significant variations of PFS depending on the sex and age. The treatment results depended on the histological subtype: for classic medulloblastoma, the five-year PFS was 0.57; for the anaplastic/largecell,0.38(р = 0.02030). The presence of metastases significantly affected the survival: PFS for stage M0 was 0.77; for stage М+,0.35(р = 0.00062). Patients with MYC amplification had a significantly worse survival compared to MYCN patients and those without MYC amplification: 0.1, 0.75, and 0.58, respectively (р = 0.00002). Three patients with MYC amplification are alive: two patients had MGMT methylation detected. CONCLUSIONS The results of treatment among the patients with molecular subgroup 3 depended on the tumor subtype, presence of metastases, MYC amplification and MGMT methylation. In the absence of unfavorable factors, the survival was the same as in molecular subgroup 4.
Strategies for improving the management of immune-related adverse events
Authors: Aung Naing, Joud Hajjar, James L Gulley, Michael B Atkins, Gennaro Ciliberto, Funda Meric-Bernstam, Patrick Hwu
Journal: Journal for ImmunoTherapy of Cancer (2020)

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient's voice, and sharing evolving data to improve the management of irAEs.
EPCO-21. STING PROMOTER EPIGENETIC SILENCING IN GLIOBLASTOMA
Authors: Justin Low, Michelle Bowie, Vidya Chandramohan, Rebecca Fuller, Andrea Muscat, Michael Brown, Seethalakshmi Hariharan, Janell Hostettler, Aaron Briley, Sarah Danehower, Ali Baker, Nick Wong, David Ashley
Journal: Neuro-Oncology (2020)

Abstract The Stimulator of interferon genes (STING) protein is a critical component of the innate immune response to pathogenic and cytosolic self DNA. The importance of STING signalling has recently been demonstrated in a number of tumor types, including glioblastoma (GBM), and its activation through STING agonism is a promising antitumor therapeutic avenue. Recent studies have shown a loss of STING expression in cancer and an overall dysregulation of the CGAS/STING pathway. A potential mechanism of STING silencing is the methylation of its promoter. Using bulk methylation array data from patient samples, we explore epigenetic control of the TMEM173 gene that encodes STING. We find that the STING promoter is highly methylated in glioblastoma and that STING RNA expression is correspondingly low. Methylation data from normal brain and non-cancer cerebral diseases reveal a consistent pattern of STING promoter hypermethylation in these diverse states. The degree of bulk STING methylation in GBM samples inversely correlates with tumor purity and markers of immune infiltration. Single-cell transcriptome sequencing reveals that STING is expressed specifically in immune cells and endothelial cells, but not glioma cells. Collectively these results suggest that STING signalling is disrupted in GBM, that STING is epigenetically silenced by DNA methylation in the tumor, and that STING expression in bulk GBM tumor samples arises from infiltrating immune cells in the tumor microenvironment. Therapeutic approaches stimulating the innate STING signalling pathway are therefore likely to be effective on infiltrating immune cells rather than tumor cells themselves. This work motivates further study into mechanisms of STING activation in the broader GBM tumor microenvironment.
Comparison of Diabetic Ketoacidosis in Adults During the SARS-CoV-2 Outbreak and Over the Same Time Period for the Preceding 3 Years
Authors: Shivani Misra, Baktash Khozoee, Jiawei Huang, Kyriaki Mitsaki, Monika Reddy, Victoria Salem, Tricia Tan, George Tharakan, David Gable, Vassiliki Bravis, Jonathan Valabhji
Journal: Diabetes Care (2020)

Diabetic ketoacidosis (DKA) is a life-threatening metabolic decompensation occurring with any diabetes subtype, often precipitated by infection. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, reports emerged suggesting that coronavirus disease 2019 (COVID-19) is associated with a higher frequency of DKA with atypical presentations (1,2) and led some to hypothesize a direct effect of SARS-CoV-2 on the pancreas itself (3).

We addressed the observational bias of such reports by comparing DKA cases and characteristics in adults during the outbreak to matched 4-month periods (1 February–31 May) from 2017 to 2019 at a large London National Health Service (NHS) Trust.

Analyzing 175 biochemically confirmed DKA cases, the 3-year average for patients admitted over the 4-month period was 44 (exact Poisson CI 32–59) vs. 43 (31–58) during the outbreak. Although adult medical admissions reduced by 33% (3-year average for the same time period 26,831 vs. 19,267), the proportion of individuals presenting with DKA during the outbreak was 0.22% of all admissions compared with a 3-year average of 0.16% ( P = 0.16).

Among those presenting with DKA, the proportion with a diagnosis of type 2 diabetes during the SARS-CoV-2 outbreak was higher compared with the preceding 3 years (37% vs. 17%, P = 0.01) (Table 1), and proportion with type 1 diabetes reduced from 68% prepandemic to 44%. Adults with type 2 diabetes had a significantly higher proportion of positivity for SARS-CoV-2 than those with other types of diabetes—89% vs. 27%, respectively ( P = 0.009). …
MBRS-16. MYC REGULATED LONG NONCODING RNA LNC-HLX-2–7 IS A PUTATIVE MOLECULAR MARKER AND A THERAPEUTIC TARGET FOR GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Keisuke Katsushima, Piyush Joshi, Stacie Stapleton, Alexandra Garancher, Rajeev Vibhakar, Eric Raabe, Charles Eberhart, Robert Wechsler-Reya, George Jallo, Ranjan Perera
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. Recent advances in the noncoding RNA genome could contribute to the sub-classification of medulloblastoma. The focus of this study is to identify novel long noncoding RNAs (lncRNAs) as molecular markers and potential therapeutic targets within each subgroup of MBs, in particular within Group 3. We analyzed publicly available 175 RNA-seq datasets to identify a group of putative lncRNA signatures that may be able to differentiate medulloblastoma subgroups accurately. Among those, lncRNA lnc-HLX-2–7 was highly upregulated in Group 3 MB cell lines, patient-derived xenografts, FFPE samples compared to other groups. CRISPR/Cas9 deletion of the lnc-HLX-2–7 followed by the fluorescence-activated sorting and generating monoclonal Group 3 MB cells significantly reduced the cell growth and 3-D colony formation together with the induction of apoptosis. Intracranial injection to mouse cerebellum using lnc-HLX-2–7 deleted cells resulted in reduced tumor growth compared to parental cells, and tumors were further characterized by single-cell sequencing. We identified that oncogene MYC regulates lnc-HLX-2–7 and its expression can be controlled by the small molecule JQ1, a BET-bromodomain (BRD4) inhibitor that disrupts interactions with MYC. RNA-FISH analysis using FFPE, PDX, and tissue microarrays revealed that lnc-HLX-2–7 expression is specific to Group 3 MB compared to other groups. We present supporting evidence that lnc-HLX-2–7 is a novel molecular marker and a potential therapeutic target for Group 3 MBs in children.
Recurrent Ventricular Tachycardia After Catheter Ablation in Post-Infarct Cardiomyopathy: “Failure” of Ablation or Progression of the Substrate?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Edward P. Gerstenfeld
Journal: Journal of the American College of Cardiology (2013)
EPCO-02. MOLECULAR CHARACTERIZATION OF TWO NOVEL MPNST SUBGROUPS IDENTIFIES THERAPEUTIC OPPORTUNITIES
Authors: Suganth Suppiah, Sheila Mansouri, Yasin Mamatjan, Jeff Liu, Vikas Patil, Minu Bhunia, Bharati Mehani, Ying Suppiah, Shirin Karimi, Olivia Singh, Kenneth Aldape, David Largaespada, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas. These tumors are resistant to all current therapies, with exception to gross total surgical resection, and unresectable or metastatic tumors are considered incurable. Our understanding of the molecular alterations driving malignant transformation is limited, and to date, targeted therapies have proven ineffective. In this study, we leverage multi-platform genomic and epigenomic profiling of human MPNSTs and neurofibromas to identify targetable molecular pathways that lead to malignant transformation. Unsupervised consensus hierarchical clustering of the top 20K most variable methylated probes yielded seven stable and robust subgroups that are clinically relevant. The high-grade MPNSTs formed two distinct methylation-based clusters (MPNST-G1 and MPNST-G2). MPNST-G1 had worse prognosis compared to MPNST-G2 (0.6 years versus 1.4 years, p &amp;lt; 0.05). PTCH1 loss or SMO gain was prevalent in MPNST-G1 compared to MPNST-G2 (75% vs 12.5%, p &amp;lt; 0.05). In addition, MPNST-G1 harbored PTCH1 CpG island promoter hypermethylation in (87.5% vs 12.5%, p &amp;lt; 0.001). Transcriptome profiling recapitulated the two distinct MPNST subgroups. We next demonstrated that that RB1 signaling pathways are aberrant in both MPNST-G1 and MPNST-G2. However, SHH pathway activation is observed in MPNST-G1, while WNT/CCND1/ ß-catenin pathway activation is observed in MPNST-G2. Network-based drug-disease proximity analysis identified SMO inhibitors as a potential FDA approved drug as a potential targeted therapy. To determine if SHH pathway activation is sufficient for malignant transformation, we knocked out PTCH1 in immortalized neurofibroma cells lines. In 3 different cell lines with PTCH1 knockout, we observed induction of a malignant phenotype, with increased cellular proliferation and invasion. Most importantly, in-vitro and in-vivo models confirm that targeting the SHH pathway, with sonidegib, was effective in inhibiting tumor growth proving SMO inhibition to be a novel therapeutic option in these lethal cancers.
GCT-72. ANALYSIS OF microRNA EXPRESSION PROFILE OF INTRACRANIAL GERM CELL TUMORS: A PROMISING TOOL FOR DIFFERENTIAL DIAGNOSIS
Authors: Yoshiko Nakano, Kaishi Satomi, Hirokazu Takami, Ryo Nishikawa, Fumiyuki Yamasaki, Maehara Taketoshi, Nobuhito Saito, Yonehiro Kanemura, Hiroaki Sakamoto, Takahiro Ochiya, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION One of the major limitations of pathological diagnosis for intracranial germ cell tumors (iGCTs) is tumor heterogeneity, which cannot be evaluated using limited amount of tumor tissues. In this study, we performed comprehensive analysis of microRNA (miRNA) of iGCTs to identify miRNAs profile to help determine tumor diagnosis. METHODS RNA was extracted from frozen samples of 16 germinoma and 14 NGGCTs. Five non-iGCT pediatric brain tumor tissues were used as control. miRNA expression analysis was performed using a 3D-Gene Human miRNA Oligo Chip ver.22 (Toray Industries, Inc) which was designed to detect 2565 miRNAs. The miRNA expression profile was analyzed using t-SNE dimensionality reduction and weighted average difference method (WAD). RESULTS Different histological subtypes of the iGCTs and control samples were clustered into distinct classes. Furthermore, we found that the germinoma, NGGCTs and control samples may be readily distinguished by expression patterns of miR-200 and miR-371a-3p: a high expression of miR-200 was observed in the NGGCTs, whereas a high expression of miR-371a-3p was observed in all cases of germinoma and some of NGGCTs. Neither of miR-200 nor miR371-3p was highly expressed in control samples. CONCLUSION Our data indicated that germ cell tumor and other pediatric brain tumors, and also germinoma and NGGCT can be distinguished by expression patterns of 2 micro RNA, miR-200 and miR-371a-3p. These 2 microRNA may serve as a useful tool for supporting the pathological diagnosis of iGCTs.
COVD-28. IMPACT OF COVID-19 IN CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN ARGENTINA. REPORT FROM THE NATIONAL PEDIATRIC CANCER REGISTRY, ROHA NETWORK
Authors: Lorena Baroni, Agustina Chaplin, Daniel Alderete, Lidia Fraqueli, Patricia Gallardo, Florencia Moreno
Journal: Neuro-Oncology (2020)

Abstract Introduction: The true impact of COVID-19 infection on children undergoing cancer treatment is unknown. At the present time, data on the clinical spectrum and outcome of children with cancer and concurrent COVID-19 are limited, and further data are awaited. Monitor the incidence and survival across this pandemic is critical to understanding the extent to which this occur and to prepare contingency plans. Results: Ninety-seven pediatric patients with cancer and COVID-19 infection have been identified by the Argentinian Oncopediatric Register since April 2020. Sixteen of them had diagnosis of CNS tumor (female=7, male=9); 5 Medulloblastoma, 3 DIPG, 2 GBM, 2 LGG, 2 anaplastic ependymoma, 1 anaplastic ganglioglioma and 1 germinoma. Most frequent aged was between 1–4 years old (6 patients), followed by 15 to 19 (4p), 5–9 (3p) and 10–14 (3p). Most patients were asymptomatic (9p) and the screening was performed regarding a virus exposed (5p), previous to a procedure with anesthesia (2p) and previous a mandatory travel (2p). The most frequent symptom was isolated fever (6p); only 1 patient presented fever with others symptoms. None received specific treatment for COVID infection. No death related to COVID-19 infection was found; 1 patient with metastatic medulloblastoma and COVID-19 infection passed away due to a rapidly tumor progression. Conclusion: Although COVID-19 infection is a new challenging in the management of pediatric brain tumor patients, our experience showed a relative indolent course in this specific population.
NIMG-63. THE APPLICATION OF MRI AND TREATMENT RESPONSE ASSESSMENT MAPS (TRAMS) FOR MONITORING TREATMENT EFFECTS DURING/FOLLOWING PROTON BEAM THERAPY – INITIAL EXPERIENCE
Authors: Leor Zach, David Last, carola Lütgendorf-Caucig, Orit Furman, Alexandra Gerasimov, Dianne Daniels, Herald Hentschel, Markus Stock, Yael Mardor, Hug Eugen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVES We have previously shown that delayed-contrast-MRI-based TRAMs enable efficient separation between tumor and treatment-effects, validated histologically, reaching 100%/93% sensitivity/PPV to active tumor. Proton beam therapy (PBT) is a highly conformal radiotherapy modality with increasing use in CNS tumors. Here, for the first time, we studied the application of standard MRI and TRAMs for monitoring patients during/following PBT. METHODS 8 patients with gliomas (4 grade II, 3 grade III, 1 grade IV) and 9 with meningiomas (6 grade 1, 2 grade II, 1 grade III) were scanned by standard MRI and TRAMs at baseline, mid-term during PBT (treatment duration 22-30 days), end of treatment and 6/12 months thereafter. Enhancing volumes (EVs) were calculated from contrast-enhanced MRI, while blue/tumor and red/radiation-changes volumes (blueV/redVs) were calculated from the TRAMs. RESULTS Three gliomas showed increased (by &amp;gt; 10%) EVs (15.2±8.7%), 3 stable and 2 decreased EVs (14.2±8.5%) during treatment. At the end of treatment 3 showed increased volumes (27.6±10.4%) and 5 decreased volumes (26.4±6.5%). One meningioma showed decreased EVs (11%) while 8 were stable during treatment. At end of treatment one showed increased EVs (22%), 5 were stable and 3 showed increased EVs (13.7±1.7%). The TRAMs showed similar trends but of varied magnitudes. In addition, the TRAMs could indicate radiation changes in two cases with increased enhancement: One glioma showed increased EVs/redVs and decreased blueVs during treatment, consistent with pseudoprogression, confirmed later by significant shrinkage of all volumes, and one meningioma with a similar pattern at 6 months. CONCLUSIONS Our initial results show for the first time significant changes in brain tumors volumes, during and at the end of PBT. The addition of TRAMs may suggest a new tool to assess PBT radiation effects. Interpretation of these results, comparison between tumor types/grades, and correlation with treatment planning and additional follow-up will be presented.
MBRS-53. CONTROL OF MEDULLOBLASTOMA VASCULATURE BY A REGULATOR OF NEUROGENESIS
Authors: Shavali Shaik, Shinji Maegawa, Amanda Haltom, Tara Dobson, Keri Schadler, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Abstract Medulloblastomas are characterized by poor neuronal lineage specification. Expression of the RE1 Silencing Transcription Factor (REST), a regulator of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Using a novel transgenic mouse (RESTTG) model, we demonstrated that REST is a driver of medulloblastoma genesis and promotes tumor progression in mice with loss of an allele of Ptch1 (Ptch+/−). Tumor formation in Ptch+/−/RESTTG mice occurred with 100% penetrance and a latency of 10–90 days in contrast to Ptch+/− mice, which developed tumors at a frequency of 15–20% at 6–9 months of age. Histopathological analyses showed leptomeningeal dissemination of tumors in Ptch+/−/RESTTG mice, in addition to a significant increase in tumor vasculature compared to tumors in Ptch+/− mice. These findings were recapitulated in xenografted tumors of isogenic low and high-REST medulloblastomas in mice. Proteome profiler human angiogenesis array analyses revealed a REST-dependent increase in vascular endothelial growth factor (VEGF) and placental growth factor (PLGF). Surprisingly, REST elevation also caused co-localization of tumor cells with tumor vasculature, specifically endothelial cells, and was associated with upregulated expression of a number of pro-angiogenic genes, including receptor VEGFR1 and the positive regulator of endothelial differentiation, E26 transformation specific-1 (ETS1), in tumor cells. In addition, expression of several anti-angiogenic molecules was downregulated. Knockdown of ETS1 reversed the above findings. Thus, our data demonstrate that REST elevation not only blocks neurogenesis in medulloblastoma cells, but also modulates the tumor microenvironment by mechanisms that likely involve vascular mimicry.