tbuckley/cabot-search huggingface dataset:
IMMU-10. CENTRAL NERVOUS SYSTEM NEUROBLASTOMA METASTASES PSEUDOPROGRESSION FOLLOWING INTRAVENTRICULAR ANTI-B7H3 RADIOIMMUNOTHERAPY
Authors: Kim Kramer, Osman Khan, Sofia Haque
Journal: Neuro-Oncology (2019)

BACKGROUND: While immunotherapy has revolutionized the treatment for several solid tumors, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors. B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules. 1 Several solid tumors overexpress B7-H3, and expression appears to be closely associated with immune escape, tumor cell invasion and metastases. The incidence of pseudoprogression after B7-H3 therapy is unknown. METHOD: A 4 year old girl with central nervous system metastases of neuroblastoma underwent resection of 2 left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion, followed by craniospinal radiation therapy, irinotecan, temozolomide, inducing a second remission with expected MR appearance in the operative cavity. She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-anti B7-H3. One month after therapy, routine MR revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma. The patient remained asymptomatic. RESULTS: A repeat brain performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema. RESULTS: Anti- B7-H3 therapy caused an immediate inflammatory reaction with spontaneous radiographic resolution and return to baseline 2 weeks later, all in the absence of concurrent steroid administration. CONCLUSION: Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are now being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.
Correlates of Future Violence in People Being Treated for Schizophrenia
Authors: Alec Buchanan, Kyaw Sint, Jeffrey Swanson, Robert Rosenheck
Journal: American Journal of Psychiatry (2019)

Violent behavior is infrequent among individuals with schizophrenia but is clinically important. The purpose of this study was to provide data on the correlates of violence, which may allow better risk assessment and care.A total of 1,435 individuals with schizophrenia who participated in the National Institute of Mental Health's Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and were followed for 18 months were examined. The dependent variables were self-reported injurious and noninjurious violence during follow-up. The independent variables, assessed at study entry, comprised participants' recent injurious and noninjurious violence, demographic and background variables, childhood risk factors, clinical condition, current circumstances, and recent contact with hospitals and prisons. Proportional hazards models of time to first injurious violence were used to generate bivariable and multivariable hazard ratios for all participants and, separately, for participants with no injurious violence at study entry.Seventy-seven participants (5.4%) reported engaging in injurious violence during follow-up, and 119 (8.3%) reported engaging in exclusively noninjurious violence. In the multivariable analysis, baseline injurious violence (hazard ratio=4.02), recent violent victimization (hazard ratio=3.52), severity of drug use (hazard ratio=2.93), baseline noninjurious violence (hazard ratio=2.72), childhood sexual abuse (hazard ratio=1.85), and medication nonadherence (hazard ratio=1.39) were associated with future injurious violence. For participants with no history of injurious violence at study entry, baseline noninjurious violence was the strongest predictor (hazard ratio=3.02). Recent violent victimization was no longer a significant correlate. The remaining correlates and the strength of their association with future injurious violence were similar to those for all participants.This is the first longitudinal multivariable analysis of predictors of injurious violence in a large cohort of patients with schizophrenia followed over 18 months. The results revealed simultaneous strong effects of baseline injurious violence and recent violent victimization on future injurious violent behavior. Among clinical variables, poor medication adherence, but not baseline symptoms of psychosis or depression, significantly predicted injurious violence. Treatment strategies to reduce risk should emphasize medication adherence.
Abstract 12310: Detection of Transient Left Ventricular Apical Hypertrophy During Recovery From Takotsubo Cardiomyopathy by Serial Echocardiography
Authors: Go Hashimoto, Makoto Suzuki, Hisao Yoshikawa, Takenori Otsuka, Yukiko Isekame, Masanori Shiba, Raisuke Iijima, Hidehiko Hara, Masato Nakamura, Kaoru Sugi
Journal: Circulation (2014)

Introduction: Takotsubo cardiomyopathy (TTC) is characterized by a transient systolic dysfunction of the left ventricle. A few case was reported about left ventricular apical hypertrophy (APH) during recovery from TTC. The purpose of this study was to investigate the incidence of transient APH and the differences in clinical characteristics in TTC patients. Methods: Forty seven TTC patients were enrolled in this study. Patients were divided into two groups as N-APH group which did not show APH like findings in the process of wall motion recovery and T-APH group which showed transient APH findings. Cardiac complications were defined as cardiac death, pump failure, sustained ventricular tachycardia or ventricular fibrillation and advanced atrioventricular block. Results: Twelve of 47 (25.5%) TTC patients demonstrate typical APH findings during recovery from wall motion abnormality. Finally, this APH findings disappeared and left ventricular morphology recovered to normal structure. There is no significant difference between two groups in clinical characteristics (table). Incidence of cardiac complication showed significantly lower in T-APH group than that in N-APH group (P&lt; 0.005). Conclusions: Transient left ventricular APH were observed in 25.5% in TCC patient by serial echocardiographic observation. Incidence of cardiac complications in T-APH group is significantly lower than that in N-APH group. Detection of T-APH is useful as a prognostic indicator in patients with TTC.
BIOL-03. TRANSCRIPTIONAL ANALYSIS OF ADULT AND PEDIATRIC CRANIOPHARYNGIOMA REVEALS SIMILAR EXPRESSION SIGNATURES REGARDING POTENTIAL THERAPEUTIC TARGETS
Authors: Eric Prince, Ros Whelan, Trinka Vijmasi, Andrew Donson, Susan Staulcup, Kevin Lillehei, Nicholas Foreman, James Johnston, Luca Massimi, Michael Handler, Todd Hankinson
Journal: Neuro-Oncology (2019)

Adamantinomatous Craniopharyngioma (ACP) imparts a significant impact on quality of life. It presents with a bimodal age distribution, with distinct pediatric and adult cohorts. Current canonical therapies of surgery and radiation are associated with short and long-term morbidity. Recent research has demonstrated potential therapeutic targets within pediatric ACP that may offer tumor growth control coupled with a decrease in treatment morbidity. To investigate if therapies identified in pediatric ACP may have efficacy in adult ACP, we performed transcriptional analysis of 28 pediatric and 8 adult ACP samples. Transforming data in order to favor identifying differential expression patterns across all magnitudes of transcriptional expression yielded no clear expression differences that differentiate adult versus pediatric patients. Further analysis examining recently identified therapeutic targets such as SRC and SHH also failed to identify discernible differences between the adult and pediatric cohorts. Geneset Enrichment Analysis (GSEA) identified statistically significant pathway enrichment between cohorts, although clustering based on enriched pathways also yielded no clear pattern. Our results demonstrate that adult and pediatric ACP patients possess similar basic transcriptional profiles, especially related to identified therapeutic targets; thus indicating that potential novel treatments should be considered for further investigation in both pediatric and adult cohorts.
THER-29. NOVEL DUAL EGFR/PI3-KINASE INHIBITORS SHOW ENHANCED POTENCY, STRONGER PATHWAY SUPPRESSION AND TARGETING OF METABOLIC PROPERTIES IN PEDIATRIC AND ADULT HIGH GRADE GLIOMA MODELS THAN SINGLE KINASE INHIBITORS
Authors: Yusha Sun, Cavan Bailey, Christopher Whitehead, Judith Sebolt-Leopold, Joya Chandra
Journal: Neuro-Oncology (2019)

High grade gliomas (HGG), including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), carry poor prognosis with median survival rates under 15 months post diagnosis. Due to dysregulation of the RTK/PI3K pathways within these tumors, targeted kinase inhibition has been considered a promising strategy to improve patient outcomes. However, many single-agent inhibitors of EGFR or PI3K have shown limited response in gliomas due to poor blood-brain barrier (BBB) penetrance and activation of compensatory signaling. Single-molecule multikinase inhibitors may decrease resistance, present a single pharmacokinetic dosage profile, and reduce risks of multi-agent toxicities, supporting this strategy over dual drug combination approaches. A panel of inhibitors exploiting known binding modes of structurally-related ATP binding site inhibitors of EGFR/PI3K were synthesized and characterized, of which six promising candidates were chosen for in vitro study. Of the compounds, MTX-241 was least likely to act as a substrate for drug efflux proteins such as P-glycoprotein. Treatment of MTX-241 in three patient-derived DIPG lines, and two glioma stem cell (GSC) lines, showed strong cytotoxic potency measured by growth inhibitory activity, with IC50s in the µM range. MTX-241 was significantly more potent than clinically relevant inhibitors targeting EGFR/RTKs (gefitinib, lapatinib, dasatinib, imatinib) or PI3K (alpelisib, idelalisib). Notably, selectivity of MTX-241 towards these HGG cell lines in comparison to normal human astrocytes (NHA) was observed, with NHA nearly insensitive to MTX-241 even at >100 µM. We found a significant inhibition of p-EGFR and p-Akt in these cell lines in comparison to DMSO controls. Further, we identified a unique glycolytic-suppressing activity of MTX-241 in the U87/DIPG lines, to a greater extent than treatment with gefitinib or alpelisib. Our data suggests that a dual inhibitor of EGFR and PI3K represents a viable therapeutic strategy in adult and pediatric HGG.
EZN-2208, a novel poly ethylene glycol-SN38 conjugate, improves pharmacological properties of SN38 in mice and rats.
Authors: Zhihua Zhang, Clifford Longley, Puja Sapra, Krutic Naik, Hong Zhao, Dechun Wu, Mary Mehlig, Jennifer Malaby, Lee Greenberger
Journal: Cancer Research (2007)

1496  Background: SN38 (10-hydroxy-7-ethyl-camptothecin) is the active moiety of CPT-11. Due to its poor solubility, SN38 has not been used clinically without extensive formulation effort. We have synthesized a novel polyethylene glycol (PEG)-SN38 conjugate (EZN-2208) by linking SN38 with a 40k 4-arm-PEG, via a glycine linker. EZN-2208 is a water soluble molecule that is highly efficacious in multiple xenograft models when given intravenously and has significantly better therapeutic efficacy compared with CPT-11. Here, we report the pharmacokinetics of EZN-2208 in mice and rats. Methods: Naive (tumor free) ICR mice were administered EZN-2208 via lateral tail vein at dose level of 20 mg/kg (SN38 equivalent). In the rat study, dose levels of 3, 10, and 30 mg/kg (SN38 equivalent) were used. Plasma samples were collected at varied time points from the animals and analyzed for EZN-2208 and released SN38. Results: In both mice and rats, EZN-2208 had a biphasic clearance from the circulation with an elimination half life of 18-22 h in mice and 12-18 h in rats, SN38 released from EZN-2208 had an apparent elimination half life of 18-26 h in mice and 21-22 h in rats. In rats, the maximum plasma concentration (Cmax) and area under the curve (AUC) increased in a dose proportional manner. The apparent half life of released SN38 from EZN-2208 in mice or rats is significantly longer than the reported apparent half life of released SN38 from CPT-11 and the exposure of released SN38 from EZN-2208 is significantly higher than the reported exposure of released SN38 from CPT-11. The clearance of the parent compound was 5.29 mL/hr/kg and 0.35 mL/hr/kg for the mice and rats, respectively. The estimated volume of distribution at steady state (Vss) of the parent compound was 132 mL/kg and 5.49 mL/kg for the mice and rats, respectively. The clearance of the released SN38 was 202 mL/hr/kg for the mice and 131 mL/hr/kg for the rats. The estimated Vss of released SN38 was 3094 mL/kg for the mice and 2384 mL/kg for the rats. Both in mice and rats, enterohepatic circulation of released SN38 was observed. Conclusions: EZN-2208 is a novel water soluble prodrug of SN38 and provides a longer circulation half life and exposure to the parent drug, SN38 in mice and rats. The excellent efficacy of EZN-2208 observed in the xenograft models may be due to its longer circulation half life and exposure. A study designed to investigate if EZN-2208 or SN38 accumulates in the tumors is underway.
Free App to Help Patients Ask Appropriate Questions
Authors: Rita Rubin
Journal: JAMA (2019)

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Abstract 464: Two Different Microdomains of β <sub>1</sub> -adrenoreceptor Signaling Revealed by Live Cell Imaging
Authors: Alexander Froese, Viacheslav O Nikolaev
Journal: Circulation Research (2017)

Background: 3’,5’-cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger and a crucial regulator of cardiac function and disease. In cardiomyocytes, it is produced predominantly after activation of β 1 -adrenergic receptors (β 1 -ARs) by catecholamines and acts intracellularly in discrete functionally relevant microdomains formed, for example, around calcium-handling proteins. Previously, we reported that β 1 -ARs are distributed across various cardiomyocyte membrane areas, including transverse (T)-tubules and cell crests. However, it is unknown whether these two β 1 -AR pools contribute differentially to the regulation of cardiac contractility and gene expression. Methods and Results: To directly visualize receptor-microdomain communication in cardiomyocytes, we established a combination of scanning ion conductance microscopy (SICM) with transgenically expressed targeted Förster resonance energy transfer (FRET)-based biosensors. Using this approach, we measured local cAMP responses in distinct microdomains of mouse ventricular cardiomyocytes (such as plasma membrane, cytosol and nucleus) after localized stimulation of β 1 -AR on different membrane structures of healthy and diseased cardiomyocytes. Using a plasma membrane targeted cAMP biosensor, we found that β 1 -AR stimulation at the crest induced stronger cAMP signals compared to β 1 -AR stimulated in the T-tubuli where cAMP was highly confined by PDE3. This difference was abolished in a pressure overload hypertrophy model due to submembrane redistribution of PDEs. Interestingly, crest β 1 -AR signals could propagate deeper inside the cell, inducing higher nuclear cAMP responses than recorded from receptors stimulated in the T-tubules. Conclusions: in the present study, we have demonstrated that β 1 -ARs located in T-tubuli and cell crests form two differentially regulated cAMP microdomains, each having its typical PDE repertoire and generating distinct second messenger signals. More detailed understanding of these two microdomains at different subsarcolemmal locations may contribute to new therapeutic strategies including more specific β-blockers.
Guselkumab 在接受 100 周治疗的银屑病患者中的安全性
Authors: K. Reich, K.A. Papp, A.W. Armstrong, Y. Wasfi, S. Li, Y.K. Shen, B. Randazzo, M. Song, A.B. Kimball
Journal: British Journal of Dermatology (2019)

银屑病是一种长期皮肤病,该病使额外的皮肤细胞形成鳞屑性红色斑块,可以产生瘙痒和疼痛。Guselkumab 是一种生物制剂,可阻滞一种与银屑病相关的分子白介素‐23,该药已获准用于治疗银屑病。两项大型临床试验(称为 VOYAGE 1 和 VOYAGE 2)显示,guselkumab 比阿达木单抗(另一种用于银屑病的生物治疗)更有效,且使用一年是安全的。由于银屑病是一种可复发的疾病,了解更新的治疗在长时间中的安全新有重要意义。因此,VOYAGE 1 和 VOYAGE 2 被延长至 5 年。这两项研究的设计相同,包括 3 个治疗组:前六个月中给予 guselkumab,在安慰剂后给予 guselkumab,或给予阿达木单抗。之后,根据具体研究,患者在下一年中不同的时间从一种治疗转换为另一种,和/或在两年中保持相同的治疗。计算了个研究中的安全性事件率,包括常见不良事件(不良副作用)、严重不良事件、严重感染、恶性肿瘤(癌症)和主要不良心血管事件,以评估各治疗的安全性。由于研究设计复杂,以不同方式比较数据:(1) guselkumab 治疗 1 年与 2 年比较和 (2) 从阿达木单抗转换为 guselkumab 之前和之后比较。结果显示,guselkumab 治疗 2 年后的累积安全性事件率总体与 1 年后一致。对于接受阿达木单抗治疗的患者,转换为 guselkumab 治疗后没有发现安全性问题。综上所述,在银屑病患者中,guselkumab 对于长达 2 年的较长期治疗和在从阿达木转换后都是安全的。
DIPG-32. COMBINATION OF ChIP-SEQ AND RNA-SEQ ANALYSIS FOR TARGET DISCOVERY REVEAL PROMISING CANDIDATES FOR VALIDATION
Authors: Yong Yean Kim, Jaclyn Andricovich, Sridevi Yadavilli, Madhuri Kambhampati, Sabine Mueller, Alexandros Tzatsos, Javad Nazarian
Journal: Neuro-Oncology (2019)

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) has one of the lowest overall survival amongst pediatric brain cancers. DIPG can be stratified into molecular subtypes dictated by histone mutational status: H3.3K27M, H3.1K27M, and H3 wildtype. Mutant histone proteins drive cellular proliferation by reprogramming epigenetic landscape. To interrogate the DIPG epigenome, we performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) in 5 DIPG tumors (H3.3K27M and H3 wildtype) and 3 healthy pons. This is the first report of ChIP-seq in DIPG tissue with H3 wildtype tumor. METHODS: ChIP-Seq was performed on DIPG tumors and control healthy pons for histone modifications indicative of active promoter (H3K4me3), repressive promoter (H3K27me3), and enhancer chromatin (H3K4me1 and H3K27ac). We focused on targets active in both H3K27M and H3 wildtype. Already existing RNA-seq data from DIPG upfront biopsy specimens (n=25) were used to narrow targets with increased transcripts. Immunohistochemistry (IHC) was performed to show protein expression. Human DIPG primary cell lines were assessed using Western blot analysis. RESULTS: Multiple targets were identified from ChIP-seq with activated histone including Notch1, CSPG4, and B7-H3. Focusing on B7-H3, RNA-seq confirmed high transcript levels at 43 Transcripts Per Million (TPM) in DIPG tumor and was significantly elevated compared to adjacent healthy brain at 5.5 TPM (p < 6x10-6). IHC analysis of 3 DIPGs showed strong B7-H3 staining compared to adjacent normal brain. To show the fidelity of preclinical models to human donor, primary DIPG cell lines (n=6) were interrogated by western blot assay. A 4.9 fold increase in B7-H3 (p=0.011) in DIPG cell lines was found when compared to protein lysates from healthy brain tissue (n=3). CONCLUSION: Using primary DIPG tumor tissue for ChIP-Seq analysis is novel and our study shows that epigenetic analysis by ChIP-seq coupled with transcriptional analysis by RNA-seq can be utilized to find new targets for DIPG therapy.
Multimedia: Duchenne and Gachet
Authors: Arpan K Banerjee
Journal: BMJ (1999)

“Duchenne de Boulogne: la mecanique des passions” is at the Ecole nationale superieure des Beaux-arts, Paris, until 4 April, and “Un ami de Cezanne et Van Gogh: le docteur Gachet” is at the Grand Palais, Paris, until 26 April

Guillaume Duchenne, born in Boulogne in 1807, studied medicine in Paris and came under the spell of Laennec, Dupuytren, and Magendie and eventually specialised in neurology. He was unconventional and eccentric and never held a hospital appointment. He discovered that external electrical stimulation could bring about muscle contractions and used this as treatment and to analyse the muscles involved in facial expression. Stimulating different muscles led to the differing facial expressions—joy, sadness, anger, alertness, and so on. The exhibition displays photographs of subjects undergoing these electrostimulation experiments and early anatomical drawings of the muscles of the face. Many of the photographs are from the original atlas Mecanisme de la physionomie humaine: au analyse electro-physiologique de l’expression des passions, avec atlas. Charles Darwin, who was also interested in facial expression, used Duchenne’s illustrations for his book Expression of Emotion in Man and Animals, published 10 years later in 1872.

The second exhibition is larger and is on display at the Grand Palais until April, when it moves to the Metropolitan Museum of Art in New York and then to the Van Gogh Museum in Amsterdam. It deals with Dr Paul Gachet’s friendships with several impressionist painters, including Pissarro, Cezanne, Renoir, and Monet.


Dr Gachet was a great art collector and early champion of the impressionists, and was the subject of several paintings by Van Gogh (Portrait of Dr Gachet, 1890), some of which are on display here. Gachet himself was also a painter, and examples of his work are also shown. The role that radiography plays in distinguishing the original paintings by Van Gogh, Monet, Cezanne, etc, from the copies is elegantly displayed in the exhibition. 




Auvers, where Gachet lived, was a Mecca for impressionists in the 1870s. Cezanne was a neighbour of Dr Gachet, Pissarro and Gauguin were visitors, and Van Gogh spent his last years there, finding the village an inspiration for his works, including The Church at Auvers-sur-Oise (1890). Gachet may have been a painter of the second rank but was a friend to some of the finest French painters of the 19th century in addition to being an astute collector of fine art. The exhibition is a feast for impressionist fans.